The

Keystone Approach: Healing Arthritis and Psoriasis by Restoring the Microbiome

Copyright ©2018 by Rebecca Fett

Published in the United States by Franklin Fox Publishing LLC, New York.

All rights reserved. No part of this book may be reproduced in any form by any means without the express
permission of the publisher.

This book is intended to provide helpful and informative material. It is not intended to provide medical
advice and cannot replace the advice of a medical professional. The reader should consult his or her
doctor before adopting any of the suggestions in this book. The author and publisher specifically disclaim
all responsibility for any liability, loss, or risk, personal or otherwise, which is incurred as a consequence of
the use and application of any of the contents of this book.

ISBN-13: 978-0-9911269-8-9 (ebook)
ISBN-13: 978-0-9911269-5-8 (print)
ISBN-10: 0-9911269-5-5


www.keystonebook.com
 Introduction

The world of autoimmune disease is a very different place than it was even five
years ago. New evidence is emerging on a daily basis that points to the gut and
the microbiome as the origin of a variety of autoimmune diseases. This new
paradigm opens up an array of treatment options—options that go beyond
merely suppressing the inflammatory response to actually addressing the
underlying causes of that inflammation.
The Keystone Approach is your guide to this novel scientific frontier, with a
particular focus on dietary changes and specific probiotics. Together, these
measures can heal the gut and restore balance to the microbiome. When we do
so, we remove the main triggers that drive inflammation in many autoimmune
diseases, particularly those conditions in the “spondylarthropathy” family. This
family includes
Psoriasis/ psoriatic arthritis
Ankylosing spondylitis
Juvenile idiopathic arthritis
Crohn’s disease
Ulcerative colitis
Uveitis

Although these conditions are the main focus of the scientific research
discussed in this book, I also cover the latest studies on how diet and gut health
impacts other autoimmune diseases, such as rheumatoid arthritis. These
research findings are then translated into simple, actionable steps. But first, the
story of my own battle against autoimmunity.


* * *

A doctor first suspected that I had psoriatic arthritis when I was 18. At the time,
my only symptoms were mild back pain and a small patch of psoriasis, but I
understood that if I did indeed have psoriatic arthritis, it could become much
worse. This form of arthritis affects up to 30 percent of people with psoriasis
and can become debilitating.
Six months after the pain began, I noticed that it seemed a little better when
I avoided bread and pasta, so I insisted on a celiac test. The test showed that I
did have celiac disease, and after completely eliminating gluten from my diet
for several months, my psoriasis and back pain mostly resolved. It appeared
that I did not have psoriatic arthritis after all.
I went on to complete a degree in biochemistry and molecular biology, and
then law school, with only minor aches and pains that I attributed to the
physical toll of spending too much time studying.
By my mid-20s, after several years of working long hours at a large law firm in
New York, my pain returned with a vengeance. My shoulders, knees, hips, and
lower back ached constantly, and joints seemed to dislocate with the slightest
provocation. The possibility of psoriatic arthritis was quickly brushed away—I
had very little psoriasis, no joint stiffness or swelling, and no blood markers of
arthritis. I simply did not fit the old-fashioned textbook definition.
I was given a wide range of diagnoses by various specialists and offered all
manner of pain medications. After experiencing severe side effects from these
medications, I elected to focus on physical therapy. I hoped that with enough
effort and perseverance, my muscles could eventually stabilize my joints. I
spent five years religiously devoted to physical therapy, wanting to believe that
my recovery was just around the corner.
It was not. By age 30, the pain in my sacroiliac joints (in the lower back) was
so severe that I started having great difficulty walking more than a few blocks
or sitting for more than 15 minutes. I had pain flare-ups that kept me
housebound for weeks at a time and kept me awake much of the night. I tried
various injections and anti-inflammatory medications, with little relief.
Around this time, my psoriasis also returned, and a range of other classic
symptoms of psoriatic arthritis emerged (such as characteristic nail changes). It
became clear that I had probably been suffering from psoriatic arthritis all
along.
Understanding the nature of the problem was both a setback and a relief. On
one hand, the diagnosis meant that no amount of exercise would ever enable
my joints to function normally. It also meant I had wasted many years that I
could have spent focusing on the root cause of the pain—a malfunctioning
immune system. But on the other hand, a malfunctioning immune system was
something I understood all too well, and now I finally had an explanation for my
pain.
The precise details of autoimmunity were at this point already very familiar
to me from my immunology studies at university and from my work as a patent
litigation attorney for biotechnology companies. As the immunology specialist
in lawsuits with billions of dollars at stake, I had actually spent much of the past
nine years analyzing the scientific and clinical evidence underpinning the
biologics used to treat various autoimmune diseases. My office was filled with
boxes of confidential clinical trial reports and FDA submissions, and it was my
job to analyze them and talk to experts in the field.
I had essentially spent nine years thinking in great detail about the invisible
inflammatory molecules that drive all the damage in autoimmune disease. And
now I learned that these same molecules were causing the pain that had taken
over my life.
I understood that the new biologic medications were likely my best hope for
recovery—if I was willing to take the risks associated with infections and
possibly a higher risk of cancer. Although biologics only slightly raise the risk of
infection, this was a major obstacle in my particular case. As a teenager, I had
undergone surgery that left me with a lifelong susceptibility to serious
infections. I had been advised to take preventive antibiotics for life because
some common infections carried a 50 to 60 percent mortality rate in my case. I
refused the antibiotics but was also reluctant to take any medication that could
add to my infection risk. Since my arthritis was progressing slowly and not
causing any obvious joint damage, it seemed prudent to exhaust every other
option first.
I knew that biologics work so well because they interrupt the specific
mediators of inflammation that orchestrate skin and joint damage. Surely there
had to be another way to accomplish the same goal. What other factors
contribute to elevated inflammatory mediators, and what other factors can
reduce them?
As I began to focus more on these questions, I made the difficult decision to
pause my legal career and focus on my health. I left New York and moved to a
small town by the beach with my husband and two young sons. My new job
became scouring the scientific literature for any evidence that diet or lifestyle
changes could change the course of my autoimmune disease. I expected to find
some clues but was unprepared for the extraordinary amount of good-quality
clinical evidence supporting relatively simple strategies.
Perhaps the biggest revelation was the discovery that gut health has a
profound impact on the level of inflammation in the skin and joints. A
persuasive body of research shows that excess immune activation in the gut is a
common feature of psoriasis and several types of inflammatory arthritis,
1
particularly juvenile, psoriatic, and ankylosing spondylitis. Importantly, the
degree of gut inflammation appears to determine the severity of these
2
conditions.
In 2016, researchers discovered one factor that could be triggering this
immune activation in the gut: a disturbance in the vast community of microbes
that make up the microbiome. Those with psoriasis or certain forms of arthritis
show characteristic disturbances in the balance of gut bacteria, with an increase
in undesirable species and a depletion of species that normally calm the
3
immune system.
Several lines of evidence indicate that this disruption to the microbiome is
not just a consequence of inflammation, but a cause. Researchers have found,
for example, that a single course of antibiotics doubles the chance of children
4
developing arthritis, while five or more courses of antibiotics triple the risk. It
may be that antibiotics deplete the bacteria that regulate the immune system
and keep harmful bacteria in check.
These protective bacteria are now regarded as “keystone” species. To
scientists studying larger ecosystems, a keystone species is one whose unique
role within an ecosystem has a disproportionate effect on the ecosystem as a
whole. Mangrove trees growing along a shoreline, for example, provide a
habitat for numerous other species, including fish and frogs. Without
mangroves, the ecosystem would collapse. The particular gut bacteria that
normally regulate our immune system also act as keystone species. Without
them, the entire environment of our gut changes. The new paradigm is that this
change is a major contributor to autoimmune disease.
The question, then, is how we can take advantage of the newly uncovered
link between the microbiome and autoimmunity. Professor Jose Scher of New
York University, who led the landmark studies of the microbiome in psoriatic
and rheumatoid arthritis, commented that “in 10 or 15 years I think the
5
microbiome will be a key therapeutic option for some of these diseases.”
But we don’t have to wait that long. Good-quality clinical studies have
already demonstrated how to restore the population of immune-regulating
keystone species. The strategies to do so are simple and low risk: a high-fiber,
vegetable-rich diet, and specific strains of probiotics. Numerous studies
performed in the context of inflammatory bowel disease show that these
strategies can rapidly shift the balance of the microbiome to an anti-
6
inflammatory state.
 My immersion in the latest scientific research also uncovered strong
evidence supporting several other strategies that can reduce inflammation. As
just one example, the studies clearly show that a Mediterranean diet rich in fish
7
and olive oil can reduce the severity of psoriasis and rheumatoid arthritis. This
has long been suspected but has been overshadowed by the recent rise of the
“autoimmune paleo diet.”
While some aspects of the paleo diet are supported by scientific research,
such as the damaging effects of certain grains and refined oils, other aspects
are contradicted by research that emerged after the paleo diet rose to
prominence.
In particular, several recent studies demonstrate beyond doubt that
8
saturated fats are highly inflammatory. Although the role of saturated fat in
heart disease has been called into question, the newest research shows that
these fats actually do increase the level of inflammatory mediators. Saturated
9
fats do this by activating certain receptors on the surface of immune cells.
Thus the paleo diet’s emphasis on coconut oil and animal fat is
counterproductive for those with inflammatory diseases such as psoriasis and
arthritis.
The Mediterranean diet, in contrast, heavily emphasizes foods that help
rebalance the microbiome and otherwise suppress inflammation; such foods
include green and cruciferous vegetables, fish, and olive oil. The scientific
research also points to strategies to optimize the Mediterranean diet by
removing foods that damage the gut and contribute to immune activation, such
as wheat.
As I gradually changed my diet and supplement regime to incorporate new
strategies supported by the latest evidence, my symptoms began to steadily
improve. At first, the only noticeable difference was less fatigue, abdominal
pain, and swelling in my hands. After three months, I was experiencing my first
pain-free days in more than a decade. The longer I followed the diet and the
more elements I tweaked, the more my joint pain improved.
Now, instead of constant and debilitating joint pain, I have only very
occasional aches and pains, typically triggered by eating something I know I
should not. My psoriasis has also been completely clear for more than a year. In
short, I have been able to take control of my health to an extent I never thought
possible.

 * * *

There is clearly an immense gap between the latest research findings and the
advice most doctors provide about the connection between diet and
inflammation. Despite a vast body of evidence to the contrary, many of us are
told that diet has no effect. This gap is not altogether surprising since it
reportedly takes at least 10 years for medical research findings to make their
10
way into clinical practice. But we deserve better. I wanted to bridge the gap
between the latest discoveries and the people who can benefit from them.
I had already witnessed the power of doing so in the fertility and IVF context
with my first book, It Starts with the Egg. After receiving countless reports from
readers that being able to implement the latest research findings had
profoundly changed their lives, I wanted to do the same for those suffering
from debilitating autoimmune disease.
With that aim, I thoroughly investigated every last detail of how diet, the
microbiome, and many other factors can impact inflammation. I carefully
analyzed hundreds of scientific papers, with a particular focus on randomized,
controlled clinical studies involving real patients, not animal or test-tube
studies. (These scientific papers are listed in the references section, along with
information about how to access them online.)
My ultimate goal in writing this book was to distill a vast and complex body of
medical research into an easily understood practical guide—to translate the
science into a plan of action.
As I developed this systematic plan, I was guided by the recognition that
some factors apply generally, such as the beneficial role of fiber and omega-3
fatty acids, while other factors, such as the consumption of sugar and starch,
impact different individuals to different degrees. The Keystone Approach is thus
designed to help you discover which factors make the most difference in your
particular case. There may be one key ingredient to your recovery, such as
reducing starch or adding a probiotic, or there may be many small, incremental
changes that together produce a dramatic benefit. (To preview the complete
plan for your specific autoimmune condition, see chapter 10.)
Importantly, the diet and supplements described in the book are intended to
complement, not replace, a conventional medical approach. It is important to
tell your doctor about any new supplements and dietary changes. You should
also continue with all prescribed medications. Many of the anti-inflammatory
strategies at the core of the Keystone Approach, such as fish oil, probiotics, and
the Mediterranean diet, have been specifically shown to help patients achieve
11
better results from conventional medicines. Eventually you may be able to
work with your doctor to reduce your medications, but that should only happen
once you see positive results from your new diet and supplement protocol.


 Part 1. The Microbiome and Autoimmunity


 Chapter 1. Understanding the Root Causes of
Autoimmunity

Autoimmune disease reflects a serious malfunction of the immune system.
Rather than protecting us from infection, our own immune cells and antibodies
mistakenly recognize normal proteins as foreign invaders and launch an attack.
But what exactly causes the immune system to become confused and lose the
ability to accurately distinguish between normal proteins and foreign antigens?
In most cases the cause is some combination of the following factors:

Damage to the gut barrier
Immune activation from certain gut microbes or other
infections
Genetics

For decades, these three factors were considered to be mutually exclusive
and competing explanations. Yet in just the past few years, more and more
evidence has emerged that links these factors together into a unifying theory of
autoimmune disease, as this chapter explains.

How the Gut Influences Autoimmunity

Although the precise trigger for autoimmune disease can differ between
individuals, there is one common underlying factor that is usually present: a
leaky gut. As explained by Dr. Sanford Newmark, a clinical professor at the
University of California, San Francisco, “A lot of doctors and people may think
that leaky gut itself is sort of a froufrou alternative concept,” but “the real
name is ‘increased intestinal permeability,’ and it is a definitive, scientific
12
fact.”
It has been known for decades that intestinal permeability is increased in
those with inflammatory bowel disease and celiac disease. There is now clear
evidence that it is also increased in a variety of autoimmune conditions. Leaky
gut is often particularly severe in those with psoriatic arthritis, juvenile arthritis,
13
or ankylosing spondylitis.
A compromised intestinal barrier is a big problem because it forces the
immune system into panic mode. Normally, the gut barrier allows the
absorption of nutrients from food while preventing bacteria, bacterial toxins,
and undigested proteins from crossing into the blood stream. The intestinal
lining can achieve this remarkable feat because it is structured as a single layer
of epithelial cells joined together by scaffolding proteins called “tight
junctions.” In healthy people, these junctions are carefully controlled to only
allow minute gaps for nutrients to pass through. There is also a protective
mucus layer that allows nutrients across, but not proteins or bacteria.
Yet this amazing system is extremely vulnerable to damage. If the epithelial
cells, tight junctions, or mucus layer is damaged, large gaps are created. This
allows larger particles to cross the barrier. These particles may include bacteria,
molecules from bacterial cell walls (such as lipopolysaccharide, also known as
endotoxin), and proteins from food that have not yet been broken down into
individual amino acids.
When these molecules breach the gut barrier, chaos ensues. Just behind the
epithelial cell wall lies a vast army of immune cells in an area called the “gut-
associated lymphoid tissue.” Up to 70 percent of the immune system resides
here, and for good reason. The gut represents a major point at which bacteria
and other infections can enter the body. There are in fact billions of bacteria in
the gut—some beneficial, some harmful. The immune system normally
conducts surveillance for harmful bacteria by taking small samples of the gut
contents. There is not supposed to be a deluge of bacteria and their toxins
14
crossing the lining of the intestine to interact with the immune system.
When the intestinal barrier becomes damaged and allows bacterial toxins to
cross through the resulting gaps, the immune system is bombarded, triggering
immune activation on a massive scale. Critically, the resulting immune
activation is not limited to the gut. The end result is systemic inflammation and
15
damage to the skin and joints.

Intestinal Damage in the Spondylarthropathy Family

Although leaky gut appears to be a common element in the development of
many autoimmune diseases, there is particularly strong evidence linking gut
16
damage to psoriasis, psoriatic arthritis, and ankylosing spondylitis.
In fact, it has been known for many years that these particular conditions are
closely related to Crohn’s disease, a form of inflammatory bowel disease. This
was discovered in the 1980s when researchers performed colonoscopies on
patients with psoriasis, psoriatic arthritis, and ankylosing spondylitis who did
not have any bowel symptoms. They found that half of these patients showed
visible intestinal inflammation that closely resembled early stage Crohn’s
17 18
disease. Many other researchers have since confirmed these findings.
We now know that patients with psoriasis and psoriatic arthritis have a
19
fourfold higher risk of developing definite Crohn’s disease. Many of those
with spondyloarthritis also go on to develop some form of inflammatory bowel
20
disease.
The link between psoriatic arthritis, ankylosing spondylitis, and inflammatory
bowel disease is in fact so strong that these diseases are now categorized
together under the umbrella of the “spondyloarthropathy” family. Other
autoimmune diseases within this family that share the same overlap are
juvenile arthritis and an inflammatory eye condition called uveitis.
As will be discussed further below, the best explanation for the overlap
between these autoimmune diseases is that they all share an origin in the gut.

Immune Activation from the Gut

How exactly can inflammation in the gastrointestinal tract drive autoimmune
diseases that primarily affect other parts of the body? For many years, this was
a mystery because it was thought that the primary immune cells involved in
autoimmunity were “specific responders” (such as B cells and T cells), which
recognize specific proteins in the skin and joints. With these cells at the center
of the process, it was not clear how leaky gut could influence joint pain or
psoriasis. Yet it is now known that other nonspecific “first responder” cells play
21
a key role.
These nonspecific immune cells include mast cells and T helper 17 cells (Th17
cells). Unlike other immune cells, they do not need to recognize a specific
antigen to become activated. Instead, they can be spurred into action by a
variety of molecules derived from the gut, including food proteins and bacterial
products such as lipopolysaccharide.
Lipopolysaccharide, which is a toxin produced by many species of gut
bacteria, is a particularly strong trigger for these nonspecific immune cells. If we
have both a compromised intestinal barrier and a lot of gut bacteria producing
lipopolysaccharide, this toxin can cross the gut barrier and bind to receptors on
the surface of nonspecific immune cells.
 When the cells detect the presence of lipopolysaccharide, they switch
into “inflammation mode” and start producing chemical mediators that drive
22
the inflammatory response. (These mediators include TNF and Interleukin-17,
which are the targets of biologic medications). This process is now thought to
23
be a key mechanism underlying many autoimmune diseases.
To stop this process and halt inflammation, we need to reduce the
population of bacteria producing lipopolysaccharide while also addressing the
root causes of increased intestinal permeability. These causes include

Celiac disease
Food allergy
A lack of beneficial microbes
An excess of specific inflammatory gut bacteria or yeast
Small intestinal bacterial overgrowth (SIBO)

The following chapters provide a step-by-step protocol for addressing each of
these factors, with a particular focus on restoring balance between beneficial
and potentially harmful gut bacteria. Before we get there, however, it is
important to understand more about how the microbiome shapes the immune
system, because this guides our decisions as to which microbes we want to
encourage, and which we want to suppress.

The Microbiome and Autoimmunity

There is now convincing evidence that we need certain bacteria to calm down
our immune system, while other species can actually drive the development of
autoimmunity, particularly in individuals with a genetic predisposition.

Beneficial Microbes

New technologies that can rapidly sequence massive amounts of DNA have led
to an explosion of new insights into the microbiome. With the revolutionary
ability to detect any bacterial species by looking for its DNA signature, scientists
can measure the relative abundance of the different species in different
individuals.
One of the major findings from this technological leap is the fact that the
microbiomes of patients with autoimmune disease often lack certain microbes
that are present in healthy individuals. This disparity has been extensively
studied in the context of Crohn’s and ulcerative colitis. In people with those
conditions, there is typically a marked reduction in bacteria with unfamiliar
names such as Faecalibacterium prausnitzii, Eubacterium rectale, and Roseburia
24
intestinalis. The more these species are depleted, the more severe the
25
disease and the more likely patients are to relapse.
What these depleted species have in common is that they are part of an
important set of bacteria known as Clostridia clusters IV and XIVa, which are
normally found in healthy humans. The decreased abundance of bacteria in
these families, compared to healthy controls, has been described as “one of the
major signatures of the microbial dysbiosis in inflammatory bowel disease,
26
especially in (active) Crohn’s Disease.”
In 2015, the link between these missing microbes and autoimmunity
expanded further. In a landmark study, Jose Scher and colleagues at NYU and
Memorial Sloan Kettering revealed that patients with psoriatic arthritis also
have lower levels of many of the same bacterial species depleted in
27
inflammatory bowel disease (IBD). Other groups have now witnessed a similar
phenomenon in psoriasis, juvenile arthritis, and rheumatoid arthritis, with a
reduction in various bacterial species that are normally found in healthy
28
individuals.
Notably, in these conditions, many of the missing species also overlap with
29
the species that are depleted in those with IBD. In a study of children with a
particular form of juvenile arthritis, for example, F. prausnitzii constituted less
than 4 percent of total bacterial species in the gut, compared to 10 percent of
30
the microbiota of healthy children. In another study of juvenile arthritis, those
children in remission had much higher levels of Clostridium cluster IV bacteria
31
compared to the children with active arthritis. In the same vein, patients with
new-onset rheumatoid arthritis were found to have fewer bacteria from
32
Clostridium cluster XIVa.

How Beneficial Microbes Influence Immunity

There is a common characteristic of the particular bacteria that are often
depleted in those with autoimmune diseases: they have an extraordinary ability
to set the dial on the immune system to a more tolerant and less reactive
33
state.
The bacteria in Clostridia clusters IV and XIVa are particularly good at directly
34
regulating our immune system. The bacteria do this in part by promoting the
development of specialized immune cells called regulatory T cells. As the name
suggests, these cells play a vital role in regulating other components of the
immune system.
Regulatory T cells are critical to suppressing the aggressive immune cells
35
involved in autoimmune disease. They also produce anti-inflammatory
mediators and reduce production of mediators that perpetuate pain and
36
inflammation, such as TNF. In short, regulatory T cells are a key part of the
system of checks and balances that normally prevents autoimmunity and keeps
37
inflammation in check.
The extraordinary discovery that certain microbes can calm the immune
system in this way sparked a race among researchers to figure out exactly how
this happens. How is it that certain bacteria can actually communicate with the
immune system to boost the number of regulatory T cells? The race was won in
May 2013, with three groups of researchers making the same discovery within
38
weeks of each other. The answer: these bacteria prompt the immune system
to make more regulatory T cells by producing a short-chain fatty acid called
butyrate. Butyrate acts as an important signaling molecule that encourages
immature immune cells to develop into regulatory T cells.
When these microbes are depleted, fewer regulatory T cells are produced,
and a powerful control mechanism that typically restrains autoimmunity is
39
compromised.
This is an incredibly important finding, because it helps us figure out exactly
which microbes we need to encourage in order to recalibrate our immune
system. In short, we need to do everything we can to boost the population of
butyrate-producing species in Clostridia clusters IV and XIVa. In subsequent
chapters you will learn how to do this through diet and other strategies, but
there is one more aspect of the microbiome to consider first.

Unfriendly Microbes

The depletion of good bacteria in those with autoimmunity is only half the
story. An excess of specific harmful bacteria may in fact be just as much of a
problem. In 2016 and 2017, a series of paradigm-shifting studies reported that
in IBD, psoriasis, and arthritis, there is not only a lower level of protective
bacteria but also a higher level of inflammatory species. These inflammatory
bacteria include E. coli, Salmonella, Prevotella, Collinsella, Streptococcus,
40
Enterococcus, and Klebsiella.
These species cause harm in two ways: firstly, they can damage the gut
barrier, rendering it more permeable; secondly, they can activate the specific
41
immune cells involved in autoimmune disease. These particular species
appear to switch the immune system into inflammation mode not only by
producing large amounts of lipopolysaccharide but also through various other
mechanisms.
Interestingly, different forms of arthritis are characterized by overgrowths of
different bacterial species. In rheumatoid arthritis, researchers have found an
increased abundance of Prevotella or Collinsella, while spondyloarthritis has
been linked to a particularly aggressive form of E. coli.
This type of E. coli is called “adherent-invasive E. coli” because it sticks to
intestinal cells and invades the protective mucus layer, which can trigger a
42
massive inflammatory response. It was already known that about half of all
Crohn’s patients have adherent-invasive E. coli, whereas it is found in only 1
43
percent of the general population. In 2017, researchers found that this type
44
of E. coli may also be a major contributor to spondyloarthritis. (The
spondyloarthritis group includes psoriatic, juvenile, and ankylosing spondylitis
[AS].)
Specifically, a group of researchers at Weill Cornell Medical Center in New
York found that patients with both spondyloarthritis and Crohn’s disease
actually had a much greater number of adherent-invasive E. coli than those
45
with just Crohn’s disease. When this specific E. coli was transferred to mice, it
triggered the precise immune response characteristic of spondyloarthritis as
well as inflammatory arthritis symptoms.
A separate body of research points to yet another possible culprit in
ankylosing spondylitis: Klebsiella pneumoniae. This common species of gut
46
bacteria was first suspected of playing a role in AS in the 1980s. Since that
time, several groups of researchers have found that patients with AS typically
have higher levels of antibodies to Klebsiella than healthy controls or those with
 47
other forms of arthritis. This has been observed in patients in Japan, the
48 49 50
Netherlands, England, and Italy.
Most recently, it was reported that antibodies directed against a specific part
of a Klebsiella protein were found in 190 of 200 patients with AS (95 percent), 3
of 200 patients with rheumatoid arthritis (1.5 percent), but only 1 of 100 (1
51
percent) patients with psoriatic arthritis.
By contrast, another collection of studies performed across the world has
found that patients with rheumatoid arthritis typically have higher levels of
52
antibodies to an entirely different species, called Proteus mirabilis.

***
To find out whether an overgrowth of pathogenic species is a likely
contributor in your particular case, a comprehensive stool analysis may be
helpful. In the United States, testing options include Genova Diagnostics,
Doctors Data, and GI-Map. At the time of writing, GI-Map appears to be the
most sensitive test for detecting the bacterial species involved in autoimmunity.
Some of these tests can be ordered by individuals located outside the United
States. Similar tests are also available from laboratories located in other
countries, such as Therapy Select in Germany.
Microbiome tests are fairly expensive (around $350–$500) but can often be
ordered directly without a doctor’s prescription. See
www.keystonebook.com/testing for further information. Although you do not
need a doctor to order these tests (in most places), you may still find that you
need the assistance of a functional medicine practitioner to help you interpret
the results and treat specific infections. See the Institute of Functional Medicine
for a directory of physicians familiar with this approach (www.ifm.org).

***

Beyond the specific bacterial species implicated in autoimmunity in the
studies to date, there is also evidence that a net overgrowth of bacteria in the
small intestine can trigger the autoimmune process. This type of overgrowth is
actually a recognized medical condition termed small intestinal bacterial
overgrowth, or SIBO for short.

What is SIBO

In contrast to the bustling ecosystem in the colon, the small intestine has a
relatively low concentration of bacteria. This is a good thing since the walls of
the small intestine are highly permeable to allow for nutrient absorption. We
do not want a large population of bacteria to be sitting idle in the small
intestine, because their toxins would be too readily absorbed into the
bloodstream.
Bacterial numbers are usually kept low in the small intestine by the combined
effect of stomach acid, bile, and the rapid sweeping away of intestinal contents
between meals. The small intestine actually goes through a “cleaning cycle”
every couple of hours, but only when the stomach is empty. SIBO can occur
when these usual mechanisms fail, whether the result of frequent snacking,
acid-blocking medication, stomach acid or enzyme deficiency, celiac disease,
53
hypothyroidism, scar tissue from abdominal surgery, or some other factor.
Whatever the cause, in those with an overgrowth of bacteria (or yeasts) in
the small intestine, a steady flow of lipopolysaccharide and other toxins across
the thin walls of the small intestine sends a powerful signal to activate the
immune system, leading to systemic inflammation. This systemic inflammation
can manifest as arthritis, psoriasis, or a variety of other conditions.
A condition sometimes called “bypass arthritis” is a dramatic illustration of
the ability of SIBO to cause arthritis. This condition typically arose from a drastic
method of weight loss surgery performed from the 1950s to the 1980s, where
the small intestine was shortened. The surgery often created “blind loops”
where bacteria could overgrow, causing severe SIBO. Up to 20 percent of
54
intestinal bypass patients eventually developed arthritis and skin rashes. This
form of arthritis became known as bowel-associated dermatosis-arthritis, or
55
bowel bypass syndrome. Fortunately, studies proved that eradicating the
56
bacterial overgrowth quickly resolved the arthritis and rashes.
Although few studies have directly explored the role of SIBO in contributing
to autoimmune diseases, a number of small studies have found SIBO in a
57 58
significant proportion of patients with psoriasis, rheumatoid arthritis,
59 60
Crohn’s disease, and fibromyalgia. Looking at psoriasis, for example, a group
of Russian scientists reported that the average number of bacteria in the small
intestine of psoriasis patients was approximately 3000 times higher than in the
61
control group.
Another study found that one-third of patients with plaque psoriasis had
fragments of DNA in their bloodstream from bacteria that are hallmarks of
62
SIBO. (E. coli, Klebsiella pneumonia, Enterococcus faecalis, Proteus mirabilis,
63
Streptococcus pyogenes, and Shigella.) Patients with DNA from these bacteria
in their bloodstream had much higher levels of inflammation. Most
persuasively, it was reported in 2018 that treating SIBO can dramatically
64
improve psoriasis.
There are also studies providing indirect evidence of SIBO playing a role in
ankylosing spondylitis and juvenile arthritis. When researchers in Sweden took
samples of fluid from the small intestine of those with ankylosing spondylitis,
they found much higher levels of antibodies to species associated with SIBO
65
(Klebsiella, E. coli, and Proteus mirabilis). A noteworthy study published in the
Journal of Rheumatology in 2017 also found that children with juvenile arthritis
have much higher levels of antibodies to lipopolysaccharide, which suggests an
overgrowth of undesirable species in the small intestine, where
66
lipopolysaccharide can more easily cross into the bloodstream. Another 2017
study found that MS patients with more severe symptoms typically had higher
levels of Streptococcus in the small intestine.

SIBO Diagnosis

SIBO becomes an even more likely culprit if, in addition to psoriasis or arthritis,
you also have the other common signs and symptoms of the condition. SIBO
often manifests as either chronic constipation or diarrhea. It is found in up to 80
percent of people with IBS and is now regarded by some experts as the most
67
common cause of the syndrome.
Other classic symptoms of SIBO include multiple food sensitivities, histamine
intolerance, nausea, bloating after meals, abdominal pain, eczema, and
rosacea. If you have any of these common symptoms of SIBO, or a major risk
factor such as celiac disease, endometriosis, or a history of food poisoning or
abdominal surgery, it may be worth taking a breath test to help determine if
SIBO is involved. The test can be ordered by your doctor, or you can order it
yourself (e.g. from www.lifeextension.com. Additional testing services are listed
at www.keystonebook.com/testing).
The SIBO breath test involves drinking a lactulose and/or glucose solution
and collecting breath samples over several hours using an in-home kit. These
tests are far from perfect: they are sometimes difficult to interpret and miss
68
many cases of true SIBO (detecting only around 60 percent of cases). Yet a
clear positive result can provide useful information.
SIBO is traditionally treated with antibiotics, but for many people this is not a
long-term solution. In fact, within nine months of antibiotic treatment, 40
percent of patients relapse, most likely because the underlying causes of SIBO
69
remain. A better approach is to support the normal mechanisms that prevent
SIBO in healthy individuals. Strategies to do so are described in chapter 3. For
some people with SIBO, carefully chosen probiotics and prebiotics can also be
extremely helpful, as discussed in chapter 2. The following chapters also explain
how reducing intake of sugar and starch can help address overgrowths of
pathogenic species of bacteria and yeasts, including in the small intestine.

Bacteria Beyond the Gut

Although the main focus of this book is the gut microbiome, some surprising
research suggests that particular bacteria in other parts of the body can also
trigger certain autoimmune diseases. Psoriasis, for example, has a particularly
strong connection to Streptococcal throat infections, while some limited studies
have raised suspicions that some cases of rheumatoid arthritis are linked to
urinary tract or periodontal infections. Knowing about these unusual links may
further help you tackle the autoimmune response.

Psoriasis and Strep Throat

The link between psoriasis and strep was first suggested after many physicians
noted that psoriasis flares often follow episodes of strep throat infections
70
(typically about two weeks later). More recently it has been found that those
with chronic psoriasis and psoriatic arthritis often have higher levels of
71
antibodies to Streptococcus pyogenes, the species that causes strep throat.
There is also some degree of cross-reactivity between streptococcal antigens
72
and human skin proteins. Thus the prevailing theory is that a low-level,
chronic infection with streptococcal bacteria in the tonsils can drive the
autoimmune reaction, with exacerbations in psoriasis following exacerbations
in the streptococcal infection.
Interestingly, there is even stronger evidence for a link between
Streptococcus and those cases of psoriasis with an earlier age of onset (before
age 40) and with either a family history of psoriasis or certain genetic
73
markers. Thus it may be that Streptococcus only triggers psoriasis and
psoriatic arthritis in those with a genetic predisposition.
If flares of strep throat make psoriasis much worse, it stands to reason that
reducing the low-level chronic infection could also make the baseline level of
psoriasis much better. That is exactly what the studies have now found. Most
persuasively, a 2012 randomized study found a major reduction in psoriasis
74
after patients had their tonsils removed (ranging from a 30 percent to 90
percent reduction in disease severity). In these patients, there was a close
correlation between the degree of improvement in psoriasis and the reduction
of T-cells that recognized peptides common to both Streptococcus and skin
75
proteins. As of 2018, the consensus appears to be that tonsillectomy
significantly improves psoriasis in about 75 percent of cases associated with
76
strep throat. Less drastic measures include frequent gargling with warm salt
water or peroxide-based mouthwash, and using S. salivarius K12 oral probiotic
77
lozenges (see www.keystonebook.com/K12).
It is worth noting that Streptococcus species are also typically found in the
gut, particularly in the small intestine. As noted above, Streptococcus is one of
the most common types of bacteria found to be elevated in those with SIBO. A
gut microbiome analysis can also help identify whether you have an overgrowth
of streptococcal species in the gut. If you do, it is highly likely that these
bacteria could continue to perpetuate psoriasis and psoriatic arthritis in much
the same way as streptococcal infections in the throat. Thus it is important to
focus on rebalancing the gut microbiome and treating SIBO, even if you suspect
that recurrent strep throat could be a major contributor in your case.
Rheumatoid Arthritis and Infections Beyond the Gut

Entirely different bacteria in the oral microbiome may potentially trigger some
cases of rheumatoid arthritis (RA). Population studies have noted that
individuals with serious gum disease (periodontitis) are more likely to develop
rheumatoid arthritis. More recently, researchers have found that the gingivalis
bacteria that often cause gum disease also produce an enzyme that could
78
potentially trigger RA. Good dental care is therefore important if you have RA.
Although the evidence is quite limited, some have also suggested a link
 79
between Proteus mirabilis urinary tract infections and rheumatoid arthritis.
Supporting this idea, elevated levels of specific antibodies against Proteus
80
bacteria have indeed been found in RA patients in 16 different countries. But
even if P. mirabilis is a contributing organism, we should bear in mind that this
species is also commonly found in the gut. In fact, it is thought that the majority
of P. mirabilis urinary tract infections actually originate in the gastrointestinal
81
(GI) tract, suggesting that the gut microbiome should remain our primary
focus.


Understanding Our Enemies

Whether we view the overarching problem as SIBO, or an overall imbalance
between good and bad bacteria, the fact remains that there is a fairly short list
of bacterial species we are most concerned about keeping under control. The
exact same species that are common culprits in SIBO have also been directly
linked to ankylosing spondylitis, psoriasis, rheumatoid arthritis, inflammatory
82
bowel disease, and other autoimmune conditions:

Escherichia coli
Klebsiella pneumonia
Enterococcus faecalis
Proteus mirabilis
Streptococcus pyogenes

These bacteria produce immune-activating toxins such as lipopolysaccharide,
along with bacterial proteins that may confuse the immune system by closely
resembling our own proteins. They have the net effect of encouraging the
immune system to shift toward a more inflammatory state by promoting the
proliferation of Th17 cells, which play a direct role in autoimmunity.
There is likely a constant fight for real estate in our gut between the
beneficial microbes that calm the immune system, and these unfriendly
microbes that antagonize it. As explained by Ivaylo Ivanov, Assistant Professor
of Microbiology and Immunology at Columbia University in New York, it is
“probably the ratio, the combination of bacteria in the gut that will determine
83
whether you will get disease or not.” Our goal, then, is to restore the ratio—
to combat autoimmune disease by boosting the protective species and
controlling the harmful species. Before we get there, however, it is important to
acknowledge one of the major culprits responsible for getting us into this mess:
antibiotics.

The Problem with Antibiotics

Due to widespread use of antibiotics, “our microbiome has changed
significantly over the past century, and especially over the past 50 years,” says
84
NYU microbiologist Martin Blaser. The destruction caused by antibiotics to
our resident gut bacteria is actually reflected in a strong link between antibiotic
use and the development of autoimmunity.
Juvenile arthritis provides the clearest example. In a recent study published
in the journal Pediatrics, any recent antibiotic use doubled the chance of
children developing arthritis, while five or more courses of antibiotics tripled
85
the risk.
There is also a correlation between exposure to antibiotics and development
86
of a range of other autoimmune diseases, including asthma and Crohn’s
87
disease. This effect is even more pronounced in children, and the risk
increases with repeated exposure and broader-spectrum antibiotics.
The best explanation for the impact of antibiotics on autoimmunity is that
antibiotics wipe out protective bacteria that regulate the immune system while
allowing a small number of rare bacterial species to flourish.
While the reasons for this are not fully understood, there is strong evidence
that antibiotics have a disproportionate effect on the beneficial butyrate-
producing bacteria. As one example, a randomized, placebo-controlled trial
published in 2015 used new genome-sequencing technology to analyze the
88
microbiome of 66 healthy adults up to a year after a course of antibiotics. The
researchers found that antibiotics “showed a severe and long-term impact on
the health-associated butyrate-producing microbial community of the gut.”
Antibiotics do not just wipe out the beneficial species we need to maintain a
well-calibrated immune system. They also allow the unfriendly species to take
over. This is well illustrated in the context of antibiotic-associated diarrhea. A
significant proportion of patients that receive broad-spectrum antibiotics can
develop severe diarrhea that persists even after the antibiotics are stopped.
This condition is most often due to an overgrowth of certain bacteria and yeasts
that are able to take advantage of a decimated ecosystem by expanding rapidly.
Although the most notorious culprit in causing antibiotic-associated diarrhea is
C. difficile, it is not the only type of infection that can occur. In fact, when we
look at the other species that are most often responsible (such as Klebsiella),
there is significant overlap with the “bad guys” seen in SIBO and autoimmune
89
conditions.
It is therefore evident that antibiotic use encourages our familiar enemies to
expand and take over, while decimating the population of good bacteria. For
anyone suffering from autoimmune disease, this provides a powerful reason to
do everything you can to avoid using antibiotics. At a practical level, this means
becoming vigilant about controlling minor infections at the first sign. For
example, if you are prone to sinus infections, it will be important to do
everything possible to minimize sinus congestion during allergy season or when
you catch a cold. If you are prone to bacterial throat infections, consider
gargling with warm salt water or antiseptic mouthwash at the first sign. For
urinary tract infections, if you catch them early enough, a simple probiotic
90
supplement can be effective. The important point is to do what you can to
combat any infection before it develops into something that requires
antibiotics.
If you do find yourself with an infection that requires antibiotics, there may
be value in asking your doctor for antibiotic injections rather than pills. When
antibiotics are administered by injection rather than taken orally, they may be
more effective against infections while having less impact on the gut
91
microbiome.
This also raises the question of antibiotics in the food supply. Modern
farming often involves giving healthy animals a variety of antibiotics to
encourage rapid weight gain. In the United States, the Department of
Agriculture tests meat and poultry to check that antibiotic residues are below a
certain level. The overall results of this testing are available online, and the vast
majority of tested samples are compliant. The wide variety of antibiotics found
in meat violating the standards is not entirely reassuring, but the total dose is
92
still negligible compared to a prescription for antibiotics. If you want to err on
the side of caution, choose beef and chicken labeled “organic” or “no
antibiotics.” This is less important for lamb, which almost never tests positive
93
for antibiotics.
 While no one can undo a past littered with antibiotics, it is possible to limit
our exposure to antibiotics in the future. By avoiding unnecessary antibiotic
prescriptions, and perhaps reducing exposure to trace amounts of antibiotics in
our food, we can halt further depletion of our anti-inflammatory microbes. Yet
the more important question is how to dial back the damage that has already
been done, and how to restore balance to the microbiome. That is the subject
of the next two chapters.

 Chapter 2. Rebalancing the Microbiome with Probiotics

Probiotics are one of the best tools we have to rebalance the microbiome.
While we cannot simply take a supplement to replace the bacteria that are
depleted, new research suggests that probiotics can actually shift the balance
of the microbiome as a whole—both lowering the abundance of harmful
species and raising the level of beneficial species. The right probiotics can
ultimately make the microbiome of someone with autoimmune disease more
closely resemble that of healthy individuals.

Using Probiotics to Support Our Beneficial Microbes

Only certain species of probiotics possess the remarkable ability to boost the
population of other important species already present in our microbiome. We
know, for example, that L. Rhamnosus GG (sold as Culturelle®) has this
property, because a 2016 study found that it significantly increased the
94
population of butyrate-producing bacteria such as Roseburia and Blautia. In
infants given L. Rhamnosus GG, the boost to these other beneficial species
resulted in higher butyrate levels and greater immune tolerance (reflected in
reduced rate of cow’s milk allergy).
The best explanation for how certain probiotics can help other good bacteria
95
thrive is by way of “cross-feeding.” In short, different bacteria are good at
performing different steps in the fermentation of fiber to short-chain fatty acids
such as butyrate. Probiotic species that are good at early steps in the process
96
effectively feed the downstream butyrate-producing bacteria.
Bifidobacteria species appear to be particularly good at cross-feeding the
97
butyrate-producers. Bifidobacteria are in fact critical to the development of a
healthy microbiome. These species are among the first to colonize the human
gut, typically constituting 95 percent of the total bacterial population in healthy
breast-fed infants. The population then drastically declines, making up only 3 to
98
6 percent of the microbiome by middle age. Common Bifidobacteria species
found in healthy humans include B. longum, B. breve, B. bifidum, and B.
99
infantis. These species are also readily found in probiotic supplements.
One of the defining characteristics of Bifidobacteria is the production of
acetate (whereas Lactobacilli primarily produce lactate). Acetate is important
because it is the preferred food source of many of the butyrate producers. If we
want to truly help the butyrate-producers flourish, we therefore need to look at
the whole ecosystem. It is important to not only provide sufficient dietary fiber,
but also ensure adequate numbers of Bifidobacteria, to turn that fiber into a
100
more useable energy source. Bifidobacteria are therefore considered
keystone species, because they have a disproportionately large influence on the
101
bacterial ecosystem as a whole.
When it comes to choosing a probiotic supplement to support the butyrate-
producing species, the recommended Bifidobacteria species include

B. infantis
B. longum
B. breve

Any Bifidobacteria strain will likely be able to perform the cross-feeding
function, but these three species have other anti-inflammatory benefits, as will
be discussed further below. Lactobacillus rhamnosus GG (found in Culturelle) is
another good choice for promoting butyrate-production and thereby calming
the immune system.

Using Probiotics to Suppress Harmful Species

The second way in which probiotics can help rebalance a microbiome in
disarray is by inhibiting the growth of harmful bacteria such as Klebsiella, E. coli,
102
Streptococcus, and other species implicated in inflammatory diseases.
Almost all probiotics will combat these pathogens to some degree, by
competing with the harmful species for nutrients. Lactobacilli and
Bifidobacteria are also generally helpful in suppressing pathogenic bacteria and
yeast purely as a function of their general metabolism. That is because these
species naturally produce acids that will change the acidity of the gut and
thereby suppress many harmful species.
Against this backdrop, some probiotic species appear to have a particularly
103
good ability to inhibit the growth of pathogenic bacteria:

B. breve
 B. infantis
B. longum
L. rhamnosus
L. plantarum

A probiotic supplement including some combination of these species is a
good starting point in the fight to reclaim territory from the pathogens that
contribute to inflammation. Yet there are even more potent options available, if
we take advantage of the fact that even within the same species, some very
specific strains of probiotics have pathogen-fighting properties that exceed that
of other strains.
For example, within the L. reuteri species, the strain L. Reuteri DSM 17938
appears to be especially good at outcompeting pathogens. As a result, this
particular strain (sold as BioGaia Protectis®) is often given to preterm infants to
104
prevent serious infections. As further evidence of its ability to suppress
pathogens, the strain helps reduce the number of episodes and duration of
105
infectious diarrhea in young children attending day care centers. A recent
study also suggests that this strain is effective in combating constipation-
dominant SIBO by reducing the population of methane-producing bacteria in
106
the small intestine.
Within the L. rhamnosus species, the Culturelle® strain L. rhamnosus GG also
107
has a slight edge in preventing opportunistic infections after antibiotics. It
also outperformed many other probiotics in a study focused on reducing the
108
severity and duration of infectious diarrhea in children. This strain is a
particularly good choice because it helps calm inflammation, boost the butyrate
producers, and restore the gut barrier.
Culturelle and BioGaia Protectis are therefore good options to consider.
These products are widely available in many countries and are relatively
inexpensive.

Advanced Pathogen-Fighting Probiotics

For a more aggressive approach to combating overgrowths of harmful bacteria
or yeasts, we can turn to even more potent probiotics. Namely, the pathogen-
fighting probiotics that have been proven effective in preventing or treating
serious infections such as post-antibiotic C. difficile infection and adherent-
invasive E. coli. These probiotics are

BioK+® (L. acidophilus CL1285, L. casei LBC80, L. rhamnosus
CLR2)
Mutaflor® (E. coli Nissle 1917)
Florastor® (S. Boulardii CNCM I-745)

These products are typically more expensive and not as widely available as
other probiotics, but they are supported by persuasive evidence from multiple
109
randomized clinical trials. These pathogen-fighting strains are exceptionally
good at combating overgrowths of harmful bacteria because they have the
unique ability to produce specific antimicrobial compounds. They can also block
other organisms from adhering to the gut lining, which makes it more difficult
for the harmful species to take up residence.
If testing shows you have an overgrowth of inflammatory species such as
Candida, E. coli, Streptococcus, or Klebsiella, it may be worth using one of these
advanced pathogen-fighting options for one or two months to help clear the
overgrowth. When it comes to choosing between these options, each has
different advantages and availability in different countries.

Bio-K+

Bio-K+ contains three proprietary strains: L. acidophilus CL1285, L. casei LBC80,
and L. rhamnosus CLR2. It is available in capsules or beverage form in
WholeFoods and other health food stores in the United States and Canada. It is
unfortunately more difficult to obtain in other countries.
The strains were originally isolated in the 1970s from the stools of a healthy
infant. Dr. Francois-Marie Luquet isolated a variety of bacterial strains then
identified three strains with the strongest antimicrobial activity against various
pathogenic bacteria. After several years of research to optimize culture
conditions and gastrointestinal survival of the strains, the Bio-K+ product was
110
developed.
Since that time, it has been used extensively in hospitals to prevent C. difficile
infections. Following an outbreak of potentially fatal C. difficile infections in one
hospital in Montreal in 2004, doctors began providing Bio-K+ to all patients
there treated with antibiotics.
Multiple randomized, double-blind, placebo-controlled trials have now
confirmed that Bio-K+ reduces the risk of developing the infections that cause
111
antibiotic-associated diarrhea. For example, one study found that 44 percent
of patients treated with antibiotics alone developed diarrhea and 24 percent
developed C. difficile infection, whereas of the patients taking two capsules per
day of Bio-K+, only 15 percent developed diarrhea and only 1 percent
112
developed C. difficile infections.
These findings are important because beyond C. difficile, many of the other
infections that cause diarrhea in those taking antibiotics correspond to the
infections that contribute to systemic inflammation, such as Klebsiella, E. coli,
113
and Candida. The strains found in Bio-K+ may therefore be helpful to combat
overgrowths of these pathogens.
Laboratory studies have also found that the strains used in Bio-K+ have
strong antimicrobial activity against E. coli O157:H7, Salmonella,
Staphylococcus, Listeria, and Enterococcus faecalis, all of which are strongly
114
inflammatory.
Bio-K+ has many other advantages, including a long history of use in
hundreds of thousands of patients. The beverage formulations are certified
gluten free and available in dairy, rice, or soy fermented drinks. Although soy is
known for containing compounds that compromise gut health, these
compounds are drastically reduced in fermented foods and unlikely to pose a
115
risk in the very small amounts likely found in the Bio-K+ drinks. For those
with celiac disease, the gluten-free certification likely outweighs the risk from
consuming a small amount of soy, given the concern of unlabeled gluten being
116
found in probiotics.
Another advantage of Bio-K+ is that the strains have demonstrated survival in
117
the gastrointestinal environment. The manufacturer also performs extensive
quality control to verify strain identity and potency in each batch of the final
product. These factors, along with its proven effects in protecting against
serious gut infections, make Bio-K+ a good choice for a short-term pathogen-
fighting protocol.

Mutaflor

Mutaflor contains an extensively studied strain of E. coli, called E. coli Nissle
1917. This particular strain was originally isolated from a soldier in World War I
who escaped a severe outbreak of diarrhea affecting his regiment. The strain is
thought to have protected the soldier from infection by Shigella. Unlike many
other strains of E. coli, Nissle 1917 does not produce any known toxins or elicit
118
an inflammatory response.
Soon after the strain was isolated, it became apparent that it could not only
help prevent infections but also treat other intestinal conditions. It began being
used as a probiotic supplement in Europe in the 1920s, under the trade name
Mutaflor. Since then, research has confirmed the value of this particular
probiotic strain in the treatment of diarrhea, constipation, and ulcerative colitis.
In patients with ulcerative colitis, two clinical studies have found that
Mutaflor shows efficacy in maintaining remission equivalent to the gold
119
standard medication treatment, mesalazine. As a result of these studies,
Mutaflor is actually one of the few probiotics licensed as a medicine in Europe.
A clinical trial in Crohn’s disease also reported a lower relapse rate after 12 
120
months of receiving steroid treatment in combination with Mutaflor.
Importantly, there is good reason to believe that in these conditions,
121
Mutaflor works in part by suppressing pathogenic E. coli. As discussed
previously, there is a growing body of research linking many cases of Crohn’s,
ulcerative colitis, and spondyloarthritis to a particularly aggressive form of E.
coli, called “Adherent-invasive E. coli” (AIEC). Researchers have now found that
E. coli Nissle 1917 can effectively inhibit the adhesion and invasion of various
122
AIEC strains isolated from patients with Crohn’s disease. In laboratory
studies, E. coli Nissle 1917 can in fact outcompete a range of pathogenic E. coli
123
strains. It also appears to be particularly good at inhibiting the growth of
Klebsiella and preventing invasion by Salmonella, Yersinia, Shigella, Listeria, and
124
various other species known to cause serious gut infections. When given to
newborns, E. coli Nissle 1917 colonizes the gut and reduces infection by
125
pathogenic bacteria.
Beyond suppressing harmful bacteria, E. coli Nissle 1917 may also directly
126
calm inflammation and help repair the gut barrier. Mutaflor is readily
available in capsule form in Europe, Canada, Australia, and the United Kingdom.
Unfortunately, the FDA barred Mutaflor from sale in the United States in 2011
because it does not fall within the technical definition of a “dietary ingredient,”
unlike other probiotic species that have long been included in foods such as
 127
yogurts. To be sold in the United States, Mutaflor would therefore have to
be approved as a drug, which is a long and expensive endeavor. Until the
situation is resolved, many people in the United States have resorted to
ordering online from Canadian pharmacies.

Florastor

Saccharomyces boulardii is a species of yeast distantly related to baker’s yeast.
In recent years, it has become a popular probiotic, particularly in the context of
treating Candida yeast and preventing the opportunistic infections that often
arise after antibiotic use. Although there are now many products available
containing S. boulardii, it is important to note that all of the clinical studies
showing efficacy in combating pathogens have been performed with a specific
strain, known as S. boulardii CNCM I-745 or the Biocodex strain. This particular
strain is sold under the trade name Florastor.
The Biocodex strain of S. boulardii was discovered in Southeast Asia in 1920
by the French microbiologist Henri Boulard. He was searching for new strains of
yeast to use in fermentation and happened to be visiting an area during a
cholera outbreak. He noticed that people drinking a tea made from the skins of
lychees were able to resist the cholera infection. Eventually, he isolated a
specific strain of yeast from the surface of the lychees and found that it was this
128
yeast that conferred protection against cholera.
Since that time, more than 50 randomized clinical studies have been
performed to investigate the extraordinary properties of this strain, with many
129
showing that it can protect against a variety of infections.
For example, numerous controlled trials have found that those taking S.
boulardii during antibiotic treatment are about 50 percent less likely to develop
antibiotic-associated diarrhea, which is usually caused by opportunistic
130
infections. A 2017 study found that taking S. boulardii in conjunction with
131
antibiotics leads to less overgrowth of E. coli.
Supplementing with S. boulardii does not just prevent gastrointestinal
infections but can also help reduce the severity of infections that are already
132
established. Studies have found that S. boulardii can reduce the severity of
infectious diarrhea, which is often caused by pathogens such as E. coli or
133
Salmonella. It has also been shown to directly inhibit other specific
 134
pathogens most often associated with inflammation and SIBO. One way in
which S. boulardii can reduce the severity of gut infections is by blocking or
135
breaking down the toxins they produce, such as lipopolysaccharide.
Furthermore, S. boulardii is particularly well known for its activity against a
136
variety of species of Candida yeast. In addition to suppressing the growth of
Candida, it helps stop Candida adhering to surfaces and forming a biofilm to
137
protect itself. The ability to combat Candida is invaluable because Candida
138
overgrowths in the GI tract are very common and highly inflammatory.
Higher levels of intestinal Candida are often seen in those with Crohn’s disease
139
and ulcerative colitis. It has been suggested that inflammation in the gut
makes it easier for Candida to colonize, which then triggers further
140
inflammation in a vicious cycle. Supplementing with S. boulardii could be one
step toward breaking this cycle. (Additional supplements to combat Candida
are discussed in chapter 3.)
In addition to suppressing harmful bacteria and yeasts, S. boulardii can also
help restore the intestinal barrier. This was evident from a study of patients
with Crohn’s disease who still show abnormal intestinal permeability even
when the disease is in remission. When a group of patients took S. boulardii for
141
three months, their intestinal permeability improved.
The effect of S. boulardii in Crohn’s disease does not end there. It also
significantly reduces symptoms and the risk of relapse. When patients with
Crohn’s disease in remission took S. boulardii for six months, only 6 percent
142
relapsed, compared to 38 percent not taking the probiotic. In another
placebo-controlled study, S. boulardii significantly reduced the severity of
143
Crohn’s disease in those with continuing moderate symptoms. Again, this
likely occurs by suppressing pathogens that would otherwise antagonize the
immune system. S. boulardii may therefore be able to play a similar role in
dialing back other related autoimmune diseases.
S. boulardii is not suitable for everyone, however. Isolated cases of S.
boulardii entering the bloodstream and causing infection have been reported in
144
seriously ill patients and those with central venous lines. This probiotic
should probably also be avoided by those with an allergy or hypersensitivity to
baker’s yeast (Saccharomyces cerevesiae), because the two are closely related.
 If you decide to try S. boulardii, it is best to choose the Florastor brand if you
can because this product contains the specific strain used in the clinical trials
discussed above. The dose used in most studies is 500–1000 mg per day, which
corresponds to two to four capsules per day.

Probiotics and SIBO

The value of probiotics in treating small intestinal bacterial overgrowth (SIBO) is
hotly debated. Some take the view that if SIBO is caused by an excess of
bacteria in the small intestine, adding further bacteria in the form of probiotics
is counterproductive. In addition, those with SIBO often find that probiotics can
worsen symptoms such as bloating and histamine reactions, at least in the short
term.
The alternate view is that the inflammation and damage caused by SIBO are
often driven by particular species of unfriendly bacteria, and probiotics can be a
key weapon in suppressing those species in the long term. Probiotics may also
combat SIBO in other ways, such as improving the speed of transit through the
digestive system, which reduces the opportunity for bacterial overgrowth.
The clinical studies that have been done so far do indicate that probiotics can
be somewhat helpful in treating SIBO. For example, we saw earlier that the
BioGaia Protectis strain of L. reuteri appears to be effective in combating
methane-dominant SIBO. Another study found that four weeks of treatment
with a probiotic combination that included several Bifidobacteria and
145
Lactobacillus species was able to eradicate SIBO in a quarter of patients. A
similar probiotic combination was able to produce a clinical improvement in 80
percent of patients with SIBO, whereas only 52 percent of patients taking
146
antibiotics improved. Other probiotic species that have been found helpful
147
for SIBO include Bacillus clausii and Bacillus coagulans. These species are not
necessarily the best choices for those with autoimmunity though, because they
can be somewhat inflammatory.
Two other types of probiotics are often recommended to those with SIBO:
soil-based organisms and so called “D-lactate-free” probiotics. There is little to
no clinical evidence supporting the use of soil-based organisms and these
products should be considered high-risk, given the possibility that they can
colonize the gut long term.
The benefit of D-lactate-free probiotics may also be oversold. The supposed
advantage of these probiotics is based on the fact that in some cases, SIBO can
148
involve an excess of D-lactate. Although the body has mechanisms to quickly
metabolize lactate, extreme excess is thought to cause fatigue, weakness, and
149
cognitive impairment. Companies have therefore marketed probiotics that
produce very little D-lactate as more suitable for those with SIBO. Yet the
original studies linking D-lactate to SIBO were done in the context of severe
SIBO caused by surgical shortening of the small intestine. This is a very unique
situation and the findings cannot be extrapolated to ordinary SIBO. Very little is
known about the role of D-lactate in producing symptoms of SIBO in those with
intact digestive systems. Nevertheless, if you do notice worsening fatigue or
cognitive impairment with Lactobacillus probiotics, note that Bifidobacteria
species typically produce very little D-lactate.
In the end, our choice of probiotic in the context of SIBO should focus on the
ultimate goal of reducing the burden of pathogens in the small intestine.
Bifidobacteria are likely helpful in this context, but we may see even more
benefit from the specialist pathogen-fighting strains discussed above: BioGaia
Protectis, Mutaflor, Bio-K+, and Florastor. These have all been studied
extensively in clinical trials and have been found to suppress a range of
pathogens that are common culprits in causing SIBO. They also share the
important properties of reducing overall inflammation and helping repair the
gut barrier, which are the other key goals of probiotic treatment.

For more advanced treatment of SIBO and pathogen overgrowth, some
people may still find that they also need to supplement with bile, digestive
enzymes, and other supplements. These strategies are covered in chapter 3.


Using Probiotics to Restore the Integrity of the Gut Barrier

Probiotics that suppress harmful species of yeast and bacteria will go a long
way toward healing leaky gut, because pathogen overgrowth is often one of the
150
root causes of increased intestinal permeability. By addressing the cause of
the problem, we give the natural repair mechanisms a chance to work.
Yet probiotics can also help directly support the healing process itself. That is
because butyrate is in fact the main energy source for the cells lining the
intestines. It powers the repair and regeneration of every component of the
 151
intestinal barrier. Because probiotics such as Bifidobacteria and L. rhamnosus
GG help support butyrate production, they can therefore help reverse leaky
152
gut. Other strains of probiotics can also promote repair and regeneration of
the intestinal lining in more direct ways. E. coli Nissle 1917 and B. infantis, for
example, have both been found to produce compounds that directly boost the
153
production of tight junction proteins.
Overall, the probiotics that are particularly good at reversing leaky gut
154
include
B. infantis
B. breve
L. rhamnosus GG
E. coli Nissle 1917
L. plantarum
L. acidophilus

Anti-inflammatory vs. Inflammatory Probiotics

All the beneficial effects of probiotics discussed so far have the net effect of
reducing inflammation. But probiotics can also directly modulate the immune
system, for better or worse. That is because different probiotics can shift the
dial on the immune system in different directions. Some can reduce the
production of inflammatory mediators, which makes the immune system more
tolerant and less likely to overreact to perceived threats. Other probiotics
activate components of the immune system that fight infection, but in the
process may increase the production of inflammatory mediators.
155
Probiotics that are known to be anti-inflammatory include

B. infantis
B. breve
B. longum
L. rhamnosus GG (Culturelle)
L. reuteri DSM 17938 (BioGaia Protectis)
B. infantis 35624 (Align)
E. coli Nissle 1917 (Mutaflor)
S. boulardii CNCM I-745 (Florastor)
 L. acidophilus

At the cellular level, these probiotics have been shown to reduce a wide
variety of inflammatory mediators, including the mediators involved in psoriasis
156
and arthritis. Clinical studies also show that these probiotics can reduce the
severity of inflammatory conditions such as ulcerative colitis, allergy, and
157
eczema.
In contrast, certain other probiotics can tend to promote immune
activation and could potentially undermine our efforts to lower inflammation.
There are two main ways in which this can occur in the autoimmune context.
The first is by activating immune cells called T helper 17 cells (Th17 cells), which
produce powerful inflammatory mediators. The second is by producing large
amounts of histamine, which can trigger the innate immune system.

Th17 cells, IL-17, and Probiotics

Th17 cells are specialized helper immune cells that have recently been
158
recognized as playing a significant role in driving autoimmune disease. Th17
cells produce a cytokine called Interleukin 17 (IL-17). This is an immune-
stimulating mediator that ordinarily plays an important role in combating gut
infection but can also orchestrate the inflammation involved in some
autoimmune diseases, particularly ankylosing spondylitis, psoriatic arthritis, and
psoriasis. In fact, the newest generation of biologics used to treat these
conditions (such as Cosentyx and Taltz) actually work by blocking IL-17.
Given that IL-17 plays a key role in driving inflammation, it stands to reason
that we should try to minimize anything that boosts IL-17. Some species of
bacteria and yeasts are very strong inducers of IL-17. This includes Klebsiella,
Candida albicans, Campylobacter, Enterococcus, and other common gut
pathogens, but also species occasionally found in probiotic supplements, such
159
as B. adolescentis.
Research in this area has only just begun, so for many species of probiotics,
we have no information about how they influence Th17 cells and IL-17
production. Yet we do know that some probiotics can actually calm
inflammation by reducing IL-17 production, while many others have very little
direct effect on IL-17. At the time of writing, the best available information we
have is as follows:

160
Mild suppressors of IL-17:

L. rhamnosus GG
B. longum subspecies infantis 35624
L. acidophilus
L. reuteri DSM17938

161
Little to no direct effect on IL-17:

B. breve
B. infantis
B. longum
B. lactis
L. rhamnosus
L. casei
S. boulardii

162
Possible inducers of IL-17:

B. bifidum
B. coagulans

163
Strong inducers of IL-17:

B. adolescentis
Klebsiella pneumoniae
Enterococcus faecalis
Campylobacter jejuni
Candida albicans
Citrobacter species
Salmonella species
Streptococcus

Until more is known, the most cautious approach is to strictly avoid
probiotics that contain B. adolescentis. What is less clear is whether we need to
avoid probiotic combinations that contain B. bifidum. On its own, this species
164
appears to be a mild-to-moderate inducer of IL-17 in laboratory studies. But
in at least one animal study, a probiotic combination that included B. bifidum
decreased IL-17 production overall (and also suppressed experimental
165
inflammatory bowel disease and rheumatoid arthritis). B. bifidum is
particularly good at combating infections, so in real life it may ultimately lower
IL-17 levels by suppressing other inflammatory bacteria or yeasts.
A similar effect has been seen with B. breve and L. casei. On their own, these
species have no direct effect on IL-17 production. But in the real-world context,
166
they significantly reduce the IL-17 triggered by other infections.
Ultimately, the major cause of high levels of IL-17 in those with autoimmune
disease is likely to be the overgrowth of species such as Klebsiella, E. coli,
Streptococcus, and Candida. Addressing these overgrowths with pathogen-
fighting probiotics is probably one of the best tools we have to naturally lower
IL-17. Other strategies that can help reduce IL-17 production include getting
adequate amounts of vitamin A, vitamin D, and omega-3 fats, along with
167
supporting our resident butyrate-producing microbes.


Histamine production by probiotics

The second way in which probiotics can potentially promote inflammation is by
producing histamine. Some species of bacteria produce large amounts of
histamine by degrading dietary amino acids. In sensitive individuals, this
histamine then activates mast cells, which triggers an increase in intestinal
permeability, along with a variety of allergy-like symptoms such as itching,
flushing, fatigue, and headaches.
The probiotic species typically regarded as the worst when it comes to
168
histamine production are S. thermophilus and L. bulgaricus. There is
unfortunately a lack of reliable data about histamine production by many other
species. Even within the same species, different strains may produce different
amounts of histamine. We do know that in general, Bifidobacteria are less likely
to produce histamine than Lactobacilli. Within the Lactobacilli species, L.
169
acidophilus and L. rhamnosus are not typically histamine producers.
The fact that a probiotic combination contains some histamine-producing
species is not necessarily a deal-breaker, however. Other strains in the
combination may be good at degrading histamine, and the combination as a
whole may be good at suppressing histamine-producing bacteria naturally
resident in your gut. The high-potency combination probiotic VSL#3, for
example, contains the high-histamine producers S. thermophilus and L.
bulgaricus. Some people will tolerate this probiotic, while others will not. (Note
that researchers have recently raised quality concerns with VSL#3, following a
170
change in manufacturing. )
If you find you are particularly sensitive to histamine-producing strains of
probiotics, the root cause may be an overgrowth of histamine-producing or
immune-stimulating microbes in your gut. Recent studies have found that
certain gut microbes can produce a significant amount of histamine. This
171
includes E. coli and Morganella morganii. (Overgrowths of these particular
species can be detected on stool tests such as the GI-Map.) Other pathogens in
the gut can also stimulate the immune system itself to release histamine. This
includes Candida yeast, for example. The net effect is that an overgrowth of
pathogens can heighten sensitivity to additional histamine from probiotics. Yet
probiotics that combat these pathogens may be part of the long-term solution
to histamine intolerance.

Probiotic Buyers Guide

There are many factors to weigh when choosing a probiotic, but perhaps the
best place to start is by identifying products containing the species we want,
without any that could spur inflammation. We can then consider whether to
choose a probiotic containing mild strains, or more potent pathogen-fighters.

Level 1 Probiotics

At the introductory level, it is best to choose a probiotic combination that
includes at least one of the preferred Bifidobacteria species, namely:
B. infantis
B. longum
B. breve

These species excel at cross-feeding the butyrate producers, restoring the gut
barrier, and calming inflammation. Recommended products with these species
and no inflammatory species include:
Jarrow-dophilus Allergen Freed
Klaire Labs Ther-Biotic Metabolic Formula
 Probiotic Pearls Digestion and Immunity

These particular combination products also contain lactobacillus strains that
may provide some further help in suppressing harmful bacteria and restoring
the gut barrier. For example, L. acidophilus is known for its ability to combat
leaky gut, while three of the specific strains used in the Jarrow Allergen Free
combination are particularly good at suppressing E.coli (namely, L. plantarum
LP01, L. rhamnosus LR-04, and B. breve BR-03).
Culturelle Health & Wellness and BioGaia Protectis are also good entry-level
probiotics. These single-strain lactobacillus probiotics have been studied
extensively and are typically well tolerated by even the most sensitive
individuals, including newborn infants.
All of these Level 1 probiotics are good options for long-term maintenance,
to continue supporting your beneficial microbes while deterring undesirable
species. If, however, you do not see sufficient improvement, or you already
know you have a significant pathogen overgrowth, you may need one of the
more potent probiotics detailed below.

Level 2 Probiotics

For stronger activity against the undesirable bacteria that can drive
inflammation, we can select a probiotic with a higher potency and broader
range of Bifidobacteria species. Good options include:
Gut Pro and Gut Pro Infant
Jarrow Bifidus Balance
Renew Life Adult 50 Plus Go Pack
Kirkman Bifido Complex

Because these probiotics contain B. bifidum, they may be slightly more
effective than the level 1 probiotics at combatting pathogens. Yet once
pathogen overgrowth is brought under control, this potent species is likely no
longer required. Because B. bifidum may theoretically spur immune activity, it
may be preferable to return to a milder level 1 probiotic for ongoing
maintenance. (You can of course continue taking a level 2 probiotic long-term,
if you find that you respond well).

Level 3 Probiotics

 For those with particularly severe inflammation, an overgrowth of persistent
species such as E.coli, Candida, or Klebsiella, or a diagnosis of SIBO, you may see
the greatest improvement by starting with 30 to 60 days of treatment with one
of the advanced pathogen-fighting probiotics:
BioK+
Mutaflor
Florastor

This intensive treatment phase is intended to suppress the harmful species
that are notoriously difficult to combat. Once you see a significant
improvement in symptoms, you can then revert to a level 1 or 2 probiotic for
long-term use. (You may also decide to continue taking a level 3 probiotic for
an extended period of time if you prefer.)

Other Factors Influencing Probiotic Choice

Within each of the levels above, the choice of probiotic may be dictated by
other factors unique to your particular circumstances. If you are located in
Europe, for example, you may have easy access to BioGaia, Mutaflor, and
Florastor, but difficulty obtaining certain other products. For individuals who
are sensitive to even trace amounts of dairy, most of the probiotics listed above
will be suitable, with the exception of Pearls Digestion & Immunity and Jarrow
Bifidus Balance.
If you find that you need to avoid fillers containing starch, prebiotics or
maltodextrin, preferred options include:
Klaire Labs Ther-Biotic Metabolic Formula (level 1)
Probiotic Pearls Digestion and Immunity (level 1)
BioGaia Protectis (level 1)
Gut Pro and Gut Pro Infant (level 2)
Kirkman Bifido Complex (level 2)
Renew Life Adult 50 Plus Go Pack (level 2)
Florastor (level 3)
BioK+ (level 3)

In the end, the probiotics identified in this chapter are good options to
consider, but some experimentation may be needed to find what works best for
you. For up-to-date information on available products and links to online stores,
see www.keystonebook.com/probiotics.

Prebiotics

An optional add-on strategy to maximize the effect of your probiotic is to
include a daily prebiotic fiber supplement. Prebiotics are typically forms of
soluble fiber that are intended to preferentially feed beneficial bacteria. They
can have a dramatic effect on the balance of species in the gut, with much
bigger boosts to beneficial bacteria than we can produce with probiotics or diet
alone.
The problem is that the resulting changes to the microbiome are quite
unpredictable. Many prebiotics can feed unwanted species, too, and help these
species multiply alongside the beneficial species we are trying to boost. In this
way, prebiotics are similar to fertilizer. Fertilizing a lawn can help grass grow,
but it may also help the weeds grow.
It may be that we can get the best results from prebiotics by doing some
“weeding” first. That is, by spending several months focused on other measures
to suppress harmful species, such as pathogen-fighting probiotics, supplements,
and dietary changes, before introducing a prebiotic to help the beneficial
species maintain the upper hand. Even with this strategy of holding off until
some balance is restored, prebiotics will remain a high-risk but high-reward
proposition. We can improve the odds somewhat by choosing particular
prebiotics that have a greater chance of favoring the right bacteria. While there
are a wide variety of prebiotic supplements available, the following section
describes five commonly available options.

Acacia Fiber

One of the most well-tolerated prebiotics currently available is acacia fiber, also
known as gum arabic or acacia gum. Derived from the sap of the African acacia
tree, this form of soluble fiber is sold as Heather’s Tummy Fiber™ and Renew
Life™ Organic Clear Fiber, among other products. Acacia fiber can very
effectively stimulate the beneficial Bifidobacteria, increase butyrate levels, and
172
improve leaky gut. The balance of the evidence suggests that it does not
173
encourage significant growth of undesirable species. (Although one
laboratory study did report that Klebsiella could ferment a similar type of
carbohydrate, so it is best avoided by those with ankylosing spondylitis or a
174
known Klebsiella overgrowth.)
 In human studies, acacia fiber typically causes little to no gas or bloating even
175
at high doses, unlike most other prebiotics. When used for several weeks, it
has a remarkable ability to reduce both diarrhea and constipation, likely due in
176
large part to its ability to promote beneficial bacteria. The optimal dose of
acacia fiber is thought to be 10 to 15 grams per day, which is approximately two
measuring tablespoons. However, it may be better to start at a much lower
dose, such as ½ a teaspoon per day, and increase the dose over the course of
several weeks.

Galactooligosaccharides (GOS)

Another form of prebiotic often used to boost beneficial bacteria is
galactooligosaccharides, or GOS for short. On their own, GOS do little to
support the butyrate producers, but they may be helpful for getting the best
response from a Bifidobacteria probiotic.
These indigestible carbohydrates are actually a major component of human
breast milk, where they are present solely to feed important beneficial bacteria
177
in the infant. With this context, it is perhaps unsurprising that
178
galactooligosaccharides are fairly selective for Bifidobacteria. Bifidobacteria
are among the predominant bacteria present in newborns, and it makes sense
that human breast milk evolved to include a prebiotic that feeds these species
but not potential pathogens.
GOS may even suppress some pathogens. When preterm infants were given
a formula supplement with GOS, the total abundance of common pathogens
dropped significantly (while the Bifidobacteria increased from 5 percent of total
179
bacteria to over 30 percent). Another recent study found that supplementing
with GOS could reduce the level of Streptococcus, a common contributor to
180
both SIBO and psoriasis. Yet this same study found that GOS can also
suppress some of the butyrate-producing species and increase the abundance
181
of Prevotella, which has been linked to rheumatoid arthritis. Therefore the
effects of GOS may be somewhat unpredictable and it is likely more
appropriate for those with psoriasis than RA.
Most of the studies finding a benefit of GOS have used a dose of 8 to 15
grams per day, but it appears that GOS can boost Bifidobacteria even at a much
182
lower dose of 2.5 grams per day, which is similar to the amount found in a
single-serve sachet of Bimuno™, the most well-known GOS prebiotic
supplement.

Partially Hydrolyzed Guar Gum

Partially hydrolyzed guar gum is an alternative prebiotic that is often well
tolerated by those with significant intestinal symptoms. This prebiotic is sold as
Sunfiber™ and Nutrisource Fiber™, for example.
Partially hydrolyzed guar gum clearly enhances the growth of beneficial
183
bacteria such as Bifidobacteria and the butyrate producers. As we would
184
expect, it also strongly boosts butyrate levels. Yet there is conflicting and
185
limited information available concerning its impact on undesirable bacteria.
We do know that in human studies, partially hydrolyzed guar gum has been
found useful in treating conditions involving bacterial overgrowth, such as
186
irritable bowel syndrome. The results are likely to differ between individuals
though. Dr. Allyson Siebecker, a physician who specializes in treating SIBO,
reports that some patients are “prebiotic responders” and do very well with
prebiotics such as partially hydrolyzed guar gum, whereas these prebiotics may
187
worsen symptoms for others.

Psyllium

Psyllium husk is yet another alternative prebiotic that feeds beneficial butyrate
188
producers, apparently without significantly feeding E. coli or Klebsiella. Yet it
has a major drawback. Unfortunately, the plants used to grow psyllium are very
good at absorbing lead from the soil. As a result, psyllium fiber supplements
often contain high levels of lead and probably should not be used long term.

Fructooligosaccharides (FOS)

The least desirable prebiotics for those with gut-related autoimmune conditions
are those made up of chains of fructose molecules, called fructans. Fructans
include short chains of fructose, known as fructooligosaccharides (FOS), or long
chains, known as inulin. These prebiotics are well known for their ability to
189
profoundly boost beneficial bacteria. Yet fructans are not suitable for
everyone.
These prebiotics not only feed the beneficial bacteria but may also feed
190
undesirable bacteria such as Klebsiella, Streptococci, and E. coli. It is
therefore best to avoid prebiotics containing large amounts of inulin or FOS.
Fructans are also found in onion, asparagus, leeks, garlic, green banana, and
some probiotic supplements. The smaller amount found in these sources is less
concerning than a concentrated prebiotic supplement and may not be a
problem for everyone. Nevertheless, some people may benefit from limiting
high-fructan foods, at least in the short term and as part of a broader program
to suppress the population of inflammatory microbes.


 Chapter 3. Additional Strategies to Combat Bacterial
Overgrowth


Probiotics and diet should be the cornerstones of a long-term strategy to
combat an excess of undesirable bacteria. Yet there are several other
approaches that can provide further help to tackle specific pathogens or SIBO,
including supporting proper digestion and the short-term use of natural
antimicrobial supplements. The conventional medical approach to treating SIBO
with antibiotics is also one option to consider.

The Conventional Approach

The standard treatment for SIBO is an antibiotic called Rifaximin (Xifaxan).
Unlike other antibiotics, Rifaximin is not absorbed into the bloodstream.
Instead, it stays in the gut where it can target the bacteria that cause SIBO. This
particular antibiotic is not as detrimental to the overall microbiome as other
antibiotics because its activity is largely limited to the small intestine. It needs
bile to dissolve, so becomes poorly soluble and loses effectiveness when it
arrives in the large intestine. As a result, Rifaximin can target overgrowth in the
small intestine without significantly harming the good bacteria in the large
intestine.
Nevertheless, this antibiotic is not a magic solution for SIBO. Rifaximin is very
expensive, often not covered by insurance, and relapses after treatment are
incredibly common. In fact, within nine months, 40 percent of patients relapse,
191
most likely because the underlying causes of SIBO are not addressed.
Yet it cannot be questioned that at least in the short term, Rifaximin often
works quite well. In a recent study in three patients with psoriasis who tested
positive for SIBO by glucose breath test, treatment with a combination of
Rifaximin and a prebiotic (guar gum) for 12 days eradicated the bacterial
192
overgrowth and significantly improved psoriasis. The redness of psoriasis
plaques was reduced by 43 percent just from this very brief treatment regime.
Another common method of treating SIBO is to use various natural
antimicrobial supplements, such as oregano oil and grapefruit seed extract.
Many of these antimicrobials will indeed suppress the bacteria involved in SIBO,
but they can also cause significant destruction to the population of beneficial
microbes. In the long term this may actually exacerbate SIBO and allow harmful
bacteria to flourish.
For long-term control of SIBO while preserving the beneficial species in the
large intestine, a better starting point is to focus on restoring the normal
mechanisms that prevent bacterial overgrowth in healthy individuals. The first
way to do this is through meal spacing.

Meal Spacing

One of the most important mechanisms that normally keeps bacteria numbers
low in the small intestine is the cleaning cycle that sweeps away the bacteria
and debris between meals. This is termed the migrating motor complex (MMC).
The MMC is a very specific pattern of gastrointestinal muscle activity that
differs significantly from the normal activity during digestion. It involves
coordinated waves to push debris along the small intestine. A small amount of
bile is also secreted to act as soap and help the cleaning function. The entire
cycle takes about two hours, culminating in a burst of activity that produces the
rumbling noises many people mistake for hunger pangs.
Importantly, the MMC cleaning process shuts down when food is ingested.
The small intestine effectively has two modes of operation: digesting and
cleaning. If food is eaten too frequently during the day, the small intestine will
remain in digesting mode and the MMC will never get the chance to clean away
food residue and bacteria.
To give the MMC as much opportunity as possible to do its important job, it is
best to eat only at defined meal times. Dr. Mark Pimental, a gastroenterologist
who has led much of the research on SIBO, recommends spacing meals at least
193
four to five hours apart, with no snacking. (Drinking water or other
noncaloric beverages between meals is not a problem.) It may not be realistic
to space your meals properly every single day, but the more often you can, the
better.
The MMC also significantly slows down during sleep, so it is best to eat
dinner several hours before bed, if possible. An example meal schedule would
be to eat at 8 a.m., 1 p.m., and 6 p.m. Alternatively, you may find it easier to eat
four smaller meals, say at 8 a.m., 12 p.m., 4 p.m., and 8 p.m.
If you find it difficult to stick to an eating schedule and maintain steady
energy levels without snacking, it is possible that you are relying too heavily on
carbohydrates for fuel. Try to include at least 30 grams of protein in each meal,
along with a source of fiber and fats such as avocado or olive oil. It may also
take some time to adjust to a new eating schedule.

Digestive Support

In healthy people, the combined action of stomach acid, enzymes, and bile salts
also plays a key role in preventing bacterial overgrowths. Bile not only acts as a
detergent to clean the small intestine, but it also directly suppresses many
undesirable species, including Streptococci, Klebsiella, E. coli, and other species
194
that produce lipopolysaccharide. Bile in fact reduces our exposure to
lipopolysaccharide in another way as well—by reducing the amount of
195
lipopolysaccharide absorbed from the small intestine.
Producing adequate stomach acid and digestive enzymes is also essential to
preventing bacterial overgrowth. If you do not produce enough, digestion will
slow and food can sit and ferment in the upper digestive system, leading to
SIBO.
Some people therefore benefit tremendously from supplementing with
enzymes, acid, or bile. Several physicians have reported that bile
196
supplementation alone can significantly improve psoriasis in many cases.
Unfortunately, it is difficult to know whether you are producing sufficient
bile, acid, and enzymes, so some element of trial and error is inevitable. A good
starting point is a bile supplement such as ox bile or Jarrow Bile Factors, taken
at the end of meals. The next step would be to consider adding a supplement
containing a combination of betaine HCL, pepsin, and pancreatin. (See
www.keystonebook.com/supplements.)

Prokinetics

Gastroenterologists who specialize in SIBO often emphasize that long-term
control of bacterial overgrowth in the small intestine depends on supporting
motility as much as possible, particularly where scar tissue or a history of food
poisoning is involved. To that end, doctors often prescribe medicines or natural
agents to stimulate the cleansing activity of the migrating motor complex.
Prescription options include low-dose erythromycin or low-dose naltrexone.
Low-dose naltrexone has other potential benefits and is discussed in chapter 9.
Nonprescription options include ginger and a herbal combination called
Iberogast. Iberogast is often regarded as the best choice, because it is well
tolerated and continues working long term. Used in Europe for the past 40
years to treat all manner of digestive complaints, Iberogast has been shown to
197
increase motility in the small intestine. In controlled clinical trials, it has also
been proven effective for irritable bowel syndrome and conditions associated
198
with delayed stomach emptying. In addition, the safety of Iberogast has been
studied extensively in clinical trials, with no serious side effects, despite use by
199
an estimated 25 million people over the past 50 years. To support the
migrating motor complex, Iberogast is best taken two hours after each meal.

Together, the combination of meal spacing, digestive supplements, and
prokinetics can provide a powerful boost to the natural mechanisms that sweep
the small intestine clear of excess bacteria. These three steps alone provide a
good starting point to begin tackling milder cases of bacterial overgrowth,
without any risk of harming the overall microbiome. The same three steps are
also important to prevent SIBO from returning after more aggressive treatment,
such as with antibiotics or natural antimicrobials.

Natural Antimicrobials

The next phase of combating either SIBO or particular inflammatory bacteria
such as Klebsiella or Streptococcus is a short-term treatment with one or more
natural antimicrobial compounds. It may or may not be necessary to go down
this path, depending on how well you respond to diet, probiotics, and other
measures.
If you do decide to use natural antimicrobials, it is best to keep the treatment
period short (typically one month) and to choose compounds that do the least
damage possible to the beneficial species of gut bacteria. To that end, it is
important to avoid broad-acting antimicrobials, such as grapefruit seed extract
and oregano oil, and instead choose the most targeted and specific options.
When it comes to suppressing the microbes most often implicated in SIBO
and autoimmunity, without harming the overall microbiome, the best options
are lactoferrin, allicin, and berberine. For the best results, all three of these can
be taken half an hour before meals for 30 days. If you have a sensitive stomach,
it may be best to start each supplement separately and begin with a single
capsule each day.
Note that many people report an initial phase of feeling worse after
beginning antimicrobial compounds, with symptoms such as fatigue, stomach
pain, or nausea. This may be caused by an immune reaction to the dying
bacteria and yeasts and should only last for one or two weeks.

Lactoferrin

Lactoferrin is an iron-transport protein that plays a key role in defending against
infection. It is present in high concentrations in tears, saliva, and breast milk.
Because human and bovine lactoferrin are quite similar, this protein can also be
purified from cow’s milk and is therefore readily available in supplement form.
Lactoferrin works in part by strongly binding to iron, making that iron
unavailable to pathogenic bacteria but still usable by our own cells. This
mechanism of action targets undesirable bacteria while leaving many beneficial
200
species untouched.
Lactoferrin is particularly effective against Klebsiella and E. coli, for
201
example. It not only inhibits the growth of these species but also helps break
down the biofilms that E. coli and Klebsiella produce to shield themselves from
our immune system. In addition, lactoferrin stops harmful bacteria from
sticking to and invading intestinal cells, including the specific type of aggressive
202
E. coli implicated in Crohn’s disease.
Importantly, lactoferrin can suppress harmful bacteria without harming
important anti-inflammatory species such as Bifidobacteria. Researchers have
actually found that it can boost the number of Bifidobacteria, especially B.
203
breve and B. infantis. In human trials, giving lactoferrin-supplement formula
204
to infants prevents serious infections while increasing Bifidobacteria levels.
Lactoferrin supplements may not be suitable for those with severe dairy
allergy because the protein is purified from cow’s milk and trace amounts of
whey or casein may therefore be present in the final supplement. The amount
of these other proteins is likely to be minute, however, so the benefits of
lactoferrin may outweigh this concern for those with only minor sensitivities to
dairy.
Lactoferrin supplements are typically available in a dose of 250 milligrams per
capsule and the usual dose is two to four capsules per day, before meals.
Recommended brands include Jarrow and Life Extension (See
www.keystonebook.com/antimicrobial-supplements.)

Allicin

Garlic has been used to treat gastrointestinal complaints and infections for
205
thousands of years. The primary compound in garlic responsible for this
infection-fighting ability is allicin, which forms when garlic is cut or crushed.
To obtain a sufficient amount of allicin to suppress harmful bacteria and
yeasts, a supplement is typically more convenient than consuming large
amounts of fresh garlic. An allicin supplement also allows us to avoid the
fructans found in fresh garlic, which cause intestinal symptoms for many people
with bacterial overgrowth.
Although allicin can combat a range of infections, this compound is
particularly good at conquering the specific bacteria that have been implicated
in psoriasis, rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis
206
(namely Streptococcus pyogenes, Proteus mirabilis, E. coli, and Klebsiella).
Allicin can also combat other inflammatory species that may contribute to
inflammation, including Enterococcus faecalis, Helicobacter pylori, and
207
Citrobacter freundii.
In addition, allicin has potent antiviral and antifungal activity. Studies have
found that it kills Candida yeast almost as effectively as the prescription
208
antifungal fluconazole.
Helpfully, allicin appears to be relatively selective for harmful species of
bacteria and has much less effect on beneficial species such as Lactobacilli and
209
Bifidobacteria. We do not yet know how allicin impacts the broader
microbiome, but initial laboratory and animal studies indicate that it may
actually increase the overall diversity and boost the all-important butyrate-
210
producing species.
The preferred supplement option is AlliMax, because it contains stabilized
allicin rather than merely a garlic extract intended to result in allicin production
in the body. AlliMax does contain a small amount of maltodextrin, which can
potentially feed unwanted microbes, but the powerful antimicrobial effect of
the supplement likely outweighs the presence of maltodextrin. Other
alternative brands include Garlinase and Pure Encapsulations GarliActive,
although these products contain garlic extract rather than allicin, so they may
be less effective and more likely to cause unpleasant side effects.

Berberine

Berberine is a compound found in several medicinal herbs, including
goldenthread, goldenseal, Oregon grape, and barberry. These herbs have been
used in traditional Ayurvedic and Chinese medicine for centuries, typically to
treat gastrointestinal infections. More recently, berberine has become a
211
popular treatment option for SIBO, diabetes, and high cholesterol. Most
importantly for our purposes, berberine has been found to kill or inhibit a
variety of inflammatory species of gut microbes, including Klebsiella,
212
Streptococcus, and many other species that produce lipopolysaccharide.
213
Berberine is particularly active against Candida yeast and E. coli.
Perhaps the most exciting prospect in the use of berberine is the potential to
not only suppress these harmful species but to actually increase the population
of beneficial species. In a series of animal studies published in 2017 and 2018,
berberine was found to boost the population of important butyrate-producing
214
species. This led to a reduction in inflammatory mediators and an improved
gut barrier.
From these extraordinary properties, we would expect berberine to be
incredibly helpful in autoimmune diseases driven by disruptions to the
microbiome. Although we do not yet have any human clinical trials in this area,
the results of animal studies are very promising. Two studies published in 2017
found that in animal models of arthritis, berberine reduces joint inflammation
215
and prevents bone erosions. Additional studies have suggested that
berberine may be useful in a variety of other autoimmune diseases that have
been linked to gut bacteria and Th17 cells, such as multiple sclerosis and
216
Behcet’s disease.
Even setting aside this new encouraging research, berberine has a long
history of use in successfully treating gastrointestinal complaints such as SIBO
and Candida, so there is particularly good reason to try this supplement if
testing reveals you have an overgrowth of yeast or bacteria.
When it comes to potential side effects, the major concern with berberine is
its interaction with other medications. Because berberine may slow down the
activity of specific liver enzymes, it is best avoided by those taking medications
that are metabolized by Cytochrome P450 enzymes (a list of these medications
217
can be found online by searching for “Flockhart table”). Do not take
berberine if you are pregnant or nursing.
Berberine also has other potential effects to be mindful of. Some of these
effects may actually be helpful, such as the ability to lower cholesterol and to
218
lower blood sugar levels in those with diabetes. Berberine may also lower
blood pressure in some individuals.
The typical dose of berberine is 500 milligrams, three times per day.
Recommended brands include Thorne and Metagenics Candibactin-BR. Since
berberine may occasionally cause nausea or stomach upset, many practitioners
recommend working up to this dose, starting with one capsule, once per day.

Yeast-Targeting Supplements

Yeasts are a natural part of the human ecosystem and may or may not cause
problems depending on their abundance and the particular species present.
Nevertheless, if testing reveals that you do have a Candida overgrowth in your
digestive system, it is worth treating because an excess of Candida can
contribute to leaky gut and activate the inflammatory response.
The question is how best to combat yeast without harming the microbiome.
Typical yeast-fighting supplements contain a myriad of broad-acting
antimicrobials that also harm beneficial bacteria and are therefore best
avoided. Safer options include allicin, berberine, and the probiotic Florastor (S.
boulardii), which are known to have strong activity against Candida without
causing significant collateral damage. In order for these supplements to work
well, it may also be necessary to add a biofilm-targeting enzyme combination,
such as Candex, Klaire Labs Interfase, or Kirkman Biofilm Defense. Candida is
known to produce a robust biofilm layer that can shield it from both the
219
immune system and antifungal compounds. Using enzymes to break down
this layer is therefore useful in combating Candida while posing little risk to the
overall microbiome.


Part 2: Using Food as Medicine

 Chapter 4. A Microbiome-Restoring Diet

For better or worse, the food we eat has a profound impact on our gut
microbes. That is because different species of resident microbes prefer
different types of carbohydrates and other nutrients. Those species that are
given a steady supply of their preferred food will multiply and out-compete
other species. Our goal then is to adopt a way of eating that gives the beneficial
species the upper hand.

Feeding the Good Species

In previous chapters we saw that the most important beneficial microbes for
preventing and calming autoimmune disease are the Bifidobacteria and the
butyrate-producing species in Clostridia clusters IV and XIVa. If we want these
microbes to out-compete the less desirable species, the key is to feed them
their preferred food: fiber.
For millennia, a diet rich in fibrous plants has nurtured these important
bacteria in the human microbiome. We have co-evolved alongside fiber-loving
bacteria with the net result that we have come to depend on them as much as
they depend on us. We provide the bacteria with energy in the form of
fermentable prebiotic fiber, and in return they produce butyrate and other key
compounds that calibrate our immune system and teach it to tolerate the
body’s own proteins.
If instead we adopt a diet based on highly processed grains and sugars, we
effectively starve our most important gut bacteria, while allowing unwanted
species to take over. This sets the stage for the immune system to lose its
equilibrium and shift toward an inflammatory state.
The lack of fiber in the modern diet is likely a major factor in the geographic
220
distribution of inflammatory disease. Diseases such as arthritis and
inflammatory bowel disease are much more prevalent in societies with highly
processed and low-fiber diets, and virtually nonexistent in traditional hunter-
gatherer societies. There are obviously many factors contributing to this
disparity (such as the use of antibiotics) but there is clear evidence pointing to
fiber as a major issue. It is beyond question that fiber shapes the microbiome
toward butyrate production, and butyrate is essential in fine-tuning the
immune system and protecting against inflammation.
 This effect can be seen when comparing the microbiome of individuals
following Western-style diets to those with diets similar to our ancient
ancestors. Children living in a rural village in Burkina Faso, for example, have a
high-fiber diet based largely on vegetables, legumes, and millet. These children
have very different microbiomes from European children, resulting in butyrate
221
levels four times higher.
In one 2015 study, switching to a high-fiber, low-fat “African-style” diet for
two weeks not only doubled butyrate levels in the colon but also reduced
222
immune activation. The reverse effects were seen when 20 rural Africans
were switched to a “Westernized” diet with less fiber: lower levels of beneficial
bacteria and butyrate production, and higher intestinal inflammation.
Population-based studies have also linked high-fiber diets to a lower risk of
223
immune-related diseases such as ulcerative colitis and Crohn’s disease. The
beneficial effects of high-fiber diets can similarly be seen in measurements of
224
inflammatory markers in the blood of otherwise healthy individuals. For
example, women consuming at least 25 grams of total fiber per day have
225
significantly lower levels of inflammatory markers such as TNF.
When it comes to feeding the microbiome, not just any fiber will do. The
term “fiber” simply refers to carbohydrates that are resistant to digestion. For
our purposes, the key is to include more fermentable fiber, which is typically
226
soluble fiber. Moreover, when it comes to feeding beneficial bacteria, the
forms of soluble fiber found in fruit and vegetables are even more effective
227
than the fiber found in grains and legumes. In one long-term human study, a
significant increase in beneficial bacteria was associated with higher fruit and
vegetable intake, while there was no clear benefit from the fiber found in
228
grains.
Cruciferous vegetables such as broccoli, cabbage, cauliflower, and kale are
229
particularly good at feeding the beneficial bacteria. Apples, pears, and
oranges are also good choices because they contain substantial amounts of
soluble fiber. Apples actually contain a specialized form of soluble fiber called
230
pectin, which has been shown to strongly boost butyrate production. These
fruits and vegetables are just examples of some of the best options to choose.
The key to encouraging a healthy and diverse microbiome is to consume a wide
variety of produce and to make nonstarchy vegetables the foundation of most
meals.

The Power of Polyphenols

Fiber is not the only tool we have for promoting the growth of beneficial
microbes. The polyphenols found in certain fruits are also extremely helpful.
Several different groups of researchers have found that cranberry,
pomegranate, and Concord grape extract dramatically enhance the growth of
231
Akkermansia muciniphila. This beneficial species helps maintain a strong gut
barrier, and it is also one of the major species depleted in those with psoriatic
232
arthritis and other autoimmune conditions.
In these studies, fruit polyphenols not only boosted beneficial Akkermansia
but also lowered serum inflammatory markers, including TNF, IL-6, and
lipopolysaccharide. Because the polyphenols found in cranberries,
pomegranate, and Concord grapes are somewhat different, the fact that all
three were effective in increasing the abundance of Akkermansia has led
researchers to suggest that related polyphenols from a wide variety of fruits
may have the same effect. The fruits with the highest levels of similar
polyphenols are those that are darkly pigmented, such as blackberries,
blueberries, black currants, and black plums.

Suppressing the Harmful Species

At the same time as feeding the good species of fiber and polyphenols, we want
to avoid feeding the harmful species too much of their favorite foods: starch
and sugars. For some people with autoimmune disease, eliminating these
components from the diet produces extraordinary results, even where biologic
233
medications have failed.
Eliminating starch appears to be particularly useful for those with ulcerative
colitis, Crohn’s, ankylosing spondylitis, psoriatic arthritis, and other forms of
arthritis that impact the spine and sacroiliac joints. These conditions are closely
related to one another and also happen to have the strongest link with starch-
loving bacteria (namely E. coli, Streptococcus, and Klebsiella). There are fewer
reports of this approach helping rheumatoid arthritis and other autoimmune
conditions, but it may still be worth trying, particularly if testing shows bacterial
overgrowth in the gut.
For those who do respond to eliminating starch, the results can be life
changing. As explained by one man with ankylosing spondylitis, “In the months
before I began the [no-starch] diet, my daily pain was about a 5 out of 10, with
no easy days to speak of. Some days, I would flare up to an 8 or 9. After two
weeks on the diet I was down to 0–1. At six months I couldn’t detect any pain or
234
inflammation at all. This completely astonished me.”

The Origins of the Low-Starch Diet for Arthritis

Although most rheumatologists do not acknowledge the role of carbohydrates
in contributing to inflammation, there is actually a long history of doctors using
low-starch and low-carbohydrate diets to treat arthritis, with great success. In
one of the earliest studies, published in 1922, 150 arthritis patients at Toronto
General Hospital were put on a low-carbohydrate diet and 80 percent
235
improved, with some making a full recovery. Several other physicians in the
1920s and 1930s reported similar success treating arthritis with a carbohydrate-
236
restricted diet. Even at that time, the doctors suspected a link between
237
carbohydrate consumption, gut bacteria, and arthritis.
This approach faded into the background until the 1980s, when Dr. Alan
Ebringer, a London rheumatologist, reported success in treating ankylosing
238
spondylitis with a low-starch diet. The story began when one of his patients
was placed on a low-carbohydrate diet for weight loss. Four months later, his
back pain was gone. Dr. Ebringer performed further research and eventually
settled on a theory: starch provides nutrients for the growth of a particular
species of gut bacteria called Klebsiella pneumoniae, and this bacteria triggers
ankylosing spondylitis. Starve the bacteria of starch, and the trigger for
inflammation is removed.
239
With some initial evidence supporting this theory, a low-starch diet began
being used as a first-line therapy for ankylosing spondylitis at the Middlesex
240
Hospital in London in the 1990s. After several years, Dr. Ebringer reported
241
that it was helpful in about half of patients with ankylosing spondylitis. There
are now vast online communities of people following this diet who report a full
or partial recovery after several months of strictly avoiding starch, and
significant pain flares from even minor lapses. (See, for example, the “NSD and
Diet Related” forum at KickAS.org and the Facebook group “The Low/No Starch
Diet for Ankylosing Spondylitis,” where hundreds of people have shared their
extraordinary success stories.)

The Current Science on the Low-Starch Diet

The exact reason why this way of eating is so effective has not been
conclusively established, but all lines of evidence point to gut bacteria as
playing a key role.
Even in healthy individuals, between 10 percent and 20 percent of starch
consumed can escape digestion. The percentage is likely even greater in those
with gut inflammation and damage, because the cells lining the small intestine
are responsible for producing starch-degrading enzymes. With fewer healthy
cells left to provide these enzymes, more starch will survive the digestive
process. The starch that remains in the gut can fuel the growth of both good
and bad bacteria but appears to particularly favor the growth of several harmful
species. Klebsiella, for example, produces specific starch-degrading enzymes to
242
allow it to take full advantage of any starch in our diet.
The connection between Klebsiella, starch, and ankylosing spondylitis
remains somewhat controversial. This is because several groups of researchers
have been unable to find higher levels of Klebsiella in the large intestine in AS
patients. Yet there is clear evidence that those with AS often have elevated
243
antibodies to Klebsiella. There are two possible explanations for this
apparent contradiction. It could be the case that the Klebsiella is present only as
small intestinal overgrowth and is thus not being detected in analysis of the
microbiome of the large intestine.
Another explanation is that those with AS do not necessarily have higher
levels of Klebsiella but rather have a heightened immune response to this
species, likely due to genetic reasons. (Research has implicated the HLAb27
gene in the immune responses to Klebsiella.) It may be that both factors are at
play. In other words, individuals with ankylosing spondylitis may have an
overgrowth of Klebsiella limited to the small intestine and an exaggerated
immune response to this overgrowth. This immune response to Klebsiella then
drives the autoimmune process, perhaps due to cross-reactivity between the
antibodies to Klebsiella and the proteins that are often attacked by the immune
244
system during AS.
But the value of reducing starch and other carbohydrates goes far beyond AS
and Klebsiella. Successful results have been seen in psoriasis, psoriatic arthritis,
 245
ulcerative colitis, and Crohn’s disease. This could be because the low- starch
diet also reduces overgrowths of other particularly harmful species in the small
or large intestine, such as E. coli.
Although E. coli is a normal resident in the human gut, a rare and aggressive
form called “adherent-invasive E. coli” is not only more likely to be found in
those with spondyloarthritis or inflammatory bowel disease, but it also appears
to trigger the precise immune response characteristic of these autoimmune
246
diseases.
This discovery lends support to the no-starch diet because adherent-invasive
E. coli happens to be particularly good at multiplying and invading cells in the
presence of maltodextrin, a carbohydrate that forms when starch is broken
247
down by our digestive enzymes. Thus, in some cases, the no-starch diet may
work so well because it starves these invasive E. coli.
In other cases, the low-starch diet may reduce inflammation by reducing a
net overgrowth of bacteria in small intestinal overgrowth (SIBO). Most dietary
approaches to treating SIBO involve the reduction or elimination of starch,
248
along with lactose and excess sugars.

Starch and Inflammatory Bowel Disease
Perhaps the clearest evidence we have on the value of reducing starch and
sugars in the treatment of autoimmune disease comes from recent studies
performed in the context of inflammatory bowel disease. These studies
involved a particular formulation of the low-starch diet known as the “specific
carbohydrate diet” (SCD). The SCD diet eliminates starch and two-unit sugars
(lactose and sucrose) while allowing simple sugars in fruit and honey. By
reducing carbohydrates that need more processing by enzymes before they can
be absorbed, the SCD diet aims to reduce the amount of carbohydrates that can
249
remain in the intestine to feed harmful bacteria.
Several groups of researchers have now found this diet to be very effective at
250
reducing intestinal and systemic inflammation, particularly in children. It
does not work in all cases, but when it does work, patients often make a full
recovery, with serious intestinal inflammation and damage disappearing in a
matter of months. As a result, the SCD diet is now being used by several top
hospitals as a first-line treatment for pediatric Crohn’s disease and ulcerative
colitis. One of these hospitals is Seattle Children’s, where Dr. David Suskind has
noted that “the specific carbohydrate diet (SCD) often times works with
amazing end results for our patients. At Seattle Children’s, we have seen great
251
improvements and the disappearance of symptoms altogether for some.”
Perhaps one of the most interesting findings from the recent studies using
SCD to treat inflammatory bowel disease is the changes that occur in the
microbiome. In 2017, doctors analyzed how the microbiome changed in 10
children with Crohn’s disease or ulcerative colitis who were following the SCD
252
diet. After three months, eight of the 10 children were in clinical remission,
with no remaining intestinal or systemic inflammation.
The children’s gut bacteria also changed substantially. There was an overall
increase in microbial diversity and an increase in the peacekeeping microbes
that are typically depleted in those with autoimmune diseases (the butyrate
producers). The diet also reduced overgrowths of E. coli and Klebsiella in the
two patients with these bacterial overgrowths.
Researchers at the University of California witnessed similar changes to the
microbiome in adults with Crohn’s following the SCD: an increase in overall
diversity and a specific increase in bacteria associated with immune regulation
253
(such as F. prausnitzii).
Although these studies were focused on inflammatory bowel disease, they
are highly relevant to other related autoimmune diseases. As explained
previously, inflammation in the gut is at the heart of the other autoimmune
diseases in the same family as Crohn’s and ulcerative colitis (namely psoriasis,
psoriatic arthritis, ankylosing spondylitis, juvenile arthritis, and uveitis). All of
these conditions show similar changes to the microbiome, the pattern of
immune activation, and intestinal inflammation.
The body of research to date strongly suggests that avoiding starch and sugar
can reduce inflammation by rebalancing the microbiome. These simple dietary
changes appear to starve the harmful species while allowing room for the
beneficial species to recover. For some, this could make a tremendous
difference to the severity of symptoms. There are, however, no guarantees of
success; the only way to know how you will respond is to perform the
experiment.

The Overall Keystone Diet

Before delving into the details of exactly how to reduce your consumption of
starch and sugar, we should set the stage with some broader dietary principles
that will also help reduce inflammation.
The most important overarching strategy is to lean toward a Mediterranean
diet, emphasizing fish, olive oil, and nonstarchy vegetables. This dietary pattern
has a proven ability to lower inflammation. An immense body of research has
found that the specific fats found in fish and olive oil can reduce inflammation
254
in the skin and joints. As chapter 5 explains, in those with psoriasis or
arthritis, a higher consumption of fish and olive oil directly correlates with
255
milder symptoms.
The Mediterranean diet is also anti-inflammatory because it is nutrient
dense. Several large-scale studies have found that the more closely children
and adults adhere to the Mediterranean diet, the less likely they are to have
256
nutrient deficiencies. You may expect that vitamin deficiencies are relatively
uncommon in modern times, but more than 40 percent of the United States
257
population is deficient in vitamin A, vitamin C, vitamin E, and magnesium.
A deficiency in any one of these micronutrients is especially problematic for
anyone with psoriasis or arthritis, because they play key roles in controlling
inflammation. A deficiency in magnesium, for instance, has been found to
258
significantly increase inflammation. While modern processed foods often
contain very little magnesium, it is found in large amounts in leafy greens, fish,
avocado, and seeds.
Many other vitamins and minerals likely play equally important roles in
regulating inflammation. Vitamins B12, C, E, and K are particularly anti-
259
inflammatory, as are other minerals such as selenium, manganese, and zinc.
The best sources of vitamin B12, selenium, and zinc are fish, lamb, and grass-
fed beef. The best sources of vitamins C, E, K, and manganese are leafy green
vegetables. In short, the vitamins and minerals we need most to reduce
inflammation are found in abundance in the foods at the core of the
260
Mediterranean diet.

Extraordinary Antioxidants

The anti-inflammatory effect of the Mediterranean diet is also a product of its
heavy emphasis on antioxidants. Clinical trials have confirmed that those who
follow a Mediterranean diet have a significantly higher antioxidant intake than
261
those on a standard modern diet.
 People with psoriasis and arthritis actually have a much greater need for
antioxidants because the cells at the site of inflammation in the skin and joints
262
produce vast amounts of reactive oxygen molecules. The usual antioxidant
defenses cannot keep up with all of these reactive molecules, and oxidative
263
damage occurs. This damage further increases inflammation and a vicious
264
cycle ensues.
Fortunately, a greater intake of antioxidants from fruit and vegetables
reduces oxidative damage and lowers the specific inflammatory mediators that
265
drive psoriasis and arthritis. Fruits and vegetables not only contain
antioxidant vitamins such as vitamins C and E, but they also contain hundreds
266
of other antioxidant compounds such as polyphenols and carotenoids. These
compounds are important because they can help fine-tune the immune system
—boosting our protection from infections while reducing inflammation.
The anti-inflammatory effect of fruit and vegetables is most pronounced for
cruciferous vegetables, such as broccoli, Brussels sprouts, cauliflower, collard
267
greens, cabbage, and kale. The more often these are eaten, the more
268
inflammation is kept under control. Olive oil, avocados, and brightly colored
fruits are also prime sources of antioxidants.
Color is a good key to antioxidant content because the phytochemical
antioxidants are often deeply pigmented. As a result, red lettuce and red
cabbage are better than standard varieties, as are purple cauliflower, purple
carrots, and black grapes. Dark green is another good clue to high antioxidant
content, with kale triumphing over most other vegetables.
Unsurprisingly, the lowest antioxidant vegetables are white or pale in color:
potato, celery, cucumber, and iceberg lettuce. The lowest antioxidant fruits are
also pale, including banana and pear.
Coffee, tea, and red wine are additional common sources of antioxidants in
the Mediterranean diet, but their benefit is more open to debate. Although
wine is often touted as anti-inflammatory, the impact on people with
autoimmune disease is not clear. In small amounts, alcohol consumption
appears to reduce the severity of rheumatoid and psoriatic arthritis, while more
269
than one drink per day worsens symptoms. There is also some evidence that
alcohol may contribute to intestinal permeability and the growth of harmful gut
270
bacteria. Alcohol also increases the risk of serious side effects from
medication such as NSAIDs and methotrexate.
Coffee is another rich source of antioxidants, and drinking coffee has been
correlated with lower inflammatory markers in four studies, while one study
reported higher inflammatory markers with “moderate-to-high” coffee
271
intake. There does not appear to be any association between coffee intake
and risk of developing psoriasis, rheumatoid arthritis, or other autoimmune
272
conditions. Thus the balance of evidence suggests that having one or two
cups of coffee per day is not problematic and may even lower inflammation.
Many traditional Mediterranean diets also include antioxidant-rich herbal
teas made from plants not typically available elsewhere in the world. We can
probably reap similar benefits from drinking green tea, which is a potent source
273
of antioxidants and has been found to reduce joint inflammation.
In sum, there are several key components of the Mediterranean diet that we
can incorporate to start tackling inflammation. Before focusing on what foods
to reduce or eliminate from your diet, it is helpful to concentrate on adding
more fish, olive oil, and nonstarchy vegetables. Doing so will allow you to reap
the benefits of anti-inflammatory fats, antioxidants, and a wide array of
vitamins and minerals that are critical to healing and balancing the immune
system. This then sets the stage for the next component of the Keystone Diet,
which is reducing starch and sugars.

Comparing the Keystone Diet to Other Healing Diets

The starch-lowering component of the Keystone Diet has much in common with
other healing diets, such as the Specific Carbohydrate Diet (SCD), the Gut and
Psychology Syndrome (GAPS) Diet, the Wahl’s Protocol, and the basic low-
starch diet adopted by many with ankylosing spondylitis. Like these protocols,
the Keystone Diet seeks to minimize the foods that encourage the growth of
pathogenic organisms, while providing as many nutrients as possible to
encourage healing and reduce inflammation. Yet there are some major
differences to note between the Keystone Diet and these other diets, which are
generally tailored to quite different autoimmune diseases.
Perhaps most importantly, the Keystone Diet seeks to minimize saturated fat
whereas paleo-based healing diets strongly encourage the consumption of
saturated fat through coconut oil or animal fats such as ghee and lard. As
chapter 5 explains, new studies show that saturated fats are particularly
harmful for those with autoimmune diseases driven by mediators such as TNF
274
and the immune response to bacterial toxins. Long-chain saturated fats in
palm oil and animal fat are especially good at boosting TNF, for example. The
saturated fats in coconut oil can also help shuttle bacterial toxins across the gut
275
barrier.
Saturated fats are therefore especially problematic for those with
autoimmune diseases such as psoriasis, psoriatic or rheumatoid arthritis, or
ankylosing spondylitis. By contrast, the fats typically used in the Mediterranean
diet are strongly anti-inflammatory and help suppress the inflammatory
mediators involved in these conditions.
For these reasons, the Keystone Diet encourages the use of oils that are rich
in monounsaturated fats, such as olive oil and avocado oil, as the only added
fats. Fish that is rich in omega-3 fatty acids is also emphasized, along with other
animal proteins that are lower in saturated fat, such as chicken, pork, turkey,
and leaner beef.
Finally, there is an optional troubleshooting phase that involves eliminating
nightshades and common allergens (such as dairy, nuts, and eggs). This is done
on a short-term basis in order to identify possible food sensitivities. In this
respect, there is some overlap with the autoimmune paleo (AIP) diet. The AIP
diet otherwise differs significantly from the Keystone Diet because it
encourages consumption of starches such as sweet potato, cassava, and
plantains, along with animal fats and coconut oil. If you are already following
the AIP diet, transitioning to the Keystone Diet will primarily involve replacing
starches with nonstarchy vegetables and switching to leaner proteins and olive
oil.
With that broader context in mind, we can now begin to focus on the
specifics of the first element of the Keystone Diet: cutting back on sugar and
starch in order to rebalance the microbiome.




 Chapter 5. The Low-Starch Diet in Practice

To reduce the overgrowth of inflammatory gut bacteria, it can be incredibly
helpful to avoid foods that contain significant starch and sugars. Many
individuals with ankylosing spondylitis find that they get the most benefit from
avoiding starch very strictly. In practice, this means not only completely
eliminating all grains and legumes but also root vegetables and bananas. Yet
individuals with autoimmune conditions other than ankylosing spondylitis can
often make dramatic improvements by removing grains and legumes and
continuing to eat fruits and vegetables with moderate amounts of starch. To
reflect these different possible approaches, the low-starch diet is therefore
divided into basic, intermediate, and advanced levels.


Level 1: The Basic Low-Starch Diet. This introductory level is based on removing
the “worst offenders.” These are foods that are almost entirely starch or sugar,
have very low nutrient density, and can potentially damage the gut barrier
(such as wheat, oats, potatoes, and corn). Level 1 is the recommended starting
point for those with rheumatoid arthritis or mild psoriasis and for anyone who
needs a more gradual approach to reducing starch.

Level 2: The Intermediate Low-Starch Diet. In addition to eliminating grains
and legumes, level 2 removes the starchiest vegetables, nuts, and seeds, along
with high-lactose dairy. This level still includes some starch in the form of fruits
and vegetables with low to moderate starch levels such as bananas, winter
squash, and carrots. It also includes some nuts and seeds. This level is the
recommended starting point if you have inflammatory bowel disease, psoriatic
arthritis, juvenile arthritis, or moderate or severe psoriasis.

Level 3: The Advanced Low-Starch Diet. The advanced version of the low-
starch diet is intended for those with ankylosing spondylitis, who typically find
that they need to keep starch intake very low to control inflammation. This
level builds upon the intermediate level by also removing moderately starchy
fruits, vegetables, nuts, and seeds. The net result is a greater focus on animal
proteins and low-carbohydrate vegetables such as salads and leafy greens. This
level may also be needed by some people with psoriatic arthritis, particularly in
cases involving the spine or sacroiliac joints.

Whichever level you start with, it is important to note that your starch
tolerance may change significantly over time as your microbiome rebalances
and your gut heals. Once you have built a healthy population of good bacteria,
and suppressed the population of bad bacteria, you may be able to consume
more starch without triggering inflammation. Furthermore, as the gut lining
heals, your capacity to break down starch is likely to improve, which could
further increase your tolerance. Thus, after following the intermediate or
advanced low-starch diet for an extended period of time (such as six months),
you may be able to step down a level and expand your diet without reigniting
inflammation.
Note that each level of the low-starch diet focuses on the choice of
carbohydrate-containing foods, namely namely fruits, vegetables, seeds, nuts,
and to some extent dairy and grains. At all levels of the low-starch diet you are
encouraged to consume lean animal proteins and healthy fats, such as avocado
and olive oil. The rationale for emphasizing these particular protein and fat
sources is covered in chapter 6.
A printable summary of each level is available at
www.keystonebook.com/low-starch

Level 1: The Basic Low-Starch Diet

The basic level starts to dial back the damage to the gut by reducing fuel for
harmful microbes and eliminating foods that directly damage the gut lining,
such as gluten-containing grains.
This basic level is the recommended starting point for those with either
rheumatoid arthritis or mild psoriasis because these two conditions are less
likely to require a stricter avoidance of starch. You may also choose to start
with the basic level as an introductory phase to get used to reducing your
reliance on starchy foods and begin to observe how these foods impact your
symptoms. In addition, the basic level can be used as a long-term maintenance
program once you have healed your gut and microbiome.
There are four components to the level 1 low-starch diet: eliminating gluten-
containing grains, eliminating other starchy foods that can directly damage the
gut barrier or trigger inflammation (such as corn, soy, and potatoes), reducing
“safe starches” to no more than two servings per day, and avoiding added
sugar.

 Step 1. Eliminate all gluten-containing grains

The extraordinarily high prevalence of celiac disease in those with autoimmune
disease provides good reason to eliminate gluten, at least for a short-term trial.
Celiac disease is not only incredibly common in those with arthritis or psoriasis,
but it also often goes undiagnosed for decades. That is because many doctors
incorrectly believe that celiac disease always produces gastrointestinal
symptoms, so they don’t think to test for the condition. We now know that up
276
to two-thirds of cases of celiac disease are asymptomatic. We also know that
those with psoriasis are twice as likely to have celiac disease as the rest of the
277
population. Up to 40 percent of children with juvenile arthritis also have
278
celiac antibodies.
In individuals with celiac disease, gluten has a particularly severe impact on
intestinal inflammation and immune activation. The levels of celiac antibodies
also correlate with psoriasis and psoriatic arthritis severity. Those with the
highest levels of celiac antibodies have greater psoriasis activity and more joint
279
stiffness. The only way to reduce these antibodies is to strictly eliminate
gluten.
As we would expect, a gluten-free diet can have a major positive impact. In
one clinical study of psoriasis patients with elevated anti-gliadin antibodies, 75
280
percent saw a significant improvement on a gluten-free diet. Others have
281
since confirmed these findings. Similarly, in a study of patients with
rheumatoid arthritis, 40 percent of patients saw a significant improvement in
282
joint pain after one year of following a dairy-free and gluten-free diet.
Although the benefit of avoiding gluten is most dramatic for those with celiac
antibodies, frequent gluten consumption is likely problematic for all individuals
with autoimmune disease because of its adverse impact on intestinal
permeability.
Several studies have now found that gluten increases intestinal permeability
283
in everyone, not just those with celiac disease. This occurs in a variety of
ways, but the major mechanism is by triggering disassembly of the tight
284
junction complex that holds intestinal cells together. This effect is more
extensive and long lasting in celiac patients but still occurs in those without
celiac.
Importantly, the increased permeability in those without celiac disease may
still be enough to allow an increased level of bacterial by-products to cross the
285
gut barrier and cause widespread immune activation. This was shown in a
recent study on a group of patients having no antibodies or evidence of celiac
286
disease but who had some symptoms of gluten sensitivity. These patients
had a very high level of bacterial by-products in the bloodstream and elevated
markers of immune activation and intestinal cell damage. These signs all
reduced significantly after six months of following a gluten-free diet,
demonstrating that gluten can in some cases contribute to leaky gut and
widespread immune activation even without celiac disease.
Even though gluten is best avoided by those with autoimmunity, regardless
of whether or not you have celiac disease, it is useful to get tested for celiac
antibodies and/or a genetic predisposition to celiac disease, because that will
determine how careful you need to be to avoid accidental gluten exposure. If
you have celiac disease, the activation of autoimmunity can be quite severe
287
from consuming even a minuscule amount. Those without celiac disease do
not need to be as vigilant about avoiding gluten.

Gluten Contamination for Celiacs

If you do have celiac disease, even gluten-free grains should be approached
with caution because there is widespread gluten contamination in products
288
labeled gluten-free. Studies have reported that one-third of products made
from gluten-free grains contained gluten above the limit set by the FDA for
289
gluten-free labeling. In a 2014 study, five out of eight breakfast cereals
290
labeled gluten-free contained gluten above the limit.
The contamination of grains and seeds with gluten may occur at any point in
the supply chain, from farming to harvest to grain processing to food
manufacture. If you test positive for celiac antibodies, this frequent
contamination means there is value in avoiding all grain products, even those
marked gluten-free.
For those with celiac disease, there is also particular value in avoiding quinoa,
oats, and corn because these grains contain proteins similar to gluten that, in
291
some individuals, can activate an immune response in the same way.
(Additional problems with these particular foods are discussed further below.)
Avoiding contaminated and cross-reactive grains can dramatically improve
the health of those with celiac disease. This effect was recently reported by a
group of gastroenterologists at Johns Hopkins and Massachusetts General
Hospital. The doctors found that when individuals with celiac disease who
showed symptoms even on a strict gluten-free diet removed all grain and seed
products except for unprocessed rice, 80 percent had a complete resolution of
292
symptoms.

Step 2. Eliminate other gut-damaging foods

Many advocates for the paleo diet suggest that even gluten-free grains,
pseudo-grains, and legumes can damage the gut barrier and should be strictly
avoided by those with autoimmune disease. This proposition is somewhat
controversial, but there is persuasive evidence with respect to the following
foods:

Corn
Peanuts
Soy
Quinoa
Potatoes

These foods are worth avoiding because they are not only high in starch and
relatively low in nutrients, but they also contain “antinutrients” that are
potentially damaging to intestinal cells. These antinutrients include lectins (in
the case of peanuts, corn, soy, and potatoes), saponins (in the case of quinoa
and soy), and glycoalkaloids (in potatoes).
Lectins are proteins that stick to carbohydrates on cell surfaces. Plants likely
evolved these proteins as a self-defense strategy—a form of chemical warfare
against animals and fungi to protect the plant’s embryo (i.e., seed) from being
eaten. While lectins are found in many plant foods, the specific lectins found in
peanuts, soy, corn, and potatoes are the most problematic because these
particular lectins not only survive cooking and digestion but also can cross the
293
gut barrier and activate immune cells, triggering inflammation. They also
294
increase intestinal permeability.
In addition to lectins, potatoes contain another type of gut-damaging
compound called glycoalkaloids. In laboratory and animal studies, potato
295
glycoalkaloids were found to disrupt the intestinal barrier. Potatoes are
therefore among the first of the starchy foods we should try to eliminate.
Quinoa and soy also earn their place on the list of foods to avoid by virtue of
another type of antinutrient that can damage the gut barrier. They contain
saponins, which are soap-like molecules that can make holes in cells that lead
296
to cell death and potentially contribute to leaky gut. In animal and laboratory
studies, quinoa and soy saponins have been found to kill intestinal cells and
297
increase intestinal permeability. While there is currently no direct evidence
that the same thing happens in humans, it is best to err on the side of caution,
particularly given our overarching goal of reducing starch intake.
It should be noted that the potential harm associated with foods such as
corn, soy, and potato depends significantly on the amount consumed. Small
amounts present in supplements, medications, and sauces may not be worth
worrying about, particularly at the basic level when you are not strictly avoiding
starch. Fermentation also significantly reduces antinutrients such as lectins, so
fermented soy products such as tempeh, miso, and soy sauce may be less
298
problematic.
Another category of potentially gut-damaging foods that you may choose to
minimize or eliminate at this stage is the nightshade family of fruits and
vegetables. In addition to white potatoes (but not sweet potatoes or yams),
nightshades include

Tomatoes
Bell peppers/capsicum/sweet peppers
Chili peppers (and derivative spices such as cayenne,
paprika, and chipotle)
Eggplant

These foods are known for worsening arthritis symptoms for many people,
likely because they contain compounds that can potentially damage the
intestinal cells and activate the immune system, as discussed in further detail in
chapter 7. You may decide to start avoiding these foods right away, or hold off
and see how you respond to other dietary changes first.

Step 3. Limit other starchy foods to no more than two servings per
day

Level 1 of the low-starch diet allows for two small servings per day of starchy
foods. This is intended to keep the diet as broad as possible without providing
excess starch for unfriendly microbes. One serving is equivalent to 1 cup of
sweet potato, or ½ cup per day of rice, beans, or lentils. Yet this limit is only an
approximate guide. Individual tolerance levels vary greatly, and you may find
you do well with an even higher starch intake, particularly when you have
healed your gut and are following this basic level as a long-term maintenance
diet. Conversely, you may find that your inflammation does not improve
significantly while you continue to include starch in your diet, in which case you
can then progress to the intermediate or advanced level.
If you do tolerate moderate amounts of starch in your diet, the best use of
your daily quota is likely starchy vegetables such as sweet potatoes, parsnips,
and yams because these vegetables come with the added bonus of fiber,
vitamins, minerals, and antioxidants. Other starches to consider include

Soaked and pressure-cooked beans
Well-cooked lentils and split peas
White rice (including rice noodles)
Plantains

Not everyone will tolerate beans or lentils, but they have the particular
advantage of being very high in soluble fiber and therefore may help support
our beneficial microbes. The key to getting the most benefit from legumes is to
properly prepare them to eliminate lectins and other antinutrients. Unlike soy
and peanut lectins, the lectins found in legumes such as navy or kidney beans
299
can be largely eliminated by cooking for a sufficient length of time. Several
hours of boiling or 45 minutes of pressure-cooking was found to abolish lectin
300 301
activity in red kidney beans. The same is likely true for other similar beans.
Some lectin activity is still found in commercially canned beans, so these should
be cooked further before use.
Soaking beans for 12 to 24 hours before cooking is also recommended. This
helps eliminate other indigestible carbohydrates that cause gas and bloating
and allows for more even cooking. According to proponents of the Specific
Carbohydrate Diet, the legumes that are easiest to digest are navy beans,
lentils, peas, split peas, adzuki beans, and lima beans.
Rice is another relatively safe starch option for many people, although there
are some reports of individuals with celiac disease cross-reacting to rice. At
least from the perspective of antinutrients such as lectins, white rice is the best
choice because the antinutrients are concentrated in the bran—the outer
protective layer that is present in brown rice but removed to produce white
rice.
A particular type of white rice called glutinous or sticky rice may be even
better than standard white rice. This distinct species grown in Southeast Asia
contains highly branched starch (amylopectin). This type of starch is more
accessible to digestive enzymes and therefore a greater proportion is absorbed
before it feeds undesirable gut bacteria. The rapid digestion of glutinous rice is
reflected in its much higher glycemic index, which measures the rise in blood
302
glucose shortly after a food is consumed. Sushi rice also has a higher
glycemic index than conventional rice and is therefore more easily digested.
Whichever starches you choose to include, it is important to remain mindful
of quantities and limit intake to two small servings per day, at least until you
determine your own personal starch tolerance.

Step 4. Cut back on sugar

Many people with autoimmune conditions see significant improvement just by
reducing their overall sugar intake. In fact, several studies have reported a link
between excess sugar consumption and a variety of autoimmune conditions,
303
including inflammatory bowel disease and rheumatoid arthritis. As one
example, the large-scale Nurses Health Study found that women who
consumed at least one sugared soda per day had a 63 percent increased risk of
304
developing rheumatoid arthritis.
The inflammatory effect of sugar is likely due in large part to its impact on the
microbiome, because sugar readily feeds undesirable bacteria and yeasts. We
should therefore try to limit overall sugar intake, whether in the form of table
sugar or other natural sweeteners such as maple syrup and honey. At the
intermediate and advanced levels, this also means moderating fruit intake, but
at the basic level the goal is simply to reduce added sugars.

Table 1: Summary of the Basic Low-Starch Diet

Allowed Avoid
All fruits Grains other than rice
Vegetables Corn
(except corn and nightshades) Soy
Well-cooked legumes Peanuts
(except soy and peanuts) Quinoa
White rice Nightshades (potato, tomato, peppers)
Nuts and seeds Added sugars
Dairy
Meats
Fish
Eggs
Olive oil
Avocado oil

If you find that you do not improve sufficiently after following the basic level
for several months, you can either progress to the intermediate or advanced
low-starch diet, or experiment with eliminating common allergens, namely
nuts, eggs, and dairy (see chapter 7). Laboratory testing may be useful to guide
your choice at that point. For example, if testing for gut pathogens finds an
overgrowth of E. coli, a stricter approach to starch and sugars may be
warranted. If, however, allergy testing finds IgE or IgG antibodies to certain
foods, eliminating those foods may be the next best step.

Level 2: The Intermediate Low-Starch Diet

The intermediate level is the recommended starting point for those with
psoriatic arthritis, juvenile arthritis, inflammatory bowel disease, moderate or
severe psoriasis, SIBO, or a known pathogen overgrowth. This level builds on
the basic level by further reducing starches and focusing more heavily on
nonstarchy fruits and vegetables.
In addition to eliminating the gut-damaging foods that are removed with the
level 1 low-starch diet, at level 2 you will remove all grains, starchy legumes, a
few very high starch vegetables, and most dairy.
What remains is a relatively low-carbohydrate diet that heavily emphasizes
vegetables and lean proteins along with a moderate intake of fruit, olive oil, and
perhaps some nuts and seeds. This is an incredibly nutrient-dense diet that
provides everything you need to build a healthy microbiome, heal the gut
barrier, and allow the immune system to reestablish its normal equilibrium.

Legumes and Vegetables on the Intermediate Low-Starch Diet

Although level 2 excludes starchy legumes such as lentils and dried beans, you
can continue to include legumes with a green edible pod, such as green beans
and sugar snap peas. Tofu is relatively low starch but is best avoided due to the
gut-damaging effects of soy lectins.
Most vegetables are included in the intermediate low-starch diet, with the
exception of the very high starch vegetables such as sweet potatoes (see Table
2). Although these very high starch vegetables are typically root vegetables, not
all root vegetables are off limits. You can continue to include carrots, radishes,
rutabaga, celeriac, and beets, for example. Pumpkin and spaghetti squash can
also be lower in starch, although this is quite unpredictable.

Table 2: Vegetables and Legumes on the Intermediate Low-Starch Diet

Allowed Allowed Limit Avoid
Low starch (under 0.5 g Moderate starch (0.6–2 (2–5 g starch per 100 g (more than 5 g starch per
 starch per 100 g) g starch per 100 g) or F: high fructan) 100 g or *nightshade)

Artichoke heart Beansprouts, mung Acorn squashT Beans (other than green
Arugula/rocket Beetroot string beans)
Asparagus Brussels sprouts AsparagusF Black eyed peas
Bok choy Collard greens BroccoliF Chickpeas
Cabbage (all varieties) Green beans Butternut squashT Corn
Carrots Mustard leaves Frozen peas Eggplant*
CauliflowerT PumpkinT GarlicF
Lentils
Parsnip
CeleriacT RutabagaT LeekF Peppers*
Celery Snow peas
Collard greens OnionF Plantains
Spaghetti squashT Potato
Cucumber Sugar snap peas Split peas
Endive
Kale SwedeT Sweet potato
Taro
Kohlrabi Tomato*
Fennel Yam
Lettuce Yucca/cassava
Mushrooms
Pak choi
Radicchio
Radish
Shallots
Snow peas
Spinach
Spring mix
Spring onion
Scallion
Summer squash
Turnip
Watercress
Zucchini

T: starchy if unripe. Test with iodine. F: high fructan (individual tolerance varies). *: nightshade

Note that all tables can be downloaded in printable format at
www.keystonebook.com/low-starch

Throughout this chapter, the categorization of foods as low, moderate, or
high starch is based on McCance and Widdowson’s “The Composition of Foods
Integrated Dataset 2015,” which is published by the Department of Health in
England. This data, also referred to as the UK food composition tables, is based
on a vast set of analytical tests and scientific publications. Yet the data is not
always reliable, due to the unpredictability of starch content in certain foods.
For some fruits and vegetables, the starch content varies dramatically
depending on growing conditions and whether they were picked ripe. This
includes pumpkin, winter squash, avocados, apples, pears, and stone fruit.
These foods may be starchy when unripe and then become quite low in starch
as they ripen and the starches are converted to sugars.
If in doubt, you can test these and other foods with iodine solution, sold as
antiseptic in pharmacies. A drop of iodine will turn blue-black or dark brown on
foods that contain a significant amount of starch but remain light orange on
nonstarchy foods. Outside its peak season, pumpkin often tests very starchy in
this way, in contradiction to the official data that reports pumpkin as having
little to no starch.
In addition to avoiding vegetables that are very high in starch, some people
may find that they need to limit their intake of vegetables that are high in
fructans, such as onion, garlic, asparagus, and leeks. Fructans are chains of
fructose molecules, also known as fructooligosaccharides or inulin. These
carbohydrates are indigestible to humans but readily fermentable by gut
bacteria. The effects of fructans on the microbiome likely vary greatly between
individuals. Fructans definitely encourage the growth of beneficial species and
boost butyrate levels, but theoretically an excess may also worsen overgrowths
of species such as Klebsiella and E. coli. Many individuals with SIBO are also
sensitive to fructans. The best solution is likely to eat these vegetables
occasionally and not in excessive portions. You can also add garlic flavor to
recipes without adding any fructans by warming olive oil with sliced garlic and
then discarding the garlic solids. To add onion flavor to recipes, use the green
parts of scallions, also known as spring onions.

Fruits on the Intermediate Low-Starch Diet

All fruit is allowed at the intermediate level, but you may find you need to
moderate your overall fruit consumption, particularly when it comes to fruits
that are particularly high in fructose or are moderately starchy, such as
bananas.
People with significant gut damage often have difficulty absorbing large
305
amounts of fructose. Given our overarching goal of choosing carbohydrates
that are quickly and easily absorbed to avoid feeding bacteria in the small
intestine, it is best to limit fruit intake to two or three small servings per day.
You may be able to eat more fruit than this by focusing on fruits that are
naturally lower in fructose, such as oranges, honeydew melon, and cantaloupe.
Even so, these fruits contain other sugars such as sucrose, and so you may need
to experiment somewhat to determine your own personal limit.
It is particularly important to be mindful of portion size when it comes to
dried fruit. Raisins, dates, prunes, and other dried fruits are very concentrated
sources of fruit sugars, including fructose and sucrose. Dried fruits often also
contain substantial amounts of fructans, which are indigestible and highly
fermentable by gut microbes.

Table 3: Fruits on the Intermediate Low-Starch Diet

Low starch and Limit (high Limit (2–5 g starch
lower fructose fructose or per 100 g)
fructans)
Avocado Apples Banana (less starch when
Blueberries Apricot ripe)
Cantaloupe Cherries Citrus peel for baking
Clementine Dates Custard apple
Dragon fruit Figs Durian
Grapes Grapefruit Sapodilla
Honeydew melon Guava Unripe pear
Kiwi fruit Mango
Lemon Nectarine
Lime Peach
Lychee Plums
Orange Prunes
Paw paw/papaya Raisins
Pineapple Ripe pear
Pomegranate Watermelon
Raspberries
Rhubarb
Rockmelon
Starfruit
Strawberries
Tangerine



Sweeteners on the Intermediate Low-Starch Diet

Although it is best to minimize all added sugars, when a small amount of
sweetener is needed, what is the best choice? The Specific Carbohydrate Diet
recommends honey because it contains primarily fructose and glucose rather
than sucrose. Fructose and glucose do not need to be broken down by enzymes
before they are absorbed, so they are less likely to remain in the
gastrointestinal tract and feed undesirable bacteria and yeasts.
Yet honey is still a concentrated source of fructose and should only be used
occasionally. Given that many people with intestinal inflammation can only
absorb a small amount of fructose each day, it is probably better to use that
daily quota for whole fruit, which provides a multitude of vitamins as well as
polyphenols and fiber to feed our beneficial microbes.
An alternative option for a natural sweetener is brown rice syrup, which is
composed of single glucose subunits, along with maltose and maltotriose.
Maltose is simply two glucose units joined together, while maltotriose is three.
These molecules are broken down and absorbed very rapidly, so they are
unlikely to fuel bacterial overgrowth when used in reasonable amounts. In fact,
the glycemic index, which rates how quickly a food impacts blood glucose
levels, indicates that the sugars in brown rice syrup are absorbed almost as
quickly as pure glucose.
One concern with brown rice syrup is potential arsenic contamination,
because rice naturally absorbs arsenic from soil. To minimize arsenic levels, it is
best to buy rice syrup from reputable companies that test for and publish their
arsenic levels. Rice that is grown in California is also typically safer than rice
grown in other parts of the United States. For those in the United States,
Lundberg Farms is the best option and their rice crops consistently test below
the regulatory limits for arsenic.
Certain noncaloric sweeteners such as stevia and monkfruit extract can also
be used. It is better to avoid significant amounts of sweeteners made from
sugar alcohols (such as mannitol, xylitol, erythritol, and sorbitol), because these
can be readily fermentable by gut bacteria and have unpredictable effects on
306
the microbiome. Artificial sweeteners such as acesulfame potassium and
sucralose may also perturb the microbiome and encourage the growth of
pathogens such as E. coli, although research in this area is only just
307
beginning.


Nuts and Seeds on the Intermediate Low-Starch Diet

Most tree nuts are relatively low starch and are good sources of vitamins and
minerals. The most significant concern with nuts is that they are highly
allergenic. Thus it can be helpful to eliminate nuts from your diet for one or two
months and then monitor your reaction when you reintroduce them.
The nuts with the lowest starch content include pine nuts, walnuts, and
macadamias. Many people who follow the low-starch diet also report tolerating
blanched almond flour, which is particularly useful for baking. Other good flour
replacements for baking include coconut flour and ground flax seed.

Table 4: Nuts and Seeds on the Intermediate Low-starch Diet

Allowed Limit Avoid
(low starch) (2–5 g starch per 100 g) (more than 5 g starch per 100 g)
Almonds Cashew nuts
Brazil nuts
Coconut flour Chia seeds Chestnuts
Coconut milk without Chocolate Peanuts
additives Cocoa
Hazelnuts Pumpkin seeds
Desiccated coconut Quinoa
Flax seeds Hemp seeds
Sunflower seeds
Macadamias Pistachios Tigernuts
Pecans

Pine nuts
Sesame seeds

Tahini paste
Walnuts



Dairy on the Intermediate Low-Starch Diet

Many people with autoimmune disease do best when they completely avoid
dairy products, particularly products derived from cow’s milk. There are two
main reasons why dairy is so often problematic. The proteins found in dairy are
highly allergenic and often trigger inflammatory immune responses, especially
308
in individuals with celiac disease or rheumatoid arthritis (although some
people with cow’s milk allergies find that they do not react to goat or sheep’s
milk, perhaps because they have not yet had sufficient exposure to develop a
sensitivity).
The second problem with dairy is lactose, which is often poorly absorbed and
can provide fuel for harmful microbes. If you do not appear to have a sensitivity
to the proteins found in dairy and would like to include dairy in your diet, the
best option is homemade yogurt that has been fermented for at least eight
hours to reduce the lactose content.
Many healing diets also recommend the use of dairy-based fats such as ghee,
which contains little to no milk protein and is therefore thought to be safe for
those with dairy sensitivities. Yet the type of fat found in ghee is highly
inflammatory, as discussed in chapter 6, and is not recommended as part of the
Keystone Diet.
When looking for a low-starch replacement for dairy milk, options include
coconut milk, hemp seed milk, flax seed milk, and nut milks such as almond and
macadamia. Avoid products that contain added starches and thickeners such as
carrageenan and maltodextrin. The thickeners that are less concerning are guar
gum, gellan gum, locust bean gum, and gum arabic. Some of these gums are
prebiotics that are fermentable by gut microbes, but they do not appear to
preferentially encourage the growth of harmful species, unlike maltodextrin
309
and carrageenan.


Miscellaneous Items on the Intermediate Low-Starch Diet

At the intermediate level, it is worth looking for hidden sources of starches in
foods such as deli meats and yogurts. In addition to checking the ingredients of
packaged foods, you can consult the nutritional information for a rough
approximation of starch content. Simply subtract the grams of fiber and sugars
from the total carbohydrate content and the remaining grams of carbohydrates
are typically starches. (This is not always accurate, for example in products that
contain other nonstarch polysaccharides, but it gives general guidance.)
Products that are usually safe include fresh and dried herbs, tea, coffee,
gelatin, and collagen peptides. Collagen peptides are the best option for protein
powder for smoothies, because they are not only low starch but also contain
the precise amino acids needed for healing the skin, joints, and gastrointestinal
tract (gelatin has these same benefits).

Table 5: Miscellaneous Foods and Additives on the Intermediate Low-starch
Diet

Allowed Best avoided
 Baking soda Arrowroot
Bicarbonate of soda
Cellulose Carrageenan
Coffee Chicory
Collagen peptides Dextrose
Cream of tartar Fructooligosaccharides Inulin
Gelatin
Maize
Guar gum
Maltodextrin
Gum arabic
Xanthan gum
Herbs
Hypromellose
Magnesium stearate
Pectin

Spices
Tea



Level 3: The Advanced Low-Starch Diet

The advanced level is the recommended starting point for those with
ankylosing spondylitis or uveitis. It may also be the right level for those with
psoriatic arthritis that impacts the spine or sacroiliac joints. These particular
conditions have the strongest connection to gut bacteria that thrive on starch.
As a result, sometimes it is necessary to keep starch intake extremely low for
several months for pain to begin subsiding.
Level 3 provides a more aggressive approach to combating harmful microbes
with a stricter avoidance of starch and other carbohydrates and a heavy
emphasis on meats, fish, olive oil, and the very-low-starch vegetables.
At level 3, the allowed vegetables are those with less than 0.2 grams of starch
per 100 grams, which include salad vegetables, greens, mushrooms, and
cabbage. (See the full list in the table below.) The allowed fruits are those that
are low in starch and do not have an excess of fructose or fructans. Even then,
fruit intake is limited to one or two small servings per day, to keep total sugar
intake very low. The net result is that carbohydrates will typically be below 50
to 60 grams per day (or much lower if you exclude fruit and adopt a ketogenic
version of the diet). To ensure adequate energy with such a low-carbohydrate
intake, make sure that each meal includes at least 30 grams of protein and
some fat, such as a tablespoon of olive oil.

Table 6: Advanced Level Low-Starch Diet

Allowed Allowed Fruits Allowed Nuts, Allowed other
Vegetables (2 servings per day) Seeds
(0–0.2 g starch per 100 (2 tablespoons per day)
g)
Arugula Avocado Chia seeds Baking soda
Cabbage Blueberries Coconut (milk, fresh, Brown rice syrup
Celery Cantaloupe flour, or desiccated) Coffee
Courgette Clementine Flax seeds Collagen peptides
Cucumber Dragon fruit Macadamia nuts Gelatin
Endive Grapes Pine nuts Herbs
Fennel Honeydew melon Walnuts Tea
Kale Kiwi fruit
Kohlrabi Lemon
Lettuce Lime
Mushrooms Orange
Radicchio Papaya
Radish Paw paw
Scallions Pineapple
Spinach Raspberries
Spring mix Rhubarb
Spring onions Rockmelon
Summer squash Starfruit
Watercress Strawberries
Zucchini Tangerine


The advanced approach likely represents a dramatic shift from your usual
diet, but it offers the best chance of producing rapid results. It also has the
advantage of simplicity. You will be starting from scratch with a relatively short
list of basic ingredients. Once you start to see results from this approach, you
can then expand your diet and determine how much starch you can tolerate.
After following this advanced level for three to six months, you may decide to
introduce additional vegetables that typically contain only very small amounts
of starch, such as carrots and Brussels sprouts. You can also experiment with
reintroducing small portions of the fruits that are higher in fructose and
fructans, as listed in the table for the intermediate level (such as apples, pears,
apricots, and cherries).
Note that the advanced level does not include asparagus, onion, leek,
broccoli, or cauliflower, despite the fact that they are quite low in starch. These
vegetables (and garlic, which is somewhat starchy) are omitted from the “safe
list” because they contain a significant amount of fructans such as inulin, which
can potentially feed both beneficial and harmful microbes. The most cautious
approach is to omit high-fructan foods during the initial stage of the advanced
low-starch diet, but you may find that you can reintroduce them without any
problems.
During the initial stage when you are trying to keep starch intake very low to
determine how you respond, it may be worth testing certain fruits and
vegetables with iodine. A drop of dilute iodine solution (sold as antiseptic in
pharmacies) will turn blue-black or dark brown on foods that contain a
significant amount of starch.
Some proponents of the low-starch diet for ankylosing spondylitis suggest an
even more extreme approach to vegetables: limiting the diet to those that
contain no starch, rather than allowing trace amounts. Based on the UK food
composition data, this would allow lettuce, cucumbers, mushrooms, and
cabbage but exclude kale, zucchini, and spinach. The concern with this
approach is that it becomes more difficult to ensure adequate fiber intake.
A high-fiber diet is imperative because fiber not only supports our beneficial
microbes, as discussed earlier, but also helps suppress the harmful bacteria. In
the study comparing the microbiomes of children in Africa with a high-fiber diet
to children in Europe, the African children had significantly lower levels of
310
harmful bacteria such as Klebsiella and E. coli. Fiber from vegetables may
also interfere with the ability of E. coli to adhere to and invade intestinal
311
cells. A vegetable-rich diet is therefore one of the best ways to arm our
defenses against bacteria that can trigger autoimmunity.


Avoiding Other Hidden Starches at the Advanced Level

At level 3 it may be worth avoiding even small amounts of starches that are
hidden in unexpected places. If you decide to try baking (using blanched
almond meal, coconut flour, or ground flax as the flour replacement), note that
conventional baking powder usually contains cornstarch, for example. To avoid
this, you can make your own baking powder using bicarbonate of soda and
cream of tartar. (Half a teaspoon of cream of tartar plus a quarter of a teaspoon
of bicarbonate of soda is equivalent to one teaspoon of baking powder.)
When it comes to spices, the UK food composition tables indicate that most
spices do not contain starch, but some followers of the low-starch diet report
reacting to spices, perhaps because unlabeled starches are used during the
manufacturing process. Ginger and mustard do contain some starch, although if
the amounts used are very small, the starch content may not be significant.

Table 7: Miscellaneous Foods and Fillers on the Advanced Diet

Allowed Better to avoid Not Allowed
Cellulose Arrowroot
Ginger Baking powder
Gelatin Carrageenan
Guar gum Mustard
Chicory
Spices
Corn starch
Gum arabic
Xanthan gum Dextrose
Hypromellose
Fructooligosaccharides
Magnesium stearate Inulin
Pectin Maize

Maltodextrin

Modified food starch

Potato starch

Tapioca starch



As for fillers in supplements such as vitamins and probiotics, the amount of
starch present is often very small. Nevertheless, some people see better results
by erring on the side of caution and avoiding supplements and medications that
list starch or maltodextrin as ingredients. When shopping for alternative
products, the best fillers for capsules are cellulose, methylcellulose, and lysine.
Liquid-based and gel-cap formulations are also good options.
At the advanced level you may also decide to avoid probiotics that contain
added prebiotics, such as fructooligosaccharides (FOS). At the time of writing,
probiotics brands without starch, maltodextrin, or fructooligosaccharides
include

Pearl’s Digestion and Immunity
BioGaia Protectis
Renew Life
GutPro
BioK+ Capsules, dairy and soy versions
Florastor


Dairy on the Advanced Low-Starch Diet

Like the intermediate level, the advanced level discourages dairy because of the
prevalence of immune reactions to dairy proteins. The lactose in dairy can also
promote the growth of undesirable gut microbes. If you do not appear to have
an allergy or sensitivity to the proteins found in dairy and would like to include
it in your diet, the best option is homemade yogurt that has been fermented for
at least eight hours to reduce the lactose content.


A Ketogenic Version of the Low-Starch Diet

It is important to note that the advanced low-starch diet can be a ketogenic diet
if you choose, but it does not need to be. A ketogenic diet involves drastically
limiting carbohydrates and relying on the conversion of fat into ketones for
fuel. In practice, this usually means having no fruit or other carbohydrate-rich
foods and significantly increasing fat consumption.
When carbohydrate intake is kept very low for several days, the metabolism
shifts from primarily carbohydrate-burning mode to primarily fat-burning
mode. The liver begins converting fat to ketones, which can then be used for
energy by most cells of the body. After several weeks of producing and using
ketones as a primary energy source, the metabolism becomes very efficient at
burning fat and one is said to be “fat adapted.” To make this shift, people
typically need to consistently keep net carbohydrate intake below 20 to 40
grams per day (excluding fiber) while significantly increasing fat intake. Most
people following a ketogenic diet will obtain approximately 75 percent of
calories from fat (approximately 100 to 150 grams) while also limiting protein
intake in order to maximize ketone production.
The ketogenic diet was originally developed in the 1920s as a treatment for
epilepsy. The goal was to mimic fasting, which was known to control seizures. It
has since become a popular approach for weight loss and for treating a variety
of other medical conditions involving the brain, such as multiple sclerosis,
Alzheimer’s, and Parkinson’s disease. The ketogenic diet also shows some initial
promise in the treatment of psoriasis and arthritis. As just one example, doctors
in Italy reported that a ketogenic diet was able to completely clear psoriasis and
psoriatic arthritis in a patient who had severe symptoms even after 12 months
 312
of treatment with Humira.
Indeed, some people respond very well to a ketogenic diet and find that it
eliminates carbohydrate cravings while providing steady energy levels
throughout the day. Others do not fare as well and instead experience flu-like
symptoms, particularly when first starting the ketogenic diet. These immediate
side effects are typically caused by electrolyte imbalances. The kidneys function
differently when you are in ketosis and excrete more water and sodium. If too
much sodium is lost, the body will try to maintain the balance between sodium
and potassium by also excreting more potassium. This loss of electrolytes, along
with dehydration, can then lead to muscle cramps, fatigue, and feeling light-
headed.
To circumvent this downward spiral, it is useful to consume at least half a
teaspoon of salt per day, along with adequate water and perhaps a magnesium
supplement. (You should also proceed with a low-carbohydrate diet only under
medical supervision if you have a chronic condition such as diabetes or high
blood pressure, because the dose of your medication may need to be adjusted.)
A ketogenic diet can also have more significant adverse effects over the
longer term, with some people experiencing worsening fatigue, insomnia, or
suppressed thyroid or adrenal function after following a ketogenic diet for
several months. This likely happens because when insulin is kept very low, less
of the active thyroid hormone (T3) is produced. The adrenal glands are also
called upon to produce more cortisol, and it is thought that this can eventually
313
become a stressor to the adrenals in some individuals.
Additional demands on adrenal function may be particularly problematic for
those with ankylosing spondylitis or psoriatic arthritis because it was recently
discovered that these conditions are already associated with a greater risk of
314
adrenal insufficiency. Poorly functioning adrenal glands can manifest as
fatigue, dizziness, low blood pressure, excess thirst, and worsening
inflammation.
It may be possible to reap many of the benefits of a low-carbohydrate diet
while minimizing these hormonal disruptions by keeping protein intake fairly
high, reflecting an approach more like the Atkins diet. A true ketogenic diet
limits protein intake because it triggers the release of insulin and glucagon,
which temporarily inhibits ketosis. A reduction in ketone production may be
suboptimal for endurance athletes or those with certain neurological diseases,
but it is likely not a problem for those who simply want to rely primarily on fat
and protein for fuel.
Humans can readily burn protein for energy. Indeed, most amino acids can
be broken down and used directly in the energy-producing Krebs cycle. In
addition, as long as carbohydrate intake is fairly low we can burn fat for fuel
through fatty acid oxidation, even if we are not in ketosis.
This combination of higher protein, low carbohydrates, and moderate fat has
actually been studied extensively in the context of epilepsy, where it is referred
to as the modified Atkins diet. This diet was developed at Johns Hopkins
Hospital as an attempt to create a more palatable and less restrictive treatment
alternative to a ketogenic diet. It limits carbohydrates to 20 grams per day with
no limits on protein. Typically, 30 percent of calories per day come from protein
and 60 percent from fat. (A ketogenic diet typically has around 15 percent of
calories from protein and 80 percent from fat). In more than 30 studies, the
modified Atkins diet was found to be as effective as a ketogenic diet for
315
controlling epilepsy, and much easier for patients to maintain long term. As
physicians at Johns Hopkins commented, “we suspect that the incidence of
adverse effects, especially the long-term ones, may be less than with the
316
ketogenic diet because of the inherently higher protein content.”
In short, for many people it is not necessary to follow the stringent ketogenic
diet requirements of being very low carbohydrate, low-to-moderate protein,
and very high fat. We can instead adopt a diet that is generally low
carbohydrate, high protein, and moderate fat. This ratio will happen naturally
on the advanced low-starch diet because the core of the diet is nonstarchy
vegetables, lean animal proteins, and olive oil. If you would like confirmation
that you are eating the right amounts, you can use a free carbohydrate tracking
phone app, such as Carb Manager, to measure your intake over the course of
the day. The app allows you to set a target for protein, fat, and carbohydrates
and track your progress. (You may, for example, aim for 50 grams of
carbohydrates, 110 grams of fat, and 140 grams protein each day.)
Prioritizing higher protein intake over higher fat intake may be advantageous
for many reasons. Additional protein not only prevents our hormonal systems
from going into starvation mode but also provides more of the amino acids,
vitamins, and minerals needed to build muscle and repair the skin and joints.
Being able to obtain sufficient energy without an extremely high fat intake is
also beneficial, given that diets very high in fat can increase intestinal
permeability and dramatically increase the level of bacterial endotoxin
 317
(lipopolysaccharide) in the blood.
As will be explained in chapter 6, the traditional sources of fat used by most
people following a ketogenic diet, such as butter and coconut oil, are especially
inflammatory. In any diet that keeps carbohydrate intake very low, moderate
amounts of fat are useful to ensure adequate energy, but we can minimize
inflammation by relying on the fats typically used in the Mediterranean diet,
such as avocados, nuts, and olive oil.
A low-carbohydrate diet should also continue to emphasize high-fiber
vegetables that can feed the microbiome. Good options include kale and
cabbage, along with high-fiber seeds such as chia and flax.

Example daily meal: low carbohydrate, high protein, and moderate fat

Breakfast
Smoothie with 2 scoops collagen peptides, 1/3 cup frozen
blueberries, ½ cucumber, 1 tablespoon flax seeds, ice, and water
Deli meat roll-up with ham, turkey, avocado, and lettuce

Lunch
Salad with canned salmon, shredded cabbage, celery, scallions,
parsley, baby spinach, olive oil, lemon juice

Dinner
Grilled chicken breast
Zucchini, kale, and mushrooms sautéed in olive oil
½ cup honeydew melon


 Chapter 6. Anti-inflammatory Fats and Oils


Modifying our diet to include more of the foods that feed our beneficial
microbes, and less of the foods that feed the harmful species, is just one piece
of the puzzle. Another important way in which we can use food to calm the
immune system is by choosing the right fats and oils. Specifically, the fats that
are emphasized in the Mediterranean diet.
The Mediterranean diet has long been hailed as one of the healthiest diets by
a variety of measures. It is correlated with a longer life expectancy and a lower
318
risk of heart disease, cancer, and diabetes. Most importantly for our
319
purposes, the Mediterranean diet also lowers inflammation. As a result, it
can significantly reduce the severity of symptoms in people with psoriasis or
320
arthritis.
It appears that three specific components of the Mediterranean diet convey
most of the anti-inflammatory effect: fish, olive oil, and antioxidant-rich
vegetables. The importance of including vegetables with the highest
antioxidant content was covered in chapter 4. This chapter focuses on how to
get the most benefit from fish and olive oil, along with the specific problems
with other fat sources.

The Power of Fish and Olive Oil

In those with psoriasis or rheumatoid arthritis, a higher consumption of fish and
olive oil directly correlates with milder symptoms and lower levels of
321
inflammatory markers.
In one study illustrating this effect, Swedish researchers asked 50 patients
with rheumatoid arthritis to follow a “Cretan Mediterranean” diet, which is rich
in fish and olive oil. After only three months, the patients following the
322
Mediterranean diet improved significantly compared to the control group.
This improvement was reflected in a wide variety of clinical measures, including
a reduction in the number of tender and swollen joints and lower levels of
inflammatory markers such as C-reactive protein (CRP). Notably, the patients
who improved the most were the ones with the highest intake of omega-3 fats
323
from fish.
 Similarly, a diet carefully designed to be high in omega-3 fatty acids was
324
found to reduce the severity of psoriasis in three months. An observational
study performed in Italy also found that the more closely people with psoriasis
325
followed the Mediterranean diet, the lower their psoriasis severity. In that
study, olive oil and fish consumption were the most important dietary factors.
These studies fit together with the immense body of research showing that
the omega-3 fats found in fish can inhibit the production of inflammatory
mediators. This effect is similar to the way in which nonsteroidal anti-
inflammatory medications (NSAIDs) work, but the effect of omega-3 fats is in
326
fact much broader, suppressing inflammation in a variety of ways.
There is also a vast body of research showing that specific components in
olive oil can protect against oxidative damage and inhibit the synthesis of
327
inflammatory mediators. After just a single meal including extra-virgin olive
oil, a reduction in inflammatory markers and oxidative stress can be detected in
328
the bloodstream. When consumed regularly, this translates into improved
symptoms of inflammatory diseases. In a double-blind, randomized study, olive
329
oil significantly decreased symptoms of rheumatoid arthritis.
Fish oil actually has even greater effects on inflammation than olive oil, but
330
the two appear to work best together. Studies have found that when a
combination of fish oil and olive oil is compared to a fish oil supplement alone,
331
the combination wins. Omega-3 fats and olive oil yield a quicker and more
significant drop in inflammation when used together than alone. The reduction
in inflammation is greater still when omega-3 fats are added in the context of a
332
diet low in omega-6 fats, discussed further below.
To fight inflammation, the type of omega-3 fat is important. The two most
useful forms are docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA),
found in fish. The types of omega-3 fats found in plant sources (such as flax
seed) have only limited anti-inflammatory effects, and humans cannot
333
effectively convert these fats to EPA or DHA.

Choosing the Best Fish

The following fish are the best choices to include in your daily diet because they
are high in EPA and DHA but low in mercury:

Salmon (farmed and wild)
Sardines
Farmed rainbow trout
Atlantic mackerel
Herring

These fish have five times more omega-3 fat than typical fish and should be
eaten two or three times per week.
Cod is another fish that is usually very low in mercury, but it has too little
omega-3 fat to combat inflammation. Sole is probably a better choice, with
about one-third the omega-3 levels of salmon and low mercury levels. Many
other fish that have substantial amounts of omega-3 fats, such as halibut,
albacore tuna, king mackerel, and swordfish, are simply too high in mercury to
eat regularly. A more detailed comparison of the omega-3 and mercury levels
334
of some popular fish is set out in the table below. A printable version is
available online at www.keystonebook.com/resources.

The Best Fish: High omega-3, low mercury

Fish DHA + EPA Mercury (ppm)
per 100 g (3.5
oz.)
Salmon, Atlantic, farmed 2.1 0.02
Salmon, Atlantic, wild 1.8 0.05
Herring 1.7 0.06
Salmon, pink 1.3 0.04
Salmon, sockeye 1.2 0.04
Mackerel, Atlantic 1.2 0.05
Farmed trout 1.2 0.03
Salmon, coho, wild 1.1 0.04
Sardines 1.0 0.08

Good Fish: moderate omega-3, low or moderate mercury

Fish DHA + EPA Mercury (ppm)
per 100 g (3.5
oz.)
Mackerel, chub 1.8 0.1
Sablefish (black cod) 1.8 0.2
Halibut, from Greenland 1.2 0.2
Sole 0.5 0.09
Hake 0.5 0.2
Flounder 0.5 0.1
Tuna, yellowfin, canned 0.3 0.1
Tuna, light, canned 0.3 0.1
Snapper 0.3 0.2
Skipjack tuna 0.3 0.2
Perch 0.3 0.1
Haddock 0.2 0.2
Cod, Atlantic 0.12 0.03

Moderate Mercury (no more than 2 or 3 times per month)

Fish Mercury
(ppm)
Halibut, Pacific 0.3
Tuna, albacore, canned 0.3
Grouper 0.4
Mackerel, Spanish 0.4
Bass, Chilean 0.4
Orange roughy 0.5

Avoid: High in mercury

Fish Mercury
(ppm)
Marlin 1.5
Mackerel, king 1.1
Swordfish 0.9
Tuna, Bluefin 0.8

Choosing salmon over tuna is an important step to limit your mercury
consumption if you eat fish regularly. A small can (3.5 oz.) of albacore tuna has
approximately 75 percent of the weekly limit for mercury, while the mercury
level in some types of tuna served at sushi restaurants (such as bigeye and
bluefin) is higher still. Even the lowest-mercury tuna, such as canned chunk
light, has 27 percent of the weekly limit of mercury in a small serving. By
comparison, the same-sized serving of salmon has only 2 percent of the
mercury limit. To look up mercury levels for other fish species, consult the
Environmental Defense Fund Seafood Selector tool, available online at
http://seafood.edf.org/.
Although wild-caught fish is generally preferable to farmed, the amount of
omega-3 fat is similar in farmed and wild salmon. It is actually sometimes
335
higher in farmed salmon due to the higher overall fat content. Farmed
salmon does pose some concern with respect to antibiotic use and potential
environmental harm, but this can be minimized by only purchasing from
sources such as WholeFoods, which impose strict standards on suppliers.
Another cost-effective option is to buy frozen wild salmon in bulk.
If budget allows, grass-fed beef is also a relatively good source of omega-3
336
fats, with levels approximately three times higher than conventional beef.

Fish Oil Supplements

Can you just take a fish oil supplement instead of eating fish? There is some
controversy on this point, but on balance the research suggests that fish oil
supplements are effective in reducing inflammation and improving the
symptoms of psoriasis and arthritis.
Numerous double-blind, placebo-controlled studies have found a consistent
benefit of fish oil supplements, particularly at relatively high doses (3–4 grams
337
per day) and when taken for several months. This benefit is seen in
338 339 340
psoriasis, rheumatoid arthritis, ankylosing spondylitis, Crohn’s
341 342
disease, and juvenile idiopathic arthritis. Supplementing with additional
fish oil has also been found to enhance the anti-inflammatory effect of a low-
343
carbohydrate Mediterranean diet.
344
Despite decades of positive results in clinical trials, controversy has arisen
in the past few years about whether supplements may do more harm than
good on the basis that the omega-3 fats in fish oil are prone to oxidation.
Omega-3 fats are polyunsaturated, which means they are long-chain fats
with many double bonds. These double bonds are inherently unstable. At each
double bond, the fat molecule can be oxidized (by losing a hydrogen atom and
ending up with a free radical), triggering chemical reactions that produce a
variety of different compounds. Some of these compounds are inflammatory,
345
theoretically undermining the anti-inflammatory effect of the fish oil.
Oxidation is more prevalent in fish oil than fish itself because oxidation
occurs during processing and storage of the isolated oil. Investigations of the
extent of this problem have yielded conflicting results; depending on the study,
anywhere between 10 percent and 75 percent of fish oil supplements exceed
346
oxidation limits.
Given the prevalence of oxidation in fish oil, experts conclude that “it is likely
that the omega-3 supplements used in many clinical trials have also been
347
significantly oxidized.” Yet the results of these trials are overwhelmingly
348
positive, particularly when high doses are given. Any oxidation that occurred
to the fish oil supplements used in these studies therefore did not cancel out
the therapeutic effects.
It is also worth noting that the average amount of oxidation products
measured in fish oil supplements is comparable to that found in conventional
349
cooking oils. By eliminating these oils (discussed further below), it is possible
to take fish oil supplements without adding to the overall burden of oxidized
lipids. Indeed, studies adding a fish oil supplement in combination with a diet
eliminating vegetable oils show the best results. In one such study, more than
half of the patients had a moderate to excellent improvement in their psoriasis,
 350
while another 20 percent had a mild improvement.
Fish oil supplements have been found to be helpful in the context of
351
aggressive medical treatment of rheumatoid arthritis. In a study at the Royal
Adelaide Hospital in Australia, patients taking a high-dose fish oil (5 grams of
EPA and DHA per day) were twice as likely as those taking a low dose (0.4 g) to
achieve remission while on “triple DMARD therapy” (methotrexate,
sulphasalazine, and hydroxychloroquine). Fish oil supplements can therefore
effectively complement conventional medical approaches.
The major advantage of fish oil supplements over just eating more fish is the
ability to reach a high daily dose. It may take at least 3–4 grams per day of EPA
352
and DHA to make a significant difference to psoriasis and arthritis, which
would require 5 to 6 ounces of high omega-3 fish every day. (In children with
353
juvenile arthritis, a dose of 2 grams per day was effective. ) To meet the daily
goal, it is probably easier in the long term to eat salmon, sardines, or mackerel a
few times per week and add a daily fish oil supplement of 2–4 grams (2000–
4000 mg).
We can also take steps to choose a fish oil supplement that is less likely to be
oxidized. The most important factor seems to be the freshness of the
supplement; in one study, almost all tested fish oil products that were more
354
than 2½ years from expiration had low levels of oxidation. Some other
factors to consider when choosing a supplement:

Light is a major contributor to oxidation during storage, so
choose a product in a dark or opaque bottle.
Krill oil has been found to have particularly high oxidation
355
levels.
356
Soft gels have lower levels of oxidation than bulk oil.
Oils in triglyceride form are better absorbed than other
357
forms.
If in doubt, cut open a capsule to smell and taste the oil. It
should be only mildly fishy and not smell rancid.
Look for a high concentration of EPA and DHA per capsule—
at least 1000 mg.

One excellent choice is Nordic Naturals Ultimate Omega 2X. The company
uses a proprietary oxygen-free manufacturing process to prevent oxidation and
reports that the oxidation markers in their products are well below standard
limits. Another good choice is Garden of Life Minami Platinum, which is
produced using a carbon dioxide process to limit oxidation; the company also
reports having independent lab verification of acceptable oxidation levels.
Like any supplement, check with your doctor before starting a fish oil
supplement. There is some concern that it may increase bleeding risk in those
taking blood-thinning medication, although this has not actually been observed
358
in tests of moderate doses of fish oil in combination with warfarin.

Buying Olive Oil

Like fish oil and other cooking oils, olive oil contains polyunsaturated fats that
are prone to damage, although in a much lower concentration than seed and
fish oils. Fortunately, olive oil also contains dozens of antioxidant compounds
that help protect the oil from oxidation.
Extra-virgin olive oil has a higher level of these compounds than virgin or
“light” olive oil. Many countries have strict guidelines for oil to meet the “extra
virgin” description. Unfortunately, not all oil labeled as extra-virgin olive oil
actually is. In 2010, researchers at the University of California found that the
majority of olive oil samples tested did not meet U.S. or international standards
for “extra virgin” status, usually because the oils were oxidized or poor
359
quality. Two brands that did meet the standards were California Olive Ranch
and Costco’s store brand, Kirkland Signature.
Beyond those two brands, the Australian and Californian certifications for
olive oil are good signifiers of quality, as is the presence of a harvest date
printed on the bottle. Experts recommend only buying olive oil within 15
months of the harvest date. In addition, you can usually taste and smell
whether olive oil is fresh and good quality. Good-quality extra-virgin olive oil
will taste slightly bitter and peppery, be greenish in color, and have a fresh,
grassy scent. Oxidized or poor-quality oil will smell musty, waxy, or rancid. To
further minimize oxidation and preserve polyphenol content, buy olive oil in a
dark glass bottle and store it in a cabinet, not next to the stove.
There is some controversy about whether cooking with olive oil is a good
idea, but the current balance of the research suggests that olive oil is
sufficiently stable to cook with, particularly at moderate temperatures. While it
does contain polyunsaturated fats, olive oil also contains more than 20
 360
different antioxidant compounds that limit oxidation during cooking.

Avocado and Avocado Oil

Avocado is another good source of anti-inflammatory fat. As in olive oil, the
predominant fat found in avocado is mostly the monounsaturated fat oleic acid.
Processed avocado oil also has a level of oxidative stability during cooking
similar to that of olive oil. It is, however, quite vulnerable to oxidation if
exposed to light at room temperature for long periods of time, so it should be
361
purchased in a dark bottle. Fresh avocados are even better because they are
particularly rich in antioxidants such as vitamin E.

Oils to Avoid

Using olive oil as the primary oil also makes it easier to sidestep the two
categories of fats that contribute most to inflammation: refined seed oils and
saturated fat.

Seed Oils

Refined seed oils such as canola, soy, and sunflower contain significant
362
amounts of polyunsaturated fats, which are quite unstable. As a result, these
363
oils readily oxidize when exposed to heat or light. Consuming too many
oxidized fats contributes to inflammation in a variety of ways, including by
364
increasing oxidized LDL.
In contrast, olive oil contains only around 10 percent polyunsaturated fats,
along with a high concentration of antioxidant polyphenols that limit oxidation.
Olive oil can therefore withstand some cooking without oxidizing
365
significantly.
The fats in seed oils are also problematic because they are more readily
366
converted to trans fats, particularly after cooking at high heat. Trans fats can
increase inflammation throughout the body (reflected in higher levels of TNF,
367
IL-6, and CRP, for example). Olive oil is therefore clearly a better choice and
oils such as canola and sunflower oil should only be used occasionally. If you
find that you need to use seed oil regularly, high oleic safflower oil is the best
choice, having a composition closer to olive oil.
Note that nut oils should also generally be avoided because they are readily
368
oxidized. Macadamia nut oil may be the exception because it is mostly
monounsaturated fat, which is more stable.

Saturated Fats

To followers of health news, advising against saturated fat may seem
antiquated. Saturated fat has long been vilified for playing a role in heart
disease, resulting in a shift away from animal fats and toward refined vegetable
oils from the 1960s to 1990s. Starting around 2007, the link between saturated
fat and heart disease began to be seriously questioned, with high-profile
studies over the subsequent decade finding no impact of saturated fat on the
369
risk of dying from heart disease. As that controversy continues, there has
been a major shift toward using more saturated fats such as coconut oil, ghee,
and palm oil, particularly among followers of the paleo diet.
While some of the authors who originally popularized the paleo diet have
cautioned against excessive saturated fat (namely Loren Cordain, Robb Wolf,
and Sarah Ballantyne), many other advocates for the paleo diet maintain that
saturated fat is healthy and recommend coconut oil and ghee as primary
cooking fats.
But saturated fat is definitely a problem for those with inflammatory
diseases, as several groundbreaking studies have now revealed. In one study
published in the journal Metabolism in 2016, a randomized crossover trial
compared the effects of a high palmitic acid diet or high oleic acid diet in 12
370
young women for three weeks. (Palmitic acid is a common saturated fatty
acid, and oleic acid is the monounsaturated fat in olive oil.) The researchers
looked at inflammatory mediators in the bloodstream and levels secreted by
immune cells when stimulated with bacterial by-products. Even over this very
short time period, the diet high in saturated fat resulted in higher levels of
inflammatory mediators, including IL-6 and IL-1β, both of which are implicated
in psoriasis and arthritis.
In a similar study published in the Journal of Nutritional Biochemistry,
researchers found that when healthy adults reduced their normal consumption
of palmitic acid for three weeks, their immune cells produced significantly
lower levels of inflammatory mediators such as IL-1β and TNF. When the
volunteers then increased their consumption of palmitic acid, TNF in the
371
bloodstream increased.
The findings from these human studies are consistent with what has recently
been discovered at a molecular level: saturated fats can activate key receptors
(called TLR-4 and NLRP3) and thereby trigger the release of inflammatory
372
cytokines. In this way, saturated fats stimulate inflammation in a range of
373 374
different cell types, including various immune cells, skeletal muscle, the
375 376 377
cells lining coronary arteries, the placenta, and brain cells.
At a practical level, this research means that those with inflammatory
diseases should definitely try to minimize saturated fat. The long-chain
saturated fats found in palm oil and animal-based cooking fats are likely the
378
worst. The medium-chain saturated fatty acids found in coconut oil are still
379
inflammatory, but to a lesser degree.
Yet coconut oil may contribute to inflammation in another way—by
facilitating the transport of bacterial by-products across the intestinal wall. As
discussed earlier, endotoxin, also known as lipopolysaccharide, is a component
of certain gut bacteria that can trigger systemic inflammation when it crosses
into circulation. Even a small amount of endotoxin can trigger a widespread
inflammatory response.
In a well-designed randomized study involving 20 healthy adults and
published in 2016, researchers found that fish oil decreased the level of
endotoxin in the bloodstream after a meal, whereas coconut oil significantly
380
increased it. Olive oil and grapeseed oil had little effect.
It appears that the fats in coconut oil have a somewhat unique ability to
381
facilitate the transport of endotoxin across the gut barrier. Animal and
laboratory studies have found that the transport of endotoxin across the
intestine was 60 percent higher in the presence of coconut oil, even without
382
any observable harm to the integrity of the gut barrier. Researchers now
believe that the fatty acids in coconut oil help to form “lipid rafts” that
383
transport endotoxin across the gut barrier.
Taken together, the new research on saturated fats gives us good reason not
to add additional saturated fats to our diet through coconut oil, butter, palm
oil, or animal-based cooking fats. Avoiding these added fats allows room in the
diet for the small amounts of saturated fat found in lean animal proteins. A
chart setting forth the best choices for animal proteins is provided at the end of
this chapter.


Omega-6 Fats

Another concern with animal-based fats is that they can be very high in a
particular type of omega-6 fat called arachidonic acid (AA). Some forms of
omega-6 fat, like the linoleic acid found in nuts and seeds, appear to have little
384 385
impact on inflammation. Yet high levels of arachidonic acid—the type
found in many animal foods—has been implicated in psoriasis and other
386
inflammatory conditions.
This is not sufficient reason to avoid animal-based proteins. Vegetarian and
vegan diets are surprisingly not that effective for controlling psoriasis or
arthritis. Arachidonic acid would be very low in a vegan diet, but the results of
387
experiments involving vegan diets for arthritis have been disappointing. In
one of the few studies showing any significant benefit of a vegan diet, the
researchers concluded that the reduction in arthritis symptoms was most likely
388
due to the fact that the experimental diet was also gluten-free. More
recently, a diet carefully designed to be low in arachidonic acid showed just a
14 percent reduction in the number of painful joints in patients with
389
rheumatoid arthritis.
Strictly excluding arachidonic acid is therefore not worthwhile, but it may be
wise to avoid the foods that contain extremely high levels of this fat.

Fatty pork such as bacon
Organ meat
Walnut oil
Farmed tilapia
Wild rainbow trout

The true value in lowering your intake of arachidonic acid may actually be
that doing so can help you get the best results from adding more fish and fish
oil. That is because omega-3 fats are much better at suppressing inflammation
390
in the context of a lower intake of arachidonic acid.


 Fats and Oils in Summary

The fats at the core of Mediterranean diet have an extraordinary ability to
reduce inflammation. We should therefore try to obtain most of our fats from
fish, olive oil, and avocado. Emphasizing these foods not only allows us to
benefit from the anti-inflammatory powers of monounsaturated and omega-3
fats, it also allows us to avoid more harmful fats such as saturated fat and
oxidized seed oils. In the end, choosing the right fats and oils is a powerful way
to bring peace to the immune system.

Table 8: Preferred Proteins

Best animal proteins Limit (2 to 3 times per Avoid
month)
Chicken (skinless) Chicken (with skin) S, 06 Fatty bacon S, 06
Pork tenderloin
Lean pork chop Marbled beef S Organ meats 06
Pork loin Pork shoulder S, 06 Farmed tilapia 06
Ham Pork ribs S, 06 Wild rainbow trout 06
Canadian bacon
Turkey Sausage S, 06 King mackerel M
Lean beef Duck S, 06 Swordfish M
Bison Pacific halibut M Bluefin tuna M
Lamb, trimmed of fat
Salmon Grouper M
Sardines Chilean sea bass M
Atlantic mackerel Orange roughy M
Cod
Haddock Albacore tuna M
Flounder Spanish mackerel M
Skipjack tuna
Light canned tuna
Yellowfin tuna
Other low-mercury fish

S: saturated fat. 06: omega-6 fat. M: mercury
Table 8: Anti-inflammatory Fats and Oils

Best Oils Limit Avoid
(damaged polyunsaturated (saturated and/or omega-6)
fats)
Olive oil Canola oil Ghee
Avocado oil Sunflower oil Lard
 Safflower oil Tallow
Soybean oil Palm oil
Corn oil Coconut oil
Nut oils Duck fat
Other seed oils



 Chapter 7. Troubleshooting and Customizing the
Keystone Diet

How to Find Your Own Trigger Foods

The Keystone Diet described so far provides the overall protocol for reducing
inflammation, but it is not always enough. If you continue to have active
inflammation, it may be worth doing further experimentation to determine
whether you have any unique food sensitivities. To do so, you will
systematically eliminate and then reintroduce foods that can trigger symptoms
in some people with autoimmune disease, namely

Common allergens (especially dairy, nuts, and eggs)
Nightshades (tomatoes, peppers, potatoes, eggplants,
certain spices)

These foods are not necessarily a problem for everyone. The only way to
know how they affect you is to eliminate them for one or two months, then
gradually reintroduce each food while carefully observing your response. The
end goal is to develop your own personal maintenance diet that is tailored to
your own particular sensitivities.

Identifying Food Allergies

Although most food allergies produce rapid and obvious symptoms, it is also
possible for food allergies and sensitivities to contribute to autoimmune disease
even in the absence of typical allergy symptoms.
For those affected by food allergy, identifying and removing the culprit can
be enormously helpful—in rare cases even resulting in a complete resolution of
joint pain. In the words of one doctor in the British Medical Journal in 1981, “No
one would be foolish enough to claim that every case of rheumatoid arthritis is
associated with a food allergy, but if only 1 in 20 is—and I suspect that it is
considerably more—I question whether we have the right to withhold such a
simple, safe, brief, and non-invasive investigation in a disease of such appalling
391
chronicity.”
In the past two decades, there has been a stream of case reports in medical
journals describing patients with severe rheumatoid arthritis who improved
392
dramatically by eliminating a food allergen. In each case, joint pain, swelling,
and stiffness reduced or disappeared while on an “allergen-free” diet, followed
by a clear exacerbation after repeated “blind” challenges. These blind
challenges involved hiding the foods in capsules to ensure that both the patient
and nurse assessing arthritis symptoms were unaware of the food being tested
each time.
Food allergy has also been implicated in juvenile arthritis, with reports of
some children making a complete recovery after eliminating an allergen, often
393
milk. One small study also found that a significant proportion of patients
with “spondyloarthritis” (including ankylosing spondylitis and psoriatic arthritis)
394
improved after eliminating dairy. Pain severity decreased, morning stiffness
improved, and joint and spine symptoms improved. Many of the patients in this
study who had a good response were still following the dairy-free diet two
years later, and some were able to discontinue all medications.
Researchers now estimate that food allergy impacts about 5 percent of
395
rheumatoid arthritis cases. We do not yet know how much of a role allergy
plays in other autoimmune diseases, but anecdotal reports of reactions to
dairy, nuts, and eggs are particularly common among those with psoriasis and
various forms of autoimmune arthritis.
Detecting food allergies can be a laborious process. The only reliable method
is to follow an allergy elimination diet and then systematically reintroduce
foods one at a time. To that end, most allergy elimination diets focus on
removing the set of foods that account for more than 90 percent of all serious
food allergies. These foods are

dairy
eggs
nuts
wheat
soy
corn
shellfish

It is also possible to have hidden allergies and sensitivities to many other
foods. To identify which other foods you should consider eliminating, skin prick
and blood tests can be helpful. These tests typically measure the antibody class
associated with true allergies, called IgE antibodies. Blood tests are also
available to look for the antibodies associated with delayed hypersensitivities,
called IgG antibodies. IgG tests are less reliable than IgE tests, because they can
produce many false positives and typically only reflect foods that have been
eaten in the preceding few weeks. (There is also a subtype of IgG antibody,
called IgG4, which can actually indicate tolerance to a food, rather than a
sensitivity.)
Nevertheless, if we take the information with a healthy dose of skepticism,
the results of allergy and sensitivity testing can be useful. The more information
we have in guiding our elimination diet, the more likely we are to identify any
culprits that are contributing to inflammation.
It is also important to note that if you do proceed with IgE and IgG testing
and the results are negative for the common allergens listed above, it may still
be worth eliminating some of these foods temporarily, particularly the worst
offenders— nuts, eggs, and dairy. This is because the currently available tests
are also prone to false negatives. That is, they fail to pick up true problems.
False negatives can happen if you have an IgG sensitivity and have not eaten
the food for a while before the blood test, or if you have a local antibody
response limited to the gut, not in the general circulation. Studies have actually
found that some arthritis patients have antibodies against foods only in the
intestines, not the general circulation, so these “allergies” would be missed by
396
standard tests.
Allergists and other doctors are often doubtful of the value of IgG food
sensitivity testing, but if the results are used only to guide an elimination diet, it
is clear these tests do have some value for those with autoimmune disease. As
one example of an IgG hypersensitivity contributing to arthritis, a case report
published in the journal Arthritis and Rheumatism described a patient who had
suffered from rheumatoid arthritis for 11 years and believed her symptoms
397
were exacerbated by foods. Blood tests showed no allergy to milk as
measured by IgE antibodies, but an increase in IgG antibodies to milk. After a
month of hypoallergenic formula, her joint pain and stiffness had improved
dramatically, and she was then given blind challenges with different foods or a
placebo hidden in a capsule. She showed a major exacerbation from milk each
time it was challenged, with an increase in swollen and painful joints peaking 24
to 48 hours after each challenge.


Practical Tips for the Allergy Elimination Diet

The most difficult aspect of eliminating dairy and eggs is developing a new
breakfast routine. Good options include

a smoothie made with collagen peptide powder, greens,
and frozen berries
meat patties or chicken sausage
leftovers from dinner
ham or turkey deli meat
salmon

The adjustment becomes easier with time, particularly as you reframe
breakfast as just another meal rather than one that involves typical “breakfast”
foods.
Another hurdle that arises from eliminating dairy is ensuring sufficient
calcium intake. Good nondairy calcium sources include leafy greens, such as
kale or collards, and canned salmon or sardines with bones. Many people are
surprised to learn that as much calcium can be absorbed from half a cup of
398
cooked collard greens as from a glass of milk. Calcium in broccoli, bok choy,
and kale is also readily absorbed, but calcium in spinach is not. For children, a
calcium supplement may be needed. Note that if you are taking a high dose
vitamin D supplement, you will need very little calcium in your diet, because
vitamin D facilitates calcium absorption.
If you end up eliminating dairy and eggs long term, it may be wise to begin
supplementing with vitamin A (or ensure your multivitamin provides most of
the recommended daily intake). Butter and eggs are often the main dietary
sources of the active form of vitamin A (also called retinol). Many plant foods
contain precursors to vitamin A (such as betacarotene), but some people may
not perform this conversion process efficiently. Vitamin A is critical for immune
regulation because it boosts regulatory T-cells and suppresses the inflammatory
Th17 cells involved in autoimmunity.


Additional Tips

It will be important to read labels to check for even small
 amounts of allergenic foods. If an allergy is present, occasional
exposure to a very low dose can still perpetuate the immune
response and obscure the results of the elimination diet.
The trace amounts of dairy in probiotic supplements may be too
trivial to cause a reaction, but you can also err on the side of
caution with a dairy-free probiotic such as GutPro Infant Powder,
Jarrow Allergen Free, or Renew Life.
Eliminate the common allergens for at least one month, or longer
if the results are not clear.
When you are ready to perform a challenge, start with a small
amount of a particular food, then gradually increase the amount
each day over the course of a week or until you observe a
reaction.
A positive reaction may include symptoms other than your usual
skin or joint symptoms. If a food causes abdominal pain, for
example, it may contribute to arthritis symptoms over the longer
term.
Wait at least a week between each challenge or until symptoms
return to normal after a positive challenge.
Test the foods in “pure” form so that other ingredients do not
interfere with the results (for example, using plain yogurt to test
dairy).
Do not perform challenges if you have a history of anaphylactic
reactions.
The most allergenic proteins in eggs are found in the white, so if
you react to whole eggs, it may be worth testing egg yolk
separately.
Reintroduce different nuts individually because some people
react to all nuts, while others only react to certain varieties.
If you find that you react to cow’s milk dairy, it may be worth
testing goat and sheep milk products. Some people with cow’s
milk allergy will cross-react to the similar proteins in these other
forms of dairy, but others will be able to tolerate them without
399
any problem.


An Allergy Impersonator: Food Chemical Sensitivity

If you notice reactions to a large number of foods, and these reactions are
inconsistent and unpredictable, bear in mind that this may not reflect a true
allergy or IgG-based sensitivity. Rather, it is possible to be intolerant to natural
chemicals found in foods, such as histamine and salicylates. It is not yet clear
the extent to which these reactions impact psoriasis or arthritis, so investigating
sensitivity to these foods should be a lower priority for most people. If,
however, you have other symptoms that are typical of food chemical
intolerance, such as headaches, flushing, and dizziness after eating certain
foods, or if you have noticed reactions to the specific foods that are highest in
amines or salicylates, it is worth exploring this possibility.
The most common symptoms of intolerance to amines and/or salicylates
400
include the following:

chronic hives
flushing, itching, or burning skin, particularly on the face
eczema
asthma
nasal congestion
headaches
stomach pain or diarrhea
low blood pressure/dizziness
fatigue or irritability
joint pain
muscle pain

Foods high in salicylates include berries, nuts, tea, watermelon, tomatoes,
401
avocado, and spices. Aspirin is another major source of salicylates.

Foods high in amines include cheese, chocolate, aged or processed meats,
and fermented foods such as wine, soy sauce, and sauerkraut. (Amines include
histamine, tyramine, and several other similar chemicals that form when
protein breaks down.)

When considering whether you may have a food chemical intolerance, it is
worth noting that this intolerance often presents very differently from allergies;
reactions are more unpredictable, and a wider variety of foods seem to be
involved. This is because the chemicals are found in a broad array of foods but
will only trigger symptoms once the cumulative dose exceeds the amount the
402
body can break down or excrete.
Depending on your threshold for reacting, a small amount of a particular
food may have no noticeable effect, yet when consumed in a larger amount or
in combination with other problematic foods over the course of the day, the
level of amines or salicylates can build up, triggering symptoms. This is quite
different from an allergy, where even a small amount of an allergenic food
predictably causes symptoms every time.
Investigating sensitivity to these food chemicals is now part of the
conventional medical treatment of hives, asthma, eczema, and chronic
headache. This is particularly true in Australia, where allergists at major
403
teaching hospitals have led research in this area for the past 30 years. As a
result of this research, salicylate sensitivity has now been found to trigger
attacks in at least 20 percent of asthmatics, while amine sensitivity has been
404
linked to chronic headache and irritable bowel syndrome.
It is likely that amines and salicylates can contribute to joint pain and
psoriasis in the same way they cause these other symptoms, but only in those
with a sensitivity. The Royal Prince Alfred Hospital’s Allergy Unit notes joint pain
405
as a common symptom of amine and salicylate intolerance. There are also
numerous anecdotal reports of joint pain and psoriasis resolving after
406
eliminating amines and/or salicylates. One small study found that when a
group of rheumatoid arthritis patients followed a low-chemical diet (eliminating
additives, preservatives, fruit, red meat, herbs, and dairy products), a small
subset of the patients showed a dramatic improvement and chose to stay on
407
the diet long term.
If you have reason to suspect amine or salicylate intolerance, it may be worth
reducing your intake of the foods with the highest concentration of these
chemicals. (For more extensive lists of high amine and salicylate foods, see
www.keystonebook.com/foodchemical.) If you find that you do have a food
chemical sensitivity, your focus should then shift to addressing the underlying
cause, rather than restricting these foods indefinitely.
Although the precise causes may differ for different individuals, experts in
this field strongly suspect that small intestinal bacterial overgrowth (SIBO) is a
major factor in histamine and salicylate intolerance. This is based on clinical
observations on the overlap between patients experiencing food chemical
intolerance and SIBO symptoms, and the frequent improvement in food
chemical intolerance when SIBO is addressed.
The detailed mechanisms for food chemical sensitivity are still poorly
understood but appear to involve hyper-responsive mast cells. An overgrowth
of bacteria, yeast, or parasites in the gut may contribute to this process by
increasing the numbers and activation of mast cells. This is effectively a form of
“mast cell activation syndrome.” When there are too many mast cells and they
are in an active state, this then sets the stage for overreactions to salicylates
408
and other chemicals from foods. (Note that mast cells are also key players in
409
the inflammatory process in psoriasis and arthritis. )
In addition, we know that many of the bacteria that can cause SIBO or
dysbiosis in the large intestine can produce large amounts of histamine,
overwhelming the body’s natural histamine-breakdown mechanisms. You can
find out if this may be a factor for you through comprehensive stool testing,
such as the GI-Map. Histamine-producing bacteria include E. coli, Citrobacter,
410
and Morganella morganii. Candida yeast and various parasites may also
trigger substantial histamine production. Addressing these overgrowths using
the strategies described in chapter 3, along with a diet that is lower in sugar
and starch, can therefore significantly improve food chemical intolerance.
There can also be other contributing factors, such as genetics and hormones
(particularly disrupted thyroid and adrenal hormones). Celiac disease can also
play a role in some cases, because when the gut lining is damaged, there is a
reduction in the enzyme that breaks down histamine (Diamine oxidase). For
most people, however, the best place to start in addressing food chemical
intolerance is reducing pathogen overgrowth, using the approaches discussed
in previous chapters.
Supplementing with high-dose vitamin C is another way to reduce histamine
sensitivity. A dose of 2 grams per day has been found to significantly reduce
411
blood histamine levels and the biological effects of histamine. Fish oil
supplementation may also be useful for those with salicylate sensitivity. A small
study found that supplementing with 10 grams per day of fish oil for six to eight
weeks produced a complete or virtually complete resolution of symptoms in
412
three patients with severe salicylate sensitivity. This is an excessive dose of
fish oil, but it is possible that a longer-term intake of a more reasonable dose
(such as 2 grams per day) could also help reduce salicylate sensitivity.
 Nightshades

The final category of foods that some people can have a particular sensitivity to
is fruits, vegetables, and spices in the nightshade plant family. Nightshades have
long been implicated in arthritis, starting with the work of a horticulturalist
named Norman Childers, who, in the 1970s, suspected that his own arthritis
413
was triggered by potatoes, tomatoes, and eggplant. He understood that
these were all members of the Solanaceae plant family—historically known as
nightshades because this family includes the deadly nightshade used by the
Romans to poison enemies. There are actually thousands of plants in the
nightshade family, many of which are toxic or inedible, such as tobacco. The
edible nightshades include

tomatoes
potatoes (but not sweet potatoes or yams)
bell peppers/capsicum/sweet peppers
chili peppers (and derivative spices such as cayenne,
paprika, and chipotle)
eggplant
tomatillos
goji berries
ashwaganda (often found in herbal thyroid supplements)

After eliminating all foods from this plant family, Dr. Childers’s symptoms
rapidly improved. He shared this finding in a book published in the 1970s, and
in the decades since, thousands of people have reported that they too have
reduced the severity of their arthritis by eliminating nightshades. A recent study
also found that 52 percent of psoriasis patients reported improvement in their
414
symptoms after eliminating nightshades. Yet there have never been any
rigorous scientific studies supporting the link between nightshades and
inflammation; all we have to rely on is a plausible biochemical explanation.
This biochemical explanation is based on two potentially toxic components
found in nightshades: glycoalkaloids and lectins. Glycoalkaloids are chemicals
produced by plants to defend against insects. The best-studied glycoalkaloids
are solanine and chaconin, found in potato; tomatine, found in tomato; and a
group of similar chemicals found in peppers.
There is no doubt that these chemicals are extremely toxic in high doses,
with reports throughout history of “solanine poisoning” from green potatoes.
Potatoes produce much larger amounts of glycoalkaloids when stored
improperly (conditions which also cause them to turn green), but even fresh
415
potatoes contain a significant amount. The critical question is what happens
when we are exposed to low doses over the long term. There is some limited
evidence that even in low doses, these chemicals can damage cell membranes
416
and contribute to increased intestinal permeability. In theory, this would
allow bacterial by-products and other molecules to cross the gut barrier and
activate the immune system, spurring further inflammation.
In laboratory and animal studies, potato glycoalkaloids were found to disrupt
417
the intestinal barrier. In another laboratory experiment, a glycoalkaloid
418
found in sweet peppers increased the permeability of human intestinal cells.
Capsaicin, the chemical responsible for the heat of hot peppers, also appears to
419
disrupt the gut barrier.
The second plausible biochemical explanation for a link between nightshades
and arthritis comes down to lectins, and here, too, we have limited but
intriguing evidence. We know that the lectins in potato and tomato survive
cooking and digestion and can cross the gut barrier and enter the circulatory
420
system. Once in circulation, the “stickiness” of these proteins allows them to
bind to molecules on the surface of mast cells, sending a signal to activate and
release histamine and other inflammatory mediators. Researchers have shown
421
that potato lectin activates human mast cells and triggers histamine release.
Tomato lectin is expected to behave in the same way because it has the same
422
binding properties. Because mast cells are the source of many inflammatory
mediators involved in psoriasis and arthritis, we should be wary of anything
suspected of increasing mast cell activation.
There is no definitive answer as to whether the glycoalkaloids or lectins are
the reason nightshades appear to worsen arthritis symptoms in many people.
But even without definitive proof, we have sufficient reason to avoid these
foods on a short-term trial basis. Some people may find that they have less joint
pain when avoiding tomatoes, potatoes, and nightshade-based spices, but they
can tolerate sweet peppers or eggplant, for example. It is also possible to
tolerate these foods in small amounts when eaten occasionally, but to react if
they are consumed too often.

 Practical Tips for Eliminating Nightshades

Nightshades are the basis of many commonly used spices such as
paprika, cayenne pepper, chili powder, chipotle, and red pepper
flakes.
Paprika and chili powder are often used in spice blends in
processed foods and may not be specifically listed as an
ingredient. For this reason, it is best to avoid any foods that
contain the catchall term “spices.”
Black pepper comes from an unrelated plant family, but it should
be used sparingly because it contains a chemical called piperine,
which appears to have similar biological effects to capsaicin,
423
causing a similar increase in intestinal permeability. In two
recent animal studies, piperine increased the ability of other
424
compounds to cross the intestinal barrier two- to fourfold.
Lectins and glycoalkaloids are typically concentrated in the skin
and seeds, so some people may be able to tolerate small amounts
of tomatoes and bell peppers that have been peeled and
deseeded.
Ripe tomatoes also have a much lower lectin concentration than
green tomatoes.
In the end, sensitivity to nightshades may vary widely between
people. The only way to determine how you are affected is
through trial and error.




 The Keystone Diet at a Glance

General Principles

Support your microbiome and antioxidant defenses by
eating more high-fiber and brightly colored fruit and
vegetables.
Eat more fish, especially salmon, sardines, and Atlantic
mackerel.
Consider supplementing with 2–4 grams of fish oil per day.
Use olive oil and avocado oil as the primary added fats.
Choose leaner proteins such as chicken, fish, and lean pork.
Trim visible fats from meat before cooking.

Level 1: Basic low-starch plan

Eliminate gluten-containing grains.
Avoid gut-damaging grains and legumes (soy, corn, potato,
peanut).
Limit other starchy foods to two servings per day,
preferably in the form of starchy root vegetables such as
parsnip or sweet potato.
Cut back on sugar.

Level 2: Intermediate low-starch plan

Eliminate grains, legumes, and very starchy vegetables.
Minimize added sugars.
Limit fruit to two or three small servings per day.
Avoid dairy, other than homemade yogurt if tolerated.
Avoid the highest-starch nuts and seeds, such as cashews.

Level 3: Advanced low-starch plan

In addition to the steps listed above for level 2:

Choose vegetables with the lowest starch content.
Limit fruit to one or two small servings per day.
 Use only the lowest-starch nuts and seeds, such as flax and
macadamias.
Try to avoid maltodextrin and other starchy fillers in
supplements.
Increase fat and protein to compensate for the reduction in
carbohydrates. If you emphasize fat this will become a
ketogenic diet. Some people may feel better long term by
emphasizing protein instead in order to prevent hormonal
disturbances.
You may need to increase salt to prevent the electrolyte
imbalances that can result from a very low carbohydrate
diet.

Troubleshooting and Customizing the Keystone Diet

Consider eliminating the following for at least 30 days to determine if you have
a sensitivity:

Common allergens: nuts, eggs, dairy, soy, corn, shellfish
Nightshades: tomatoes, potatoes, peppers, chili spices,
eggplant

If you have symptoms of food chemical intolerance and react to a wide range
of foods that are high in histamines or salicylates, you may be able to reduce
this sensitivity by addressing SIBO and pathogen overgrowth. Other alternative
strategies include testing for thyroid and adrenal hormones and adding a high-
dose vitamin C supplement to reduce histamine levels.

 Part 3. Beyond Food

 Chapter 8. Anti-inflammatory Supplements


Our primary focus throughout this book is targeting the underlying causes of
autoimmunity through diet and other strategies that aim to heal the gut and
rebalance the microbiome. For even further help, there are additional
supplements that can help fine-tune the immune system. These supplements
may only make an incremental difference to the severity of symptoms, but they
are worth considering as optional extras to your own personalized program.

Vitamin D

Vitamin D performs many important functions, including regulating immunity
and calcium absorption. When vitamin D levels are low, bone density suffers
and the immune system becomes unbalanced, with a weaker defense against
425
infections and greater autoimmune activity and inflammation.
Vitamin D is obtained primarily from sun exposure, and most people simply
do not get enough sunlight to produce an adequate amount. A substantial
length of time outdoors is required even on sunny days, and in winter in most
climates the sunlight is simply too weak to generate any vitamin D. As a result,
426
serious deficiencies are widespread.
More than one-third of otherwise healthy young adults in the United States
have low levels of vitamin D. This figure may be even higher in those with
autoimmune disease, with studies finding that more than half of those with
rheumatoid arthritis, ankylosing spondylitis, psoriasis, and juvenile arthritis are
427
deficient. In each of these conditions, vitamin D deficiency is also correlated
with disease activity: those with the lowest levels have the most severe
428
symptoms.
For many with psoriasis, adding a vitamin D supplement can make an
extraordinary difference. Although most clinical studies in this area have been
open label (not blinded or placebo controlled), they have consistently found a
benefit when high doses are given for three to six months. Five separate studies
have reported a moderate or greater improvement in psoriasis in at least 50
429
percent of patients. Some patients taking high doses even show complete
430
resolution of their psoriasis. Vitamin D is in fact so effective in psoriasis that
topical vitamin D–based prescription creams, such as calcipotriene, are now
431
used as first-line therapy.
Vitamin D supplements also appear to improve joint symptoms in psoriatic
and rheumatoid arthritis, with several open-label studies finding that most
patients taking a high-dose supplement for three to six months had a significant
432
reduction in pain. It is unclear whether this approach can also reduce pain in
other forms of arthritis such as juvenile arthritis or ankylosing spondylitis. Yet
even with these conditions, vitamin D is worth supplementing for another
reason.
Aside from potential pain reduction, supplementing with vitamin D is useful
433
for preserving bone strength. Inflammatory arthritis is typically associated
with a significant loss of bone minerals, causing bones to become more prone
to fracture. This is especially pronounced in juvenile arthritis and ankylosing
434
spondylitis as well as in those using steroids such as prednisone. Vitamin D
limits this loss of bone density because it facilitates calcium absorption. The
American College of Rheumatology in fact recommends vitamin D
435
supplementation for all patients using steroids such as prednisone. (To
further support bone density, supplementing with calcium, magnesium, and
vitamin K2 may also be useful, particularly if you do not include kale or collards
in your daily diet.)
More broadly, a panel of 25 experts from 15 countries recently
recommended that all people with autoimmune disease or musculoskeletal
436
health problems should have their vitamin D level tested. The panel
established clinical practice recommendations stating that in this group, the
optimum level is 30 ng/mL, higher than typically considered sufficient for the
general population. The panel also recommended that even without testing for
a deficiency, people with autoimmune disease should take a low-dose
supplement (800 IU) each day. In the winter or for those not often exposed to
sunlight, a significantly higher dose may be needed to maintain an adequate
437
vitamin D level. In one study, more than 60 percent of rheumatoid arthritis
patients taking 800 IU of vitamin D were still below the preferred level of 30
438
ng/mL.
For those with a known deficiency, the expert panel recommends a short-
term treatment of approximately 7000 IU per day (as 50,000 IU once per week)
for eight weeks, followed by a maintenance dose of 800 IU per day, with regular
monitoring to ensure that this low-maintenance dose is sufficient.
An alternative approach, if regular testing is not feasible, is to start with 5000
IU each day for one to two months, then continue at 2000 IU per day as a
maintenance dose. The clinical practice recommendations state that
“international authorities consider a vitamin D intake of 2000 IU daily as
absolutely safe, although a recent review found that even doses of up to 10,000
IU per day supplemented over several months did not lead to any adverse
439
events.”
For children, the U.S. government’s recommended daily intake for vitamin D
is 600 IU per day. Clinical trials of vitamin D to prevent other childhood diseases
440
often use 1200–2000 IU per day.
To maximize absorption, the preferred form of vitamin D supplement is
vitamin D3 (cholecalciferol) as a liquid softgel (or liquid drops) rather than a
solid tablet. Good-quality brands (such as Doctor’s Best, Jarrow, and Seeking
Health) often use extra-virgin olive oil as the carrier oil rather than soy or corn
oil.


Glucosamine and Chondroitin

Glucosamine and chondroitin are among the most commonly used
supplements to treat joint pain, with a long track record of safety and minimal
side effects. Both are components needed to make cartilage and the fluid that
cushions joints. They have also been studied in clinical trials for decades,
although largely in the context of osteoarthritis.
In osteoarthritis, it is clear from several large, double-blind, placebo-
441
controlled studies that glucosamine can help limit cartilage destruction. In
one of the best-known studies, published in the Lancet in 2001, those patients
taking 1500 mg of glucosamine sulfate per day had significantly less pain and
442
cartilage loss after three years.
Although most glucosamine products contain a combination of glucosamine
and chondroitin, it may be that this combination adds no further benefit. One
large study funded by the National Institutes of Health (at a cost of $12.5
million) compared glucosamine and chondroitin alone or in combination in 500
patients with knee osteoarthritis. The patients with the least cartilage loss after
two years were those taking glucosamine alone. Those taking the combination
of glucosamine and chondroitin actually fared no better than those taking the
placebo. This could have been a random aberration, but it led the authors to
suggest that the two compounds may interfere with one another when used in
443
combination.
The question for those with autoimmune forms of arthritis is whether the
cartilage-sparing effect of glucosamine is limited to osteoarthritis or applies
more generally. There is little research in this area, but what is known so far
does point to a likely benefit for long-term cartilage protection in rheumatoid,
psoriatic, and juvenile arthritis.
Osteoarthritis is driven by a different process than autoimmune forms of
arthritis, but they share similarities, including degradation of cartilage by the
444
same enzymes (called matrix metalloproteinases). In one of the only trials of
glucosamine in rheumatoid arthritis, there was a modest reduction in pain after
12 weeks, but most interestingly, there was also a decrease in the level of
445
matrix metalloproteinase-3 (MMP-3) in the bloodstream. This enzyme is
activated by inflammation and causes much of the destruction to cartilage in
446
both rheumatoid arthritis and osteoarthritis. MMP-3 is also elevated in
447
psoriatic and juvenile arthritis and correlates with greater disease severity.
The finding that glucosamine reduces MMP-3 in patients with rheumatoid
arthritis suggests that this supplement not only provides a building block for
new cartilage and joint fluid but also lessens the attack on existing cartilage.
This finding is also supported by numerous animal and laboratory studies
448
showing that glucosamine does indeed reduce the production of MMP-3.
When we put together the pieces of the puzzle, it is reasonable to expect
that glucosamine can limit long-term cartilage damage in all these forms of
arthritis, not just osteoarthritis. It may therefore be worth adding a
glucosamine supplement, particularly since this compound has been studied
extensively for safety and side effects. The two common forms of glucosamine
supplements, sulfate and hydrochloride, are roughly equivalent. The typical
dose is 1000 to 1500 milligrams per day.
Many glucosamine and chondroitin products now also include a compound
called MSM, which stands for methylsulfonylmethane. This is included because
it provides a source of sulfur, which is needed to make connective tissue. A
small number of studies have found that MSM produces a mild benefit in
osteoarthritis, but side effects such as gastrointestinal symptoms, insomnia,
449
and headaches have been reported. Unlike glucosamine and chondroitin,
there have not been any large studies establishing the safety of MSM
supplements. As a result, it may be preferable to choose a glucosamine
supplement that does not contain MSM. (An alternative source for the sulfur
needed to make and repair connective tissue is sulfur-rich vegetables,
particularly those in the cabbage family and mushrooms.)

Gamma-Linolenic Acid (GLA) as Borage or Evening Primrose Oil

Borage oil and evening primrose oil are mildly anti-inflammatory because they
contain a specific omega-6 fatty acid called gamma-linolenic acid (GLA). This
fatty acid can inhibit the production of one particular inflammatory mediator
450
called leukotriene B4 (LTB4). LTB4 attracts immune cells to the site of
451
inflammation and helps orchestrate the immune attack. LTB4 plays a
particularly key role in psoriasis because it is also involved in the proliferation of
452
skin cells to produce plaques. GLA helps block the conversion of arachidonic
acid to LTB4. This mechanism explains the anecdotal reports that borage or
evening primrose oil supplements can significantly reduce psoriasis, although
this has not been established in clinical trials.
In the rheumatoid arthritis context, there have been some human studies,
although the results have been mixed. Studies involving low doses or short time
453
periods often find little to no benefit, while very high doses have been found
454
to reduce the number of tender and swollen joints. The successful high-dose
studies have given doses of 1.4 or 2.8 grams per day of GLA. Since borage oil is
only about 20 percent GLA, this would translate to five to 10 large capsules.
Evening primrose oil is only 10 percent GLA, so 10 or 20 capsules would be
required. There is no data supporting the long-term safety of these high doses.
A middle-ground dose of 500 milligrams (0.5 grams) per day of borage oil
(typically two capsules) would be a more reasonable approach and may be
sufficient to noticeably reduce inflammation in the context of an anti-
455
inflammatory diet.
One of the concerns with GLA supplements is that they can increase the level
456
of arachidonic acid in the bloodstream. This could in theory worsen
inflammation in the long term and increase the risk of blood clotting. One study
indicated that it is possible to prevent the increase in arachidonic acid after
457
taking GLA supplement by adding an omega-3 supplement. As a result, if you
are using a borage or evening primrose oil supplement, it is particularly
important to take at least 2 grams of fish oil per day. This combination does
458
appear to reduce inflammation more than fish oil alone.

Vitamin E

Vitamin E is widely known as a powerful antioxidant. This vitamin is actually a
group of eight similar compounds (four tocopherols and four trienols), usually
present as a mixture in different plant oils, nuts, and seeds. Although vitamin E
compounds are typically known for their antioxidant properties, some forms
have entirely separate anti-inflammatory effects because they directly suppress
459
the enzymes that produce inflammatory mediators.
Several clinical studies have found vitamin E supplements useful for
rheumatoid arthritis, producing an equivalent pain reduction as the NSAID
460
diclofenac. A double-blind, placebo-controlled clinical study also found that a
combination of vitamin E, selenium, and CoQ10 significantly decreased the
461
severity of psoriasis and joint pain.
Yet the Mediterranean diet is naturally high in vitamin E, so a supplement is
probably unnecessary in the context of the diet outlined in this book. In a
clinical trial of rheumatoid arthritis patients following the Mediterranean diet,
462
all patients exceeded the minimum recommended vitamin E intake. It is also
preferable to obtain vitamin E from food (such as avocado and olive oil)
because foods contain a mixture of the different tocopherols and trienols,
whereas supplements often contain only alpha-tocopherol. Studies suggest that
a mixture of different forms of vitamin E produces a greater anti-inflammatory
463
effect than alpha-tocopherol alone.

Turmeric / Curcumin

Turmeric is a spice from the ginger family that has been used for thousands of
years in Indian cuisine and traditional medicine. Curcumin is one of the many
compounds found in turmeric and is widely regarded as having powerful anti-
inflammatory effects, based on thousands of laboratory studies.
 Yet the ability of curcumin to calm inflammation is limited by its poor
464
absorption and stability. As a result, the real-world effects of curcumin are
less impressive than lab studies would suggest. Many human clinical studies of
standard curcumin supplements have produced underwhelming results,
465
particularly in the context of autoimmune disease.
There are, however, some new formulations of turmeric that are better
466
absorbed and much more effective. Among these new formulations, Meriva®
is supported by the most clinical research, particularly in the context of joint
pain and psoriasis.
Meriva contains all three curcuminoids found in turmeric, rather than just
curcumin. These curcuminoids are combined with phosphatidylcholine (a
component of our cell membranes) to make the curcuminoids more soluble and
stable. Meriva is sold by various good-quality supplement brands, including
Doctor’s Best, Thorne, Jarrow, and Pure Encapsulations.
There is convincing evidence that Meriva can improve joint inflammation and
pain, at least in the context of nonautoimmune arthritis. In a placebo-controlled
clinical study of osteoarthritis, patients taking Meriva saw a significant
improvement in pain, swelling, and stiffness, along with a drop in all measured
467
inflammatory markers. The patients taking Meriva were also able to reduce
their NSAIDs usage by 63 percent and as a result had fewer gastrointestinal
complaints.
Although this study was done in the context of osteoarthritis, not
autoimmune arthritis, it does support the view that the Meriva form of
curcumin can reduce joint pain and inflammation. By contrast, similar studies
using other formulations of curcumin, such as BCM-95 (in CuraMed) produced
very little reduction in joint pain and no improvement in inflammatory
468
markers.
In addition to reducing some aspects of inflammation, Meriva also reduces
perception of pain in the short term, in a similar way to acetaminophen.
(Acetaminophen is the active ingredient in Tylenol, also known as paracetamol.)
A dose of 2 grams of Meriva was found to produce a short-term reduction in
469
pain equivalent to a full dose of acetaminophen. In this study, the pain-
relieving effects started about two hours after it was taken and lasted about
four hours. Note that pain relief was barely noticeable at a lower dose. A
relatively large dose of 2 grams is required, which is typically four capsules.
 Although the main value of Meriva is likely pain reduction, it does also show
promise in directly controlling some autoimmune diseases. For example, one
study found that Meriva can reduce the relapse rate in chronic anterior
470
uveitis. This is an autoimmune eye condition that is closely linked to psoriatic
arthritis and ankylosing spondylitis. Another clinical study found that Meriva is
471
helpful for maintenance of remission in ulcerative colitis. Finally, in the
context of psoriasis, Meriva significantly reduced the severity of psoriasis after
12 weeks, along with a reduction in one of the main inflammatory mediators
472
that drives psoriasis (IL-22). This lies in sharp contrast to the disappointing
results seen with other versions of curcumin, which produced no benefit in
473
psoriasis.
It may be that Meriva is so much more effective than standard curcumin
supplements because this formulation specifically improves the absorption of
other related compounds found in turmeric, not just curcumin. In fact, the
major curcuminoid present in plasma after taking Meriva is not actually
curcumin, but demethoxycurcumin, a related compound that may have even
474
more potent anti-inflammatory effects.
An area of research to watch when it comes to curcumin is the effect on the
microbiome. Initial studies published in 2017 and 2018 suggest that curcumin
may have beneficial effects on the microbiome, such as increasing the
abundance of beneficial butyrate-producing microbes and thereby boosting
475
regulatory T cells.
New studies also hint at a possible role for curcumin in improving the gut
476
barrier. This is at odds with the old idea that the gut barrier was an obstacle
that needed to be overcome in order for curcumin to work. Older formulations
of curcumin actually used an ingredient called piperine to improve the
477
absorption of curcumin by increasing intestinal permeability. This is
counterproductive because it also helps other molecules cross the gut barrier
too, including bacterial toxins that may increase immune activation.
If you decide to add curcumin to your supplement regime, the best option is
to choose one of the many Meriva supplements available, such as Thorne
Meriva 500-SF, Jarrow Curcumin Phytosome, or Pure Encapsulations
Curcumasorb. Clinical trials showing beneficial effect in autoimmune disease
and joint pain use either 1 or 2 grams per day, which is typically two to four
capsules.

Approaching Supplements with Caution

Apart from the thoroughly investigated supplements discussed above, it is
prudent to consider other “anti-inflammatory” supplements with great
skepticism, given the lack of regulation and oversight of the supplement
industry. It is important to keep in mind that supplement manufacturers are not
required to test for safety or effectiveness. As a result, most supplements have
not been studied in clinical trials, and it is difficult to know their true impact on
inflammation. Contamination of supplements with lead and other toxins is also
a major concern. “Not only are the advertised ingredients of some supplements
potentially dangerous,” says Pieter Cohen, MD, Assistant Professor of Medicine
at Harvard Medical School, “but because of the way they’re regulated, you
478
often have no idea what you’re actually ingesting.”
Supplements can also obscure the results of dietary changes, as explained by
Dr. Suskind of Seattle Children’s Hospital: “Caution should be used when
considering additional herbal supplements or other alternative therapies . . . I
have met families where the SCD did not seem to be working effectively, but
479
when other adjunct therapies were removed, the SCD worked.” For this
reason, it is useful to keep other supplements to a bare minimum while
experimenting with dietary changes.


Summary of Anti-inflammatory Supplements Supported by Clinical
Studies

Supplement Priority Example products Typical Dose
Probiotic High - Culturelle 10 billion CFU per
- Jarrow Allergen day (varies
Free greatly
- BioK+ depending on
- Florastor strain)
Fish oil High - Nordic Naturals 2000–4000 mg
Ultimate Omega 2x (2–4 grams) per
- Garden of Life day EPA + DHA
 Omega 3 Minami
Platinum
Vitamin D High - Doctor’s Best 2000 IU per day
Vitamin D3 Softgels
Glucosamine Medium - Jarrow 1000–1500 mg
Glucosamine HCL per day
Mega
- NOW Glucosamine
1000
Meriva Medium - Pure 1000–2000 mg
Encapsulations per day
Curcumasorb
- Jarrow Curcumin
Phytosome
- Thorne Meriva
500-SF
Borage oil Low - Nature’s Way EFA 500 mg GLA per
Gold Borage day (~2500 mg
- Jarrow Formulas borage oil)
Borage GLA


 Chapter 9. The Science of Low-Dose Naltrexone

Naltrexone is a pharmaceutical that has been used for decades to treat opioid
addiction, but more recently it has shown great promise as a medication for
various inflammatory diseases. When taken in very low doses, naltrexone can
480
regulate the immune system and reduce pain.
In one of the earliest studies on low-dose naltrexone (LDN), researchers
found that it could reduce muscle spasms associated with multiple sclerosis
481
(MS). In 2010, a placebo-controlled study at the University of California, San
Francisco, also found that LDN significantly reduced pain and improved quality
482
of life in MS patients.
Low-dose naltrexone has also been found to significantly reduce pain in some
483
people with fibromyalgia. The treatment does not work for everyone, but a
small double-blind trial at Stanford University reported that the majority of
484
fibromyalgia patients taking LDN had at least a 30 percent reduction in pain.
Aside from these pain-relieving effects, LDN may actually be able to reduce
underlying inflammation, particularly in the gut. There is good evidence for this
485
from double-blind, placebo-controlled trials in Crohn’s disease. In one such
study, when patients were examined by endoscopy after taking naltrexone for
three months, 78 percent showed significant intestinal healing, compared to
486
just 28 percent of those taking a placebo. Even more starkly, one-third of the
patients taking naltrexone achieved remission, compared to 8 percent of those
on the placebo. These extraordinary effects suggest that naltrexone can
actually disrupt the inflammatory process in the gut.
Although most of the controlled trials in Crohn’s disease have so far
originated from a single research institution, other gastroenterologists have
487
also reported success in some patients. A case report from the Cleveland
Clinic, for example, describes a 14-year-old girl who had suffered from
abdominal pain for three years and had intestinal damage consistent with
Crohn’s disease. After four weeks of LDN treatment, her symptoms were
significantly reduced, and by three months an endoscopy showed complete
488
healing of the damaged intestinal lining. A 2018 study found that LDN
induced clinical improvement in three-quarters of patients with inflammatory
 489
bowel disease and induced remission in one-quarter of patients. Physicians
in Australia also reported that LDN was successful in treating five out of 14
Crohn’s patients, and four of those patients also showed gut healing on an
490
endoscopy.
It was initially suggested that naltrexone has this powerful anti-inflammatory
effect because it boosts natural endorphins and it is these endorphins that
491
regulate the immune system. More recently, another mechanism has come
to light, one that is particularly relevant to psoriasis and various forms of
inflammatory arthritis.
This newly discovered mechanism is entirely separate from the
opioid/endorphin system. It is instead based on the fact that naltrexone can
directly interfere with the activation of immune cells by bacterial toxins such as
492
lipopolysaccharide.
493
Naltrexone does this by binding to and blocking a receptor called TLR4.
This receptor is normally how “first-responder” immune cells (such as mast
cells) can detect the presence of lipopolysaccharide and other bacterial by-
products. When lipopolysaccharide binds to TLR4 on the surface of cells, this
triggers the release of inflammatory mediators. In effect, TLR4 receptors are the
eyes that allow a variety of different immune cells to see bacterial by-products
in the intestines and in the bloodstream. Naltrexone blindfolds these cells and
stops them from overreacting to the presence of bacteria.
The TLR4 mechanism suggests that the extraordinary effects seen in Crohn’s
disease could also apply in several other autoimmune diseases. This is
particularly true in those conditions where TLR4 clearly plays a role, including
psoriasis, psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis. In
each of these conditions, mutations in the TLR4 genes are more common than
494
in the rest of the population, and there is a higher than normal level of TLR4
495
receptors on immune cells. When bacterial by-products bind to TLR4
receptors, this also triggers the production of the precise inflammatory
496
mediators that are the hallmarks of psoriasis and inflammatory arthritis.
Naltrexone could disrupt this process and thereby calm the immune system.
Interestingly, in the fibromyalgia clinical study, the patients with the greatest
drop in pain on LDN treatment were those who started out with the highest
level of inflammation, shown by erythrocyte sedimentation rate (ESR).
According to the researchers performing the study, this suggested “that the
clinical effect of LDN may be physiologically associated with the reduction of
497
inflammation.” The researchers further commented that “the observed
relationship between ESR and LDN response raises the intriguing possibility that
other chronic conditions characterized by high ESR may also benefit from LDN
therapy.” Psoriasis and inflammatory arthritis are unquestionably conditions
characterized by high ESR levels, and ESR is in fact used by rheumatologists to
monitor disease severity. The pain-reducing and anti-inflammatory effects of
low-dose naltrexone thus hold great promise for those with these conditions.
In the United States, naltrexone is already approved by the FDA to treat
addiction, so physicians are allowed to prescribe it “off-label” for other uses.
When used to treat inflammatory diseases, the dose is far lower than that used
for addiction (1.5–4.5 mg compared to 50–100 mg). As a result, the prescription
must be filled at a specialist compounding pharmacy that can prepare capsules
containing low doses. The dose is often titrated, meaning one starts at a dose of
1.5 mg or 2 mg and then increases to 3 mg after several weeks. The dose is only
increased further if necessary.
The side effects of LDN reported in the clinical studies so far are headache,
difficulty sleeping, and vivid dreams, but it has also been reported that these
498
side effects can be minimized by keeping the dose at or below 3 mg per day.
LDN cannot be used in conjunction with opioids, because it causes withdrawal
symptoms, but rheumatologists have been prescribing LDN in combination with
methotrexate and biologics. At the time of writing, several clinical trials are
underway to determine the efficacy of LDN in treating conditions such as
rheumatoid and psoriatic arthritis.
LDN is not yet an FDA-approved treatment option for autoimmune disease,
but as explained by Stanford researchers, “Our replicated observation that low-
dose naltrexone affects levels of pain, together with the low cost and tolerable
nature of low-dose naltrexone, makes it a promising target for future
499
investigation.”

 Chapter 10: Putting It All Together


The Basic Plan

If you suffer from any form of autoimmune disease, there is a small set of
fundamental dietary changes and supplements that can produce an immense
payoff when it comes to calming inflammation. These basic steps are the most
critical for shifting the balancing of species in the microbiome, healing the gut
barrier, and giving the immune system the healthy fats it needs to return to a
normal equilibrium.

Diet

Start by focusing on what you should be eating more of: high-
fiber and antioxidant-rich vegetables, fish, poultry, lean meat,
and olive oil. These foods should be the foundation of most
meals.
Adopt the Level 1 low-starch diet by removing gluten-containing
grains, corn, soy, peanuts, quinoa, and potatoes. Limit other
starches to two servings per day (preferably rice, legumes, or
starchy vegetables).
Cut back on added sugar.
Try to space meals four hours apart with no snacking, to allow
time for the digestive system to perform its important cleaning
cycle.

Supplements

To help support the levels of other anti-inflammatory resident
microbes, suppress harmful bacteria, and heal the gut, start
taking a Level 1 probiotic with breakfast each day. Look for a
product that includes L. rhamnosus GG (e.g., Culturelle) or B.
infantis, B. breve, or B. longum (e.g., Jarro-dophilus Allergen-Free,
Klaire Ther-Biotic Metabolic Formula). Take the probiotic with
breakfast each day.
Consider adding a vitamin D supplement containing at least 2000
 IU of vitamin D3 (cholecalciferol) in an oil-based liquid or soft-gel.
You may need a short-term treatment with a higher dose, such as
5000 IU per day, if you are deficient.
On days that you do not eat oily fish such as salmon, sardines, or
mackerel, add a fish oil supplement containing at least 2 grams of
DHA and EPA.

Beyond the Basics

To go further and address more specific root causes of autoimmunity, it is
helpful to tailor the approach to your particular autoimmune condition. To that
end, intermediate and advanced diet and supplement plans are provided below
for psoriasis, psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis.
If budget permits, it may also be useful to pursue laboratory testing to guide
the next steps in your personalized program. The most helpful tests are (in
order of priority)

a stool test to detect overgrowth of specific pathogens
a breath test to detect SIBO
a blood test for IgE-based food allergy and IgG-based food
sensitivity

Depending on where you live, you may be able to order these tests yourself,
or you may need the assistance of a functional medicine physician. (See
www.keystonebook.com/testing.)
Laboratory testing is not always reliable, however, and it is certainly not
required. We can instead look to the factors that are most likely to be at play in
a given autoimmune disease to guide our plan of attack. In doing so, we are
effectively relying on the body of scientific research to identify the most likely
root causes.

Psoriasis and PsA—Intermediate and Advanced Plans

If you have psoriasis or psoriatic arthritis (PsA), the basic plan above will
provide the most important groundwork for healing, but there are additional
steps you can take that focus on the unique issues and contributing factors that
are more likely to play a role in psoriasis than other autoimmune conditions.
These potential contributing factors include small intestinal bacterial
overgrowth (SIBO), Candida yeast, and Streptococcus bacteria, whether in the
gastrointestinal tract or in the form of chronic low-level throat infection.
Note that individuals with psoriatic arthritis that impacts the spine and
sacroiliac joints may benefit the most from reducing or eliminating starch,
because this form is closely related to ankylosing spondylitis and has a clearer
link to the harmful bacteria that thrive on starch.

Psoriasis/PsA Diet—Intermediate

The foundation of your diet should be high-fiber and antioxidant-
rich vegetables, fish, poultry, lean meat, and olive oil.
To combat SIBO and Streptococcus overgrowth, adopt the level 2
low-starch diet, which eliminates grains, legumes, and very
starchy vegetables. Minimize high-fructose fruits, added sugars,
dairy, and very starchy nuts and seeds.

Psoriasis/PsA Diet—Advanced

Experiment with the level 3 low-starch diet for at least three
months and then try to gradually return to the intermediate low-
starch diet to determine your tolerance for starches. If psoriatic
arthritis impacts your spine or sacroiliac joints, you may benefit
from keeping starch very low for an even longer period of time.
For at least one month, eliminate nightshades, nuts, eggs, dairy,
and any other foods that test positive for an allergy or IgG-based
sensitivity. Systematically reintroduce these foods one at a time
to find out how they affect you.
For further troubleshooting, another possible culprit to
investigate is fruit. Some individuals may feel better avoiding fruit
entirely and following a very low-carbohydrate diet. This diet can
be ketogenic but does not need to be if protein intake is increased
to meet energy demands.

Psoriasis/PsA Supplements—Intermediate

In addition to the vitamin D and fish oil recommended for the basic level above,
consider adding the following supplements:

 A Level 2 probiotic such as a high potency Bifidobacteria
combination containing multiple strains and including B.
bifidum (e.g., Jarrow Bifidus Balance, GutPro, Renew Life 50
Plus).
If you are prone to throat infections or tonsillitis, add a
probiotic lozenge containing S. salivarius K12, such as
HyperBiotics ProDental.
If you suspect SIBO, consider adding further supplements to
support the digestion and cleansing cycle. This may include bile
and a combination of betaine HCL, pepsin, and pancreatin with
larger meals and Iberogast between meals.

Psoriasis/PsA Supplements—Advanced

To reduce excess Candida, Streptococcus, and other harmful
bacteria in the small intestine, follow a short-term pathogen-
fighting protocol for 30 days. This includes a Level 3 probiotic
(BioK+, Mutaflor, S. boulardii), taken before bed each day,
along with lactoferrin, allicin, and berberine half an hour
before meals.
To combat SIBO, consider adding supplements to support the
digestion and cleansing cycle. This may include bile and a
combination of betaine HCL, pepsin, and pancreatin with larger
meals and Iberogast between meals.
For additional long-term anti-inflammatory maintenance,
consider supplementing with Borage oil or curcumin in the
form of Meriva.

Rheumatoid Arthritis—Intermediate and Advanced Plans

If you have rheumatoid arthritis (RA), it is particularly helpful to adopt the core
tenets of the Mediterranean diet. Clinical studies show that RA often responds
quite well to dietary changes such as increasing the consumption of fish, olive
oil, and antioxidant-rich vegetables. From that point you can begin to explore
whether your inflammation may be influenced by food allergy, an overgrowth
of bacteria such as Proteus mirabilis, or a combination of factors.

Rheumatoid Arthritis Diet—Intermediate

Start by focusing on what you should be eating more of: high-
fiber and antioxidant-rich vegetables, fish, poultry, lean meat,
and olive oil. These foods should be the foundation of most
meals.
Adopt the level 1 low-starch diet by removing gluten-containing
grains, corn, soy, peanuts, quinoa, and potatoes. Limit other
starches to two servings per day (preferably rice, legumes, or
starchy vegetables).
Avoid sugar.
Try to space meals four hours apart with no snacking, to allow
time for the digestive system to perform its important cleaning
cycle.

Rheumatoid Arthritis Diet—Advanced

For at least one month, eliminate nightshades, nuts, eggs, dairy,
and any other foods that test positive for an allergy or IgG-based
sensitivity. Systematically reintroduce these foods one at a time
to find out how they affect you.
Consider experimenting with the level 2 low-starch diet for three
months, to determine whether you may be sensitive to starch and
other carbohydrates.

Rheumatoid Arthritis Supplements—Intermediate

In addition to the vitamin D and fish oil recommended for the basic level above,
consider adding the following supplements:

Level 2 probiotic such as a more potent Bifidobacteria
combination containing multiple strains and including B.
bifidum (e.g., Jarrow Bifidus Balance, GutPro, Renew Life 50
Plus).
If you suspect SIBO, further supplements to support the
digestion and cleansing cycle may be helpful. This can include
bile and a combination of Betaine HCL, pepsin, and pancreatin
with larger meals and Iberogast between meals.

 Rheumatoid Arthritis Supplements—Advanced

Consider following a short-term pathogen-fighting protocol for
one month to target pathogens implicated in RA, such as
Proteus mirabilis. This includes a Level 3 probiotic (BioK+,
Mutaflor, S. boulardii), taken before bed each day, along with
lactoferrin, allicin, and berberine half an hour before meals.
When additional pain relief is needed, consider supplementing
with turmeric in the form of Meriva.
A glucosamine supplement may help prevent further cartilage
deterioration in the long term.

Ankylosing Spondylitis—Intermediate and Advanced Plans

If you have ankylosing spondylitis (AS), you have the most to gain from a stricter
approach to starch and sugars. The low-starch diet has a long history of
successfully treating many patients with AS, and there is substantial evidence
that this condition is driven by the immune response to starch-loving bacteria,
such as Klebsiella and adherent-invasive E. coli. Because overgrowths of these
bacteria often occur in the form of SIBO, you may also benefit from strategies
that reduce the overall bacterial population in the small intestine.

AS Diet—Intermediate

The foundation of your diet should be high-fiber and antioxidant-
rich vegetables, fish, poultry, lean meat, and olive oil.
Start with the level 3 low-starch diet for several months to find
out how starch impacts your symptoms. If you experience a
significant reduction in inflammation, at that point you can
gradually introduce additional fruits and vegetables from the
intermediate level to determine your tolerance.
If you continue to have active inflammation even on the advanced
low-starch diet, it may just be that more time is required to see a
benefit. Dr. Ebringer reports that from his three decades of
experience treating AS with a low-starch diet, “it normally takes
500
around six to eight months for the diet to show its effects.”

AS Diet—Advanced

Continued inflammation on the advanced low-starch diet may
also be due to a food sensitivity. For at least one month, eliminate
nightshades, nuts, eggs, and dairy and then reintroduce each
food individually to gauge your reaction.
For further troubleshooting, another possible culprit to
investigate is fruit. Some individuals with AS feel better avoiding
fruit entirely and following a very low carbohydrate diet. This diet
can be ketogenic but does not need to be if protein intake is
increased to meet energy demands.

AS Supplements—Intermediate

Consider a Level 2 probiotic such as a more potent
Bifidobacteria combination containing multiple strains and
including B. bifidum (e.g., Jarrow Bifidus Balance, GutPro,
Renew Life 50 Plus).
Given that Klebsiella and E. coli overgrowths can take the form
of SIBO, consider adding further supplements to support the
digestion and cleansing cycle. This may include bile and a
combination of Betaine HCL, pepsin, and pancreatin with larger
meals and Iberogast between meals.

AS Supplements—Advanced

To combat E. coli and Klebsiella, follow a short-term pathogen-
fighting protocol for one or two months. This consists of a
Level 3 probiotic (Mutaflor is the preferred option for AS)
taken before bed each day, along with lactoferrin, berberine,
and allicin taken half an hour before meals. Mutaflor can also
be continued longer term if needed.
For additional anti-inflammatory maintenance or pain relief,
consider supplementing with curcumin in the form of Meriva.


Part 4. In the Kitchen

***
 Chapter 11. Planning Ahead and Other Kitchen Tips


Adapting to a new diet is challenging enough, but if you are also battling joint
pain or chronic illness, it is particularly important to minimize the stress and
effort involved in preparing healthy meals. The best way to do this is by keeping
meals simple, planning ahead, and taking every shortcut available to you. To
that end, this provides basic tips to make low-starch, allergen-free food
preparation quicker and easier.

General Tips

Keep it simple. Rather than trying to alter recipes for favorite foods by
substituting with “safe” ingredients, start with a clean slate and focus on simple
meals built around vegetables and protein.

Double recipes. Whenever you cook something that will store well, double or
triple the recipe then save a portion for breakfast or lunch the next day and
freeze the leftovers. This strategy will dramatically cut down on meal
preparation time.

Batch cook. Every two to four weeks, spend a couple of hours batch cooking
foods to have on hand in the freezer. Good freezer staples include chicken
soup, stews, and breakfast sausage patties (specific recipes are provided in
chapter 12).

Order supplies online. Items such as collagen peptides and good-quality canned
salmon are useful to have on hand and are often cheaper if you order online,
particularly if you buy in bulk or through programs such as Amazon’s Subscribe
and Save.

Rely on meals, not snacks. Snacking halts the natural process that sweeps the
small intestine clear of food debris and pathogens between meals. Separating
meals by four hours is therefore a useful tool to treat and prevent bacterial
overgrowth and to allow the digestive system time to enter into cleaning and
repair mode. To avoid snacking, it is important to eat meals that are substantial
enough to hold you over until the next meal, with a good amount of protein
and fiber at each meal. If you do need to snack, the best options are fruit,
additive-free deli meat, and raw vegetables with guacamole.

Take shortcuts. If joint pain makes chopping vegetables difficult for you, cook
them whole, use a food processor, microwave briefly to soften before cutting,
or buy precut vegetables. It is also worth investing in a very sharp knife and
vegetable peeler.

Freeze herbs. To save fresh herbs such as basil, parsley, or cilantro, simply
blend with olive oil and then pour the mixture into ice cube trays to freeze.
When frozen, the herb cubes can be transferred to a zip-top bag until you need
them. Fresh ginger also freezes well. If you have excess thyme or rosemary,
allow the leaves to dry thoroughly in the sun or a low oven (200°F) then
combine with sea salt in a small jar.

Stock your freezer with proteins. Freeze uncooked hamburger patties, chicken
pieces, and fish fillets so you are never caught without an easy dinner option.
To thaw, the best method is a warm-water bath. Place the food in a zip-top bag
then submerge in a pot or large bowl filled with warm water. (Partially immerse
the bag in the water before sealing, to force the air out.) Individual portions will
typically take 10 to 30 minutes to thaw. To speed up thawing, replace the water
with more warm water after 10 minutes. Larger items such as a whole chicken
may take over an hour to thaw, so the container must be refrigerated during
thawing.

Rely on add-ons for family members. Instead of cooking entirely different
meals for children or other family members who are not following such a
restrictive diet, an easier approach is to prepare a protein and one or two
vegetables, then round out meals for other family members with an easy-to-
prepare carbohydrate such as rice or gluten-free pasta.

Breakfast Strategies

Breakfast is usually the meal that changes the most when people begin an anti-
inflammatory elimination diet because typical Western breakfast foods heavily
emphasize starch, dairy, and eggs. Yet a protein-rich breakfast without these
problematic ingredients does not have to be complicated or time consuming.
By stocking your freezer in advance, breakfast can be as simple as heating one
or two chicken sausage patties and then adding fresh berries or melon. You can
also make a quick roll-up with turkey or ham deli meat, avocado, and lettuce.
Another good option is to make a smoothie with frozen berries and hydrolyzed
collagen protein powder.
Collagen powder has the added bonus of including the specific amino acids
needed to repair skin and joints. The optimal form of collagen for this purpose
is marine collagen, but hydrolyzed beef collagen is also a good choice for most
people. (The main advantage of marine collagen is that it is much lower in
glutamate, which can cause insomnia or mood disturbances in some
individuals.) Note that most collagen supplements are a combination of type 1
and type 3 collagen, which provide the amino acids needed to repair collagen
throughout the body. Specialized type 2 collagen powders are also available to
target cartilage repair, but these are typically taken in small doses as a
supplement, rather than a dietary protein source.

Lunch Strategies
Salads are the best default for quick and easy lunches. A good way to
streamline weekday lunches is to wash and slice enough salad vegetables for
several days then store each prepared vegetable in its own individual container
in the fridge. You will then be able to assemble a salad in a few minutes on busy
weekday mornings. Vegetables that store well preprepared include sliced
radishes, shredded carrots, shredded cabbage, sliced mushrooms, and raw or
very lightly steamed broccoli florets, green beans, and snap peas. All of these
vegetables will typically stay fresh for at least three days. You can also preroast
a large batch of vegetables to add to salads, including carrots, zucchini, Brussels
sprouts, and fennel.
For a complete meal, just assemble the salad with a basic dressing, then add
a preprepared protein such as good-quality deli meats, canned salmon, or
leftover roast or grilled chicken. (The next chapter includes a simple recipe for
brining chicken, which allows cooked chicken to freeze well without drying out.)
Another simple strategy for lunches is to make a large batch of chicken soup
and freeze individual portions. You can then either microwave the soup at work
if you have that option, or heat the soup at home and take it in a thermos
container.

Dinner Strategies

There are three basic approaches for preparing quick and easy dinners in the
context of the Keystone Diet:

1. Sheet-pan dinners. Add a protein with one or two vegetables and
roast together on a single sheet pan. The entire meal typically
takes 20 to 30 minutes to prepare and is almost entirely hands-off
(see specific tips below).
2. Simply grilled, stir-fried, steamed. By pan-frying fish, chicken, or
steak while steaming or stir-frying a mix of vegetables, you can
make a complete meal in 10 minutes.
3. Pressure-cooker stews. By investing in an Instant Pot, you can
combine inexpensive cuts of meat (such as lean beef stew or
bone-in chicken thighs) with herbs and vegetables, then cook for
20 to 40 minutes to make a large batch of fork-tender meat that
freezes well.


Tips for Sheet-Pan Dinners

Sheet-pan dinners are a perfect way to make a quick meal with very little
cleanup. For best results, use a rimmed metal sheet pans and take care not to
overcrowd the sheet. When there is not enough space around chicken and
other meats for juices to evaporate, they can steam and become tough. (If
needed, use two separate sheet pans.)
There are endless combinations of ingredients to use for sheet-pan dinners,
but the process is even simpler if you pair proteins with vegetables that take
approximately the same time to cook. Examples include

Chicken drumsticks with Brussels sprouts and carrots (35 to
40 minutes)
Chicken breasts with mushrooms and zucchini (20 minutes)
Salmon with green beans (15 minutes)

You can also use whatever combination you have on hand by adding
components to the sheet pan in stages, giving ingredients that require longer
cooking times a head start. Before roasting, lightly coat everything with olive oil
and add flavorings such as dried herbs. Herbs that work well include thyme,
rosemary, sage, and oregano. You can also finish dishes with fresh basil,
parsley, cilantro, or chives.
 Precise cooking times will depend on sizes, spacing on the sheet pan, and
taste preferences, but a rough guide is provided below (for a preheated 400°F
oven).

Chicken drumsticks 40 minutes
Bone-in chicken thighs 35 minutes
Boneless chicken thighs 25 minutes
Chicken breasts 20 minutes
Lamb chops 17 minutes
Salmon 15 minutes
Meatballs 15 minutes
Shrimp 8 minutes

Brussels sprouts, halved 35 minutes
Carrots 35 minutes
Fennel 35 minutes
Baby carrots 25 minutes
Cauliflower 25 minutes
Mushrooms, sliced 20 minutes
Zucchini 20 minutes
Broccoli 20 minutes
Summer squash 15 minutes
Green beans 15 minutes


Perfectly Steamed Vegetables

For maximum antioxidants (and flavor), it is important to steam vegetables for
only a very short time, until they are just tender but still crisp. The exact time
will vary depending on your setup and how much you are cooking at once, but
approximate times are given below.

Asparagus 3 to 5 minutes
Broccoli 2 to 3 minutes
Cabbage 2 to 3 minutes
Carrots 5 to 7 minutes
Cauliflower 4 to 5 minutes
Green beans 3 to 5 minutes
 Sugar snap peas 2 to 3 minutes
Summer squash 3 to 4 minutes
Zucchini 3 to 4 minutes

Basic Steaming Method
Place a large metal steamer basket (OXO is a good brand) in a pot with 1 inch of
boiling water. Vegetables will cook more evenly if the pot is large enough for
the metal basket to remain fully open. Chop vegetables into large chunks (1 to 2
inches). Distribute the vegetables evenly in the steamer basket, ideally in a
single layer. Cover the pan and set a timer for 2 or 3 minutes. Check whether
the vegetables have become slightly tender and continue cooking a few
minutes longer if needed. Immediately transfer to a plate to serve. If using a
mixture of different vegetables, add longer-cooking vegetables, such as carrots
or cauliflower, a couple of minutes before adding quicker-cooking vegetables,
such as broccoli and zucchini.
Leftover steamed vegetables can be stored in the refrigerator for several
days. They can then be added to salads or used as crudité with guacamole. For
these uses, it is particularly important to remove the vegetables from the heat
when still slightly crunchy.

Adding flavor
After steaming, you can drizzle the vegetables with olive oil and flavorings.
Examples include

2 tablespoons olive oil and juice of ½ lemon with ½
teaspoon salt
2 tablespoons olive oil and 1 tablespoon rice syrup (works
best for carrots)
2 tablespoons olive oil and 5 to 10 fresh basil leaves, sliced

 Chapter 12. The Recipes

All the recipes in this section are suitable for the basic, intermediate, and
advanced low-starch plans, although minor modifications may be noted for the
advanced plan. The recipes are also suitable for those eliminating nightshades,
dairy, nuts, and eggs.
To avoid the fructans in garlic and onion, the recipes use garlic-infused oil
and the green part of scallions (spring onions) instead of red or white onions. If
you do not notice any benefit from limiting fructans, you can modify recipes to
simply use crushed garlic and red or white onion if you prefer.
For the recipes that contain mayonnaise, an olive oil– or avocado oil–based
mayonnaise is the best choice for those that tolerate egg. If you are eliminating
egg, there are egg-free brands available (such as Hellman’s vegan), but these
should be used sparingly because they typically contain a small amount of corn
or potato starch and undesirable oils.
Most recipes include a small amount of added salt, but this can be omitted or
reduced if you prefer. There is some evidence that a high-salt diet is
501
inflammatory, but more than 75 percent of the salt Americans consume
comes from packaged, processed, and restaurant foods. Once these foods are
eliminated, you can add salt to meals and still maintain a relatively low-sodium
diet. A very low carbohydrate diet also requires additional sodium to maintain
proper electrolyte balance.


 Breakfast


Green Juice
(serves 1)

1 small bunch kale or collard greens (or ½ large bunch)
4 celery stalks
½ cup cubed honeydew melon
½ cucumber, peeled
½ cup parsley (optional)
5 to 10 mint or basil leaves (optional)
Juice of ½ lemon

Juice all the ingredients except the lemon in an electric juicer or high-speed
blender. Squeeze the lemon juice into a glass then add ice and the green juice.
Stir to combine.


Blueberry Smoothie
(serves 1)

2 to 3 scoops collagen peptide powder
½ cup water
½ cup frozen blueberries
½ banana (omit for advanced low-starch)
½ cup crushed ice
1 tablespoon olive or avocado oil

Mix the collagen powder and water in a glass. Add to the blender with the
other ingredients and blend until smooth.


Keto Green Smoothie
(serves 1)

2 to 3 scoops collagen peptide powder
¾ cup water
3 to 5 kale leaves or a handful of spinach
 ½ avocado
½ cup crushed ice
Juice of ½ lime
Handful parsley, basil, mint, or a combination

Mix the collagen powder and water in a glass. Add to the blender with the
remaining ingredients and blend until smooth.


Apple and Sage Chicken Sausage
(serves 6)

2 pounds ground chicken (preferably made from a mix of skinless
thighs and breast)
2 peeled apples, finely diced (optional)
5 fresh sage leaves, finely chopped, or 1 teaspoon dried sage
1 teaspoon sea salt
2 tablespoons olive oil
1 to 2 teaspoons honey or brown rice syrup (optional)

Preheat the oven to 425°F. In a large bowl, mix together all the ingredients
and then shape into patties about 2 inches wide. Bake on a foil-lined baking
sheet for 12 to 15 minutes. Alternatively, for additional flavor (but more effort),
pan-fry the patties in olive oil.
To freeze, allow the patties to cool then place in small zip-top freezer bags or
wrap in plastic wrap and store in freezer-safe containers.


American Breakfast Sausage
(serves 6)

2 pounds lean ground beef
1 tablespoon olive oil
1 scallion/spring onion, green portion, chopped
1 teaspoon sea salt
1 teaspoon dried sage
¼ teaspoon dried marjoram
1 tablespoon brown rice syrup (optional)

 Preheat the oven to 425°F. In a large bowl, mix together all the ingredients
and then shape into patties about 2 inches wide. Bake on a foil-lined baking
sheet for 12 to 15 minutes.
To freeze, allow the patties to cool then place in small zip-top freezer bags or
wrap in plastic wrap and store in freezer-safe containers.


Chia Protein Pudding
(serves 1)

2 scoops collagen peptide powder
½ cup water (or any form of milk)
2 tablespoons chia seeds
1 tablespoon nut butter or sunflower butter (optional)
Fresh, frozen, or dried berries (optional)
½ tablespoon avocado oil (optional)
2 tablespoons unsweetened shredded coconut (optional)

Put the collagen peptides in a small bowl or cup then pour the water and stir
to combine. Add the chia seeds, stir, then refrigerate overnight. When ready to
eat, top with your choice of nut butter or sunflower butter, berries, avocado oil,
or dried coconut.


Flax Porridge
(serves 1)

2 tablespoons freshly ground flax seeds
½ cup boiling water
2 tablespoons hemp hearts
2 tablespoons unsweetened shredded coconut
2 tablespoons collagen peptide powder
¼ teaspoon ground cinnamon
1 teaspoon brown rice syrup (optional)
½ tablespoon avocado oil (optional)
Fresh, frozen, or dried berries (optional)

Combine the ground flax seeds and boiling water in a bowl. Add the
remaining ingredients and stir until well combined. Add additional water or a
milk of your choice if needed and any toppings you choose, such as berries or
chopped nuts. If you prefer, hemp hearts can also be substituted with chia
seeds that have been soaked in water or a milk of your choice.


Chicken and Kale Hash
(serves 1)

3 large kale leaves
1 leftover cooked chicken breast
2 tablespoons avocado oil
¼ teaspoon salt
1 pinch poultry seasoning
¼ cup water
¼ cup chopped parsley

Remove the center ribs from the kale and chop the leaves. Slice the chicken
into cubes and fry in the avocado oil until lightly browned. Transfer the chicken
to a plate. Add the kale to the pan with the salt, poultry seasoning, and water.
At this stage you can also add any other leftover cooked vegetables. Cover and
cook for 3 minutes. Return the chicken to the pan, along with the parsley, and
toss to combine.

Salads


Perfect Brined Roast Chicken Breasts for Salads
(serves 6)

2 tablespoons salt
1 tablespoon fresh rosemary
1 teaspoon dried thyme
½ cup boiling water
2 cups ice water
3 large chicken breasts
Olive oil

Brining chicken allows it to retain its flavor and moisture when stored in the
refrigerator or freezer. To prepare the brine, dissolve the salt, rosemary, and
thyme in the boiling water. In a large glass bowl or zip-top bag, mix the salt
solution with the ice water. Add the chicken breasts then cover and refrigerate
for 2 to 12 hours. (If brining for more than 3 or 4 hours, only use 1½
tablespoons of salt.) When ready to cook the chicken, preheat the oven to
425°F. Rinse then dry the chicken with paper towels. Coat lightly with olive oil
and then roast for 17 to 20 minutes until cooked through. (Alternatively, grill or
broil until cooked through.)
Store in the refrigerator for 2 to 3 days or in the freezer for 1 month. If
freezing, allow to cool completely, wrap individual portions tightly in plastic
wrap, then combine portions in a labeled zip-top bag. Thaw briefly in the
microwave then add to salads or other dishes.
This approach also works well with a whole chicken. Simply double the brine
recipe then roast the chicken at 425°F for 1 hour, 15 minutes or until the juices
run clear.


Californian Chicken Salad
(serves 2)

2 to 3 tablespoons mayonnaise
1 tablespoon olive oil
1 tablespoon freshly squeezed lemon juice
2 roast chicken breasts, cubed
½ cup black or red grapes, halved
2 celery stalks, sliced
5 basil leaves, sliced into ribbons
½ avocado, diced (optional)

In a large bowl, combine the mayonnaise, oil, and lemon juice and whisk. Add
the chicken, grapes, and celery, and stir to combine. Add the basil and avocado.
Stir gently to combine again.


Ranch Chicken Wrap
(serves 2)

2 to 3 tablespoons mayonnaise
1 tablespoon olive oil
1 tablespoon freshly squeezed lemon juice
 1 tablespoon each chopped fresh dill, parsley, basil, chives (or any
combination)
½ teaspoon onion powder (optional)
½ teaspoon mustard (optional)
½ avocado, mashed
1 scallion/spring onion
1 celery stalk, finely chopped
2 roast chicken breasts, cubed
Lettuce, collards, or kale for serving

Whisk together the mayonnaise, oil, lemon juice, herbs, onion powder, and
mustard. Add the avocado, chopped scallion, and celery, then stir in the
chicken. Serve in lettuce cups or wrap in a collard or kale leaf with the rib
removed.
Arugula Chicken Salad
(serves 2)

Juice of 1 lemon (3 tablespoons)
1 teaspoon brown rice syrup
2 tablespoons extra-virgin olive oil
½ teaspoon salt
1 package arugula/rocket (or baby kale or spinach)
1 roast chicken breast, shredded

In a small bowl, whisk together the lemon juice, brown rice syrup, olive oil,
and salt. Pour the dressing over the arugula, add the chicken, and toss to
combine.


Salmon Salad Wrap
(serves 1)

¼ or ½ avocado, mashed
1 tablespoon mayonnaise
½ scallion/spring onion, white and green parts
Squeeze of lemon juice
1 teaspoon olive oil
1 can salmon, drained
 ½ celery stalk, chopped

In a small bowl, combine the avocado, mayonnaise, scallion, lemon juice, and
olive oil. Lightly mash the salmon and add to the dressing along with the
chopped celery. Mix to combine.
Enjoy as is, wrap in a sturdy green leaf (collard, kale, lettuce), or use as a dip
for sliced cucumber or celery sticks. To use as a dip, omit the celery from the
salmon mixture. If you prepare the salad in advance to take to work, omit the
avocado.


Kale Salad
(serves 2 to 4)

1 garlic clove, crushed
2 tablespoons olive oil
1 bunch kale, rinsed
Juice of 1 lemon
½ teaspoon salt

Crush or chop the garlic and add it to the olive oil in a small pan. Heat gently
for 5 minutes. Meanwhile, cut each kale leaf lengthwise to remove the tough
rib, then stack the leaves and slice into small ribbons. Transfer the kale to a
large bowl and add the lemon juice and salt. Scrunch and release handfuls of
kale to massage the juice into the leaves to soften them. Drizzle over the olive
oil (remove and discard the garlic) and toss to combine. Allow to sit for at least
15 minutes before serving.

Main Dishes

Fish

Simple Crispy Salmon
(serves 4)

4 fresh salmon fillets (about 6 ounces each)
1 tablespoon olive oil
Salt

 For a crispy flesh side: Preheat the oven to 400°F. Set an oven-safe pan over
medium-high heat. While the pan heats, thoroughly dry the salmon with paper
towels and lightly coat with the olive oil and a sprinkle of salt. Place the salmon
in the pan, flesh-side down, and cook for 5 minutes or until it releases easily
from the pan. Flip the salmon to skin-side down and immediately transfer the
pan to the oven. Bake for 5 to 10 minutes until cooked.

For a crispy skin: Heat a pan over medium-high heat. Dry the salmon with
paper towels and coat with the olive oil and a sprinkle of salt. Lower the heat to
medium-low. Place the salmon skin-side down in the pan and continuously
push down on the fillets with a spatula for several minutes to keep the skin in
contact with the pan. (For multiple fillets, push down using a metal pot lid
smaller than the skillet.) After the first few minutes, push down occasionally
until the skin is browned and crispy, about 6 minutes. Flip the salmon to flesh-
side down and cook another 1 to 2 minutes.

Tartare Sauce
2 teaspoons fresh chives
2 teaspoons fresh dill
2 teaspoons fresh parsley
2 scallions/spring onions
1 teaspoon capers
4 tablespoons mayonnaise
¼ teaspoon Dijon mustard
Juice of ½ lemon

Finely chop the herbs, scallions, and capers, then combine with the
mayonnaise, mustard, and lemon juice. Allow the flavors to combine before
serving, preferably for at least an hour. Store in the refrigerator for up to 2
days.


Cuban Salmon
(serves 4)

4 salmon fillets
Zest of 1 lime
1 teaspoon orange zest
 ¼ cup finely chopped fresh cilantro
1 tablespoon chopped fresh rosemary
¼ cup olive oil
½ teaspoon turmeric
½ teaspoon salt
1 teaspoon brown rice syrup (optional)
Juice of ½ lemon

Remove the skin from the salmon. To prepare the marinade, combine the
lime and orange zest, cilantro, rosemary, oil, turmeric, salt, and brown rice
syrup. Marinate the salmon for 2 to 6 hours. Remove from the refrigerator 30
minutes before cooking and add the lemon juice. When ready to cook, lightly
pat the salmon dry, then grill, broil, or panfry until cooked through.


Parisian Fish
(serves 4)

3 shallots
2 teaspoons capers, drained
3 tablespoons mayonnaise
1 tablespoon Dijon mustard
1 tablespoon olive oil
1 tablespoon freshly squeezed lemon juice
1 teaspoon grated lemon zest
4 fish fillets (any flaky white fish)
Chives or parsley (optional)

Preheat the oven to 425°F. Finely chop the shallots, then combine with the
capers, mayonnaise, mustard, olive oil, lemon juice, and zest. Place the fish
fillets skin-side down in a shallow baking dish. Spread the sauce over the top of
each fillet, then bake for 10 to 15 minutes until the fish flakes easily with a fork.
Serve garnished with finely chopped chives or parsley.

Ginger Lime Fish Parcels
(serves 4)

4 fish portions (salmon or any flaky white fish)
1 tablespoon olive oil
 Zest and juice of 1 or 2 limes
2-inch piece of fresh ginger, thinly sliced
3 scallions/spring onions, sliced
½ teaspoon salt

Preheat the oven to 400°F. Place each piece of fish on a large square of
parchment paper. Brush the fish lightly with the oil, then top with the lime zest,
ginger, scallions, and a sprinkle of salt. Bring the edges of the parchment paper
together and fold over several times to close into a parcel. Bake for 12 to 16
minutes, depending on the thickness of the fish. When cooked through, remove
the fish from the parcel, discard the ginger pieces, and sprinkle with the lime
juice.


Peruvian Ceviche
(serves 2 to 4)

1 pound very fresh white fish (such as halibut), skin removed
½ cup freshly squeezed lime juice
2 scallions/spring onions (green part only), finely sliced
1 tablespoon chopped fresh cilantro or parsley
1 teaspoon salt

Using a large, very sharp knife, slice the fish into 1½-inch cubes. Place the
cubes in a bowl of chilled water. Drain the fish and combine with the lime juice,
scallions, cilantro, and salt. Cover and refrigerate for 30 minutes before serving.


Panfried Fish with Greek Herb Sauce
(serves 2)

2 to 4 fillets of any flaky white fish
1 garlic clove
½ cup olive oil
¼ cup fresh oregano, chopped
¼ cup fresh parsley, chopped
2 to 3 tablespoons freshly squeezed lemon juice
½ teaspoon salt

 To prevent sticking, rest the fish at room temperature between layers of
paper towel for 20 minutes before cooking. To prepare the sauce, slice the
garlic and add to the olive oil in a small pan. Heat gently for 5 minutes. Discard
the garlic and blend the garlic-infused oil with the oregano, parsley, lemon
juice, and salt in a blender or small food processor.
When ready to cook the fish, heat the olive oil in a large pan over medium-
high heat. Place the fish in the pan, skin-side down. Cook until the skin is crisp
and releases from the pan, 3 to 4 minutes. Flip the fish and finish cooking 1 to 2
minutes longer. Serve with the herb sauce.


Sardine Salad
(serves 1)

1 can sardines in water, drained
1 scallion/spring onion, finely chopped
2 tablespoons chopped fresh parsley and/or chives
2 tablespoons freshly squeezed lemon juice
1 tablespoon olive oil
1 teaspoon capers
Bib lettuce

Drain and lightly mash the sardines. Combine the sardines with the remaining
ingredients and serve in lettuce cups.


Chicken

Chicken and Vegetable Soup
(serves 8)

3 to 4 pounds bone-in chicken pieces or whole chicken, cut into pieces
2 teaspoons salt
4 large carrots (omit for advanced low-starch), divided
4 celery stalks, divided
2 teaspoons dried thyme (or 2 fresh sprigs)
1 teaspoon dried sage (or 5 fresh leaves)
2 bay leaves
2 zucchini (or summer squash)
 ½ cup broccoli florets
2 tablespoons chopped fresh parsley
2 tablespoons chopped fresh dill

Remove the skin from the chicken pieces. Place the chicken in a large soup
pot and cover with water. Add the salt, 2 carrots, 2 celery stalks, thyme, sage,
and bay leaves. Simmer for approximately 1½ hours, occasionally skimming the
foam that appears on the surface. Use tongs to transfer the chicken pieces to a
plate to cool. Strain the broth into another pot, discarding the solids. Dice the
remaining carrots and celery, zucchini, and broccoli then add to the broth and
simmer for 5 minutes. Meanwhile, pull the chicken meat from the bones and
chop into small pieces. Return the chicken to the pot, along with the parsley
and dill.
(Alternatively, if you prefer chicken breast, you can add two skinless chicken
breasts after the first hour of simmering the broth, then discard the dark-meat
chicken on the bones.)


Lemon-Herb Roast Chicken
(serves 4)

1 lemon, zested and then quartered
1 to 2 tablespoons fresh thyme (or 2 teaspoons dried)
1 teaspoon dried sage or dried mixed herbs
2 tablespoons olive oil
1 teaspoon sea salt
1 whole (4- to 5-pound) chicken
6 garlic cloves

Preheat the oven to 425°F. To prepare the herb rub, combine the lemon zest
in a small bowl with the thyme, sage, olive oil (substitute garlic-infused oil for
additional flavor), and salt. Remove any giblets from the chicken cavity and dry
the outside with paper towels. Gently separate the skin from the chicken
breasts and add spoonfuls of the herb rub to the space underneath the skin.
Cover with the skin again and rub the outside to evenly distribute the herb
mixture. Rub any leftover mixture (or a drizzle of olive oil and salt) over the
outside of the bird.
Stuff the chicken cavity with the lemon quarters and whole garlic cloves.
Roast for 1 hour, 15 minutes until juices run clear when a knife is inserted near
the thigh.
(To serve with roasted vegetables, add carrots and Brussels sprouts on a
rimmed baking sheet after the first 45 minutes of cooking time.)

Chicken Souvlaki
(serves 4)

2 garlic cloves, sliced
¼ cup chopped fresh oregano (or 2 tablespoons dried)
1 teaspoon dried marjoram, rosemary, or mixed herbs
¼ cup olive oil
Zest and juice of ½ lemon (2 to 3 tablespoons)
1 teaspoon sea salt
3 large chicken breasts, cut into quarters

Warm the garlic, oregano, and marjoram in the olive oil over low to medium
heat for 5 minutes. Allow the oil to cool then discard the garlic. Pour the
infused oil into a bowl or zip-top bag, reserving 1 tablespoon for the sauce. Add
the lemon zest, lemon juice, salt, and chicken breasts. Marinate the chicken for
30 minutes at room temperature. Place the chicken on a rimmed baking sheet
lined with foil and broil under high heat until cooked through, 5 to 10 minutes
(or grill).
To serve with a Greek tzatziki-style sauce, combine 1 avocado, 1 grated
cucumber, 1 tablespoon garlic-infused oil, the juice of ½ lemon, ½ teaspoon
salt, and 1 tablespoon chopped fresh dill.


Grilled Italian Lemon Chicken
(serves 2)

2 chicken breasts
3 tablespoons olive oil
2 tablespoons freshly squeezed lemon juice
1 tablespoon finely chopped fresh rosemary
2 garlic cloves, sliced
1 teaspoon grated lemon zest

Place the chicken breasts in a plastic bag and pound to an even thickness.
Transfer the chicken to a glass bowl or baking dish, add the remaining
ingredients, and marinate for 30 minutes at room temperature or several hours
refrigerated. Remove the garlic slices. Grill or panfry the chicken until cooked
through, 3 to 5 minutes on each side.


Chicken Florentine
(serves 2)

1 (8-ounce) package mushrooms, such as chanterelle, crimini, or button
1 shallot
2 garlic cloves
2 boneless skinless chicken breasts
1 teaspoon dried thyme (or Italian seasoning)
½ teaspoon salt, plus more to taste
4 tablespoons olive oil, divided
1 (6- to 8-ounce) package baby spinach

Quarter the mushrooms and finely slice the shallot and garlic. Place each
chicken breast between two layers of plastic wrap and pound lightly to flatten
to an even thickness. Sprinkle the chicken with the thyme and salt. Set a cast-
iron skillet over medium heat and add the olive oil. Add the chicken and cook
until lightly brown, about 5 minutes on each side. Meanwhile, in a separate
pan, heat the remaining 2 tablespoons of olive oil over medium heat. Add the
mushrooms, garlic, and shallot and sauté 5 minutes. Remove the garlic and add
the spinach. Cover the pan and cook until the spinach wilts. Stir well and add
salt to taste. To serve, top each chicken breast with the spinach and mushroom
mixture.


Chicken Stir-Fry with Ginger and Garlic
(serves 4)

8 boneless chicken thighs
3 tablespoons olive oil, divided
3 garlic cloves
1 to 2 cups sliced red cabbage
1 zucchini, sliced
1 cup mushrooms
 2 tablespoons grated ginger
2 scallions/spring onions (green parts), sliced
1 teaspoon salt
½ teaspoon white pepper
¼ cup water

Panfry the chicken thighs in 1½ tablespoons of olive oil over high heat, 3 to 5
minutes per side. Meanwhile, in a separate large pan, heat the remaining 1½
tablespoons of olive oil over medium heat. Add the garlic and cook for 2
minutes then remove and discard the garlic. Add the cabbage, zucchini,
mushrooms, grated ginger, scallions, salt, and pepper. Add the water. Cover the
pan and steam the vegetables for 2 minutes. Slice the chicken thighs then add
to the pan with the vegetables. Toss to combine.


Chicken with Mushrooms and Sage (Instant Pot)
(serves 4)

2 tablespoons olive oil
4 garlic cloves, sliced
8 boneless chicken thighs, skin removed
2 cups mushrooms, halved
8 fresh sage leaves, chopped
½ cup water
½ teaspoon dried thyme
½ teaspoon sea salt
2 tablespoons chopped fresh basil

Set the Instant Pot to sauté. Combine the olive oil and garlic in the pot and
lightly brown the chicken thighs. Remove and discard the garlic. Add the
mushrooms, sage, water, thyme, and salt. Close the lid and cook at high
pressure for 15 minutes (or 25 minutes if the chicken is frozen). Quick release
the pressure. Serve topped with the fresh basil.

Alternate cooking method: Brown the chicken in an oven-safe cast-iron pan.
Add the remaining ingredients and braise in a 325°F oven for 30 to 40 minutes.



 Beef

Steak with Argentinian Chimichurri
(serves 2)

2 steaks
½ teaspoon salt
¾ cup extra-virgin olive oil, plus 1 tablespoon
2 garlic cloves, sliced
1 bunch flat-leaf parsley
Zest and juice of 1 lemon
1 tablespoon diced onion

Take the steaks out of the refrigerator 30 minutes before cooking and
sprinkle lightly with the salt. Warm ¾ cup of olive oil with the garlic for 5
minutes. Allow the oil to cool then discard the garlic. To prepare the chimichurri
sauce, process the garlic-infused oil with the parsley, lemon zest and juice, and
onion in a blender or food processor.

To prepare the steaks, preheat the oven to 325°F. Dry the steaks thoroughly
with a paper towel then coat with the remaining tablespoon of olive oil. Heat
an ovenproof cast-iron pan over medium-high heat. Briefly sear the steaks on
one side (2 to 3 minutes). Flip the steaks and transfer the pan to the oven to
finish cooking, about 5 minutes for rare, 10 minutes for well done. (Use caution
removing the pan from the oven, as the handle will be hot.) Allow to rest for 5
minutes before serving with the chimichurri.


Burger Salad
(serves 4)

2 pounds lean ground beef
Salt
1 tablespoon olive oil
1 cup mushrooms
2 radishes
2 small cucumbers
1 scallion (green parts)
 1 head lettuce
1 avocado, pitted and sliced

Dressing
¼ cup olive oil
2 tablespoons Dijon mustard
½ teaspoon brown rice syrup (optional)
Juice of ½ lemon

Shape the ground beef into four large patties. Heat a grill pan over medium-
high heat. Lightly coat the burger patties with salt and olive oil. Grill for 3 to 5
minutes on each side until cooked through. In a small bowl, whisk together the
dressing ingredients. Slice the mushrooms, radishes, cucumber, and scallion,
then combine with the lettuce in a large bowl. Dress the salad and toss to
combine. Serve to individual plates, then top with the burger patties and sliced
avocado.


Beef and Cabbage Stir-Fry
(serves 4)

2 pounds ground beef
2 tablespoons olive oil
½ red cabbage, shredded
2 garlic cloves, sliced
½ teaspoon powdered ginger or 1 teaspoon fresh ginger
1 teaspoon salt
2 scallions/spring onions (green parts), chopped
3 small bunches baby bok choy
1 tablespoon freshly squeezed lemon or lime juice

Sauté the beef in the olive oil until cooked through. Transfer the beef to a
bowl, then in the same pan sauté the cabbage with the garlic, ginger, and salt
until the cabbage is tender, approximately 5 minutes. Remove and discard the
garlic. Add the scallions, bok choy, cooked beef, and lemon juice. Cook for 1 to
2 minutes more, then serve.


Turkish Beef Kebabs
 (serves 4)

¼ cup minced fresh parsley
2 teaspoons finely chopped fresh rosemary
1 teaspoon dried oregano
1 scallion/spring onion (green part), finely chopped
1 teaspoon salt
1 pinch saffron (optional)
2 pounds lean ground beef

In a large mixing bowl, combine the parsley, rosemary, oregano, scallion, salt,
saffron, and ground beef. Shape into sausages and place on skewers to grill (3
to 5 minutes on each side) or on a foil-lined rimmed baking sheet to bake or
broil. (Bake at 425°F for 10 to 15 minutes.)

Pork

Pork tenderloin
(Serves 2 to 4)

1 garlic clove, sliced
1 tablespoon chopped fresh rosemary
1 tablespoon chopped fresh thyme
2 tablespoons olive oil
1 pork tenderloin
1 teaspoon salt

Warm the garlic, rosemary, and thyme in the olive oil over low to medium
heat for 5 minutes. Allow to cool then remove and discard the garlic solids. Rub
the garlic-infused oil over the pork tenderloin, sprinkle with the salt, then
refrigerate for at least 2 hours or overnight. Take out of the refrigerator 30
minutes before cooking. Preheat the oven to 425°F degrees. Roast for 18 to 20
minutes or until a thermometer shows an internal temperature of 145°F.
(Additional time may be needed if the tenderloin is larger than 1 pound.) This
recipe can also be made with boneless pork loin by doubling the amount of
herbs, garlic, and oil, and roasting at 350°F for 1 to 1½ hours.

Turkey

Turkey Burgers
(serves 2 to 4)

1 medium zucchini
1 carrot (omit for advanced low-starch)
1 pound lean ground turkey
3 scallions/spring onions (green parts), finely chopped
1 teaspoon salt
2 tablespoons olive oil or avocado oil

Grate the zucchini then wrap in a clean kitchen towel and squeeze out as
much moisture as possible. Grate the carrot and combine with the zucchini and
remaining ingredients. Form into patties and refrigerate for at least 2 hours or
overnight. Separate the patties with plastic wrap or parchment paper if needed
to stop them sticking together. Grill or panfry over medium-high heat for about
4 minutes each side until cooked through.


Turkey Meatball Soup

3 carrots (omit for advanced low-starch)
3 celery stalks
3 cups low-sodium chicken broth
1 pound lean ground turkey
1 tablespoon olive or avocado oil
1 teaspoon salt
1 to 2 cups chopped kale or spinach

Place the carrots, celery, and broth in a pot over medium-high heat. Bring to
a boil then reduce the heat to low and simmer for 5 minutes. While the
vegetables are cooking, prepare the meatballs. Combine the turkey, oil, and salt
in a bowl and form into one-inch meatballs. Add the meatballs to the broth and
simmer over low heat for 10 to 15 minutes or until cooked through. In the last 5
minutes of cooking, add the kale, spinach, or any other leafy greens.


Lamb

 Roast Leg of Lamb
(serves 8 to 10)

10 garlic cloves, halved or quartered into long slivers
¼ cup olive oil
½ cup fresh rosemary leaves
½ tablespoon salt
1 (5 pound) boneless leg of lamb, tied with netting

Preheat the oven to 425°F. Prepare the garlic-infused oil by warming the
sliced garlic in the olive oil. Allow to cool, then remove and discard the garlic.
Combine the garlic-infused oil, rosemary, and salt then rub over the lamb to
coat. (If it is tied with stretchy netting, remove the netting, unroll the lamb and
coat the inner surface with the flavored oil before rolling back up and re-
covering with the netting.)
Place the lamb in a roasting pan and transfer to the oven. After 15 minutes,
turn the oven down to 325°F and continue roasting for another 1½ to 2 hours
(add or subtract 20 minutes per pound for larger or smaller roasts) until a meat
thermometer reads 120°F for rare, 130°F for medium-rare, or 140°F for well
done. Cover tightly with foil and let rest for 20 minutes before carving.
Cut leftovers into thick steaks, wrap tightly with plastic wrap, and place slices
together in a labeled zip-top bag. Freeze. When ready to use, thaw slightly in
the microwave then slice thinly and fry in olive oil.


Lamb Shawarma Salad
(serves 2)

12 ounces leftover roast lamb
2 tablespoons olive oil
2 teaspoons chopped fresh rosemary (or ½ teaspoon dried)
1 teaspoon dried oregano
½ teaspoon salt
½ head lettuce

Tzatziki dressing
1 cucumber, grated
1 avocado, mashed
 1 tablespoon olive oil
2 tablespoons freshly squeezed lemon juice
2 teaspoons chopped fresh dill
1 to 2 tablespoons water (if needed)


Combine the ingredients for the tzatziki dressing and set aside. Thinly slice
the leftover roast lamb (this is even easier if the lamb is still slightly frozen). Fry
the lamb in the olive oil with the rosemary, oregano, and salt, until warmed
through and slightly browned. Serve over lettuce, topped with the tzatziki
dressing.


Moroccan Lamb Stew (Instant Pot)
(serves 4)

2 pounds lamb stew meat
1 tablespoon olive oil
3 carrots, chopped
2-inch piece fresh ginger
1 teaspoon dried rosemary
Zest and juice of 1 orange
1 tablespoon brown rice syrup
1 teaspoon salt
1 cup water
2 zucchini, chopped
2 tablespoons chopped fresh parsley or cilantro

With the Instant Pot set to sauté, lightly brown the lamb in the olive oil. Add
the carrots, ginger, rosemary, orange zest and juce, brown rice syrup, salt, and
water. Close the lid and cook at high pressure for 35 minutes. Manually release
the pressure, then add the zucchini and cilantro and set to sauté for 5 minutes
until the zucchini softens and the sauce reduces.

(Alternatively, lightly brown the lamb in a large Dutch oven. Add the
remaining ingredients then simmer over low heat for 1½ hours, adding the
zucchini in the last 5 minutes.)


 Side Dishes

Kale Slaw
(serves 4)

½ head red cabbage
4 large kale leaves
3 carrots (omit for advanced low-starch)

Dressing
¼ cup olive oil
¼ cup freshly squeezed lemon juice
2 tablespoons finely chopped fresh parsley
1 tablespoon chopped fresh basil
1 scallion/spring onion, finely chopped
1 teaspoon brown rice syrup
½ teaspoon salt

Shred the cabbage in a food processor or finely slice. Remove the ribs from
the kale and finely chop the leaves. Grate the carrots. Combine the remaining
ingredients to make the dressing and pour over the vegetables, tossing to coat.


Fennel Slaw
(serves 4)

1 fennel bulb
½ head cabbage, shredded
2 scallions/spring onions, finely chopped

Dressing
2 tablespoons egg-free mayonnaise
1 tablespoon olive oil
Juice of ½ lemon
1 teaspoon honey
1 teaspoon sea salt
1 tablespoon chopped fresh parsley
2 tablespoons roughly chopped fennel fronds

 Quarter the fennel bulb, remove the core, and then slice thinly. Reserve
some of the fennel fronds for the dressing. Combine the sliced fennel with the
shredded cabbage and scallions. Combine the dressing ingredients in a small
bowl and whisk. Pour the dressing over the vegetables and toss to coat.


Garden Salad with Citrus Dressing
(serves 2 to 4)

1 yellow squash
½ head lettuce
2 cups baby spinach or other salad greens
3 radishes
½ cup white mushrooms

Dressing
2 tablespoons orange juice
2 teaspoons freshly squeezed lime juice
2 teaspoons freshly squeezed lemon juice
6 tablespoons olive oil
½ teaspoon salt

Slice the squash into thin ribbons with a vegetable peeler. Chop the
remaining vegetables. In a small bowl, whisk together the dressing ingredients.
Pour the dressing over the salad and toss to combine.


Kale Chips
(serves 2 to 4)

1 bunch kale
1 tablespoon olive oil
½ teaspoon sea salt

Preheat the oven to 275°F. Wash the kale and dry thoroughly using paper
towels (or wash well in advance and allow to dry). Remove the center ribs and
tear or cut the kale leaves into large pieces. Pile the leaves on a large baking
tray and lightly coat with the olive oil and salt. Mix with your hands then spread
the kale out evenly across the tray. If the leaves are overlapping, it may be
necessary to split into two batches or use two trays. Bake until crisp, about 20
minutes.


Celery Fennel Salad
(serves 4)

1 large fennel bulb
4 celery stalks
3 tablespoons olive oil
2 tablespoons freshly squeezed lemon juice
¼ teaspoon salt
¼ cup fresh basil leaves

Remove the stems and core from the fennel bulb. Slice the fennel as thinly as
possible (or use a mandolin). Cut the celery diagonally into thin slices. Combine
the fennel and celery with the olive oil, lemon juice, and salt and toss to coat.
Stack the basil leaves on top of each other then roll up and slice into thin
ribbons. Sprinkle the basil over the salad and serve immediately.


Sautéed Kale
(serves 2 to 4)

1 bunch kale
2 garlic cloves, sliced
2 tablespoons olive oil
¼ cup water
½ teaspoon sea salt
Juice of ½ lemon

Rinse the kale leaves then remove the ribs and chop the leaves into large
pieces. In a deep pan, cook the garlic in the olive oil over medium heat for 2 to
5 minutes. Remove and discard the garlic then add the kale, water, and salt.
Cover the pan for 3 minutes. Uncover and continue cooking for another few
minutes. Squeeze the lemon juice over the kale and serve.

Marinated Mushrooms
(serves 4)

1 pound small mushrooms
2 tablespoons freshly squeezed lemon juice
½ teaspoon salt
½ teaspoon dried thyme
¼ cup chopped fresh parsley

Bring a pot of water to the boil. Remove the stems from the mushrooms and
add the caps to the pot. After 5 minutes, drain the mushrooms and transfer to a
bowl with the lemon juice, salt, thyme, and parsley. Allow to marinate
overnight. Serve at room temperature.


Fried Cabbage with Ham
(serves 4)

3 slices ham (or lean Canadian bacon)
3 tablespoons olive oil
1 head cabbage, chopped
½ teaspoon salt
¼ cup water

Dice the ham and fry in the olive oil until lightly browned. Add the cabbage,
salt, and water. Cover the pan and cook over medium heat for 3 to 5 minutes.
Remove the lid and continue cooking until the cabbage is tender.


Desserts

Blueberry Mint Jelly
(serves 4)

2 tablespoons gelatin
½ cup pomegranate juice
1 cup frozen blueberries
1 cup boiling water
6 mint leaves, roughly chopped

Combine the gelatin and pomegranate juice. Microwave the blueberries for 1
to 2 minutes until they release some juices. Pour the boiling water over the
gelatin and stir well until dissolved. Mix in the blueberries and mint. Pour into a
muffin tray or a large baking dish and refrigerate until set.


Berry Compote
(serves 2 to 4)

1 ripe pear, grated or finely chopped
½ teaspoon vanilla extract
1 cup frozen blueberries, divided
1 cup frozen blackberries, divided
1 tablespoon freshly squeezed lemon juice

Place the pear, vanilla, half the blueberries, and half the blackberries in a
microwave-safe bowl. Microwave for 5 minutes. Stir in the remaining berries
and lemon juice and microwave for an additional minute. The compote will
thicken slightly as it cools. For an even thicker consistency, add 1 tablespoon of
gelatin mixed with ¼ cup of water to the berries before microwaving.


Pomegranate Jelly
(serves 8)

2 tablespoons gelatin
1½ cups pomegranate juice, divided
1 cup boiling water

Bloom the gelatin in ½ cup of pomegranate juice. Add the boiling water and
stir to combine. When the gelatin is fully dissolved, stir in the remaining 1 cup
of pomegranate juice. Pour into a rectangular baking dish, silicon molds, or a
muffin tray. Refrigerate until set (1 to 2 hours).


Melon Mint Salad
(serves 2 to 4)

1 to 2 tablespoons freshly squeezed lime juice
1 tablespoon olive oil
 2 cups cubed honeydew melon
2 tablespoons chopped fresh mint
1 teaspoon grated lime zest

Pour the lime juice and olive oil over the melon, add the mint and lime zest,
then toss to combine.


 Author’s Note

There is something uniquely unsettling about having a chronic health condition
in which the body essentially turns upon itself. Many of us are told that
autoimmune disease will be a permanent fixture in our lives and that
medication to suppress the immune system is the only answer. This perspective
is not only disheartening, it is also just plain wrong.
The latest science shows that we are not helpless. There is so much we can
do to address the underlying causes of autoimmunity. It may take a great deal
of effort and persistence, but we can work to reset our microbiome, heal our
gut, and recalibrate our immune system. By doing so we can directly tackle the
autoimmune process, rather than merely subduing the symptoms.
Until the medical establishment catches up with this new paradigm, it is up to
all of us to learn as much as possible and make the best use we can of the latest
research. When we use this research to guide our everyday choices, the
cumulative effect can be extraordinarily powerful.
 Appendix: The Keystone Diet at a Glance

General Principles:

Support your microbiome and antioxidant defenses by eating
more high-fiber and brightly colored fruit and vegetables.
Eat more fish, especially salmon, sardines, and Atlantic mackerel.
Consider supplementing with 2–4 grams of fish oil per day.
Use olive oil and avocado oil as the primary added fats.
Choose leaner proteins such as chicken, fish, and lean pork.
Trim visible fats from meat before cooking.

Level 1: Basic low-starch plan

Eliminate gluten-containing grains.
Avoid gut-damaging grains and legumes (soy, corn, potato,
peanut).
Limit other starchy foods to two servings per day, preferably in
the form of starchy root vegetables such as parsnip or sweet
potato.
Cut back on sugar.

Level 2: Intermediate low-starch plan

Eliminate grains, legumes, and very starchy vegetables.
Minimize added sugars.
Limit fruit to two or three small servings per day.
Avoid dairy, other than homemade yogurt if tolerated.
Avoid the highest-starch nuts and seeds, such as cashews.

Level 3: Advanced low-starch plan

In addition to the steps listed above for level 2:

Choose vegetables with the lowest starch content.
Limit fruit to one or two small servings per day.
Use only the lowest-starch nuts and seeds, such as flax and
 macadamias.
Try to avoid maltodextrin and other starchy fillers in supplements.
Increase fat and protein to compensate for the reduction in
carbohydrates. If you emphasize fat this will become a ketogenic
diet. Some people may feel better long term by emphasizing
protein instead in order to prevent hormonal disturbances.
You may need to increase salt to prevent the electrolyte
imbalances that can result from a very low carbohydrate diet.

Troubleshooting and Customizing the Keystone Diet

Consider eliminating the following for at least 30 days to determine if you have
a sensitivity:

Common allergens: nuts, eggs, dairy, soy, corn, shellfish
Nightshades: tomatoes, potatoes, peppers, chili spices,
eggplant

If you have symptoms of food chemical intolerance and react to a wide range
of foods that are high in histamines or salicylates, you may be able to reduce
this sensitivity by addressing SIBO and pathogen overgrowth. Other alternative
strategies include testing for thyroid and adrenal hormones and adding a high-
dose vitamin C supplement to reduce histamine levels.

 References

Scientific publications are available from the National Institutes of Health
database at www.ncbi.nlm.nih.gov/pubmed

 Chapter 1. Understanding the Root Causes of Autoimmunity

 Notes
[←1]


Cypers, H., Varkas, G., Beeckman, S., Debusschere, K., Vogl, T., Roth, J., ... & De Vos, M. (2015).
Elevated calprotectin levels reveal bowel inflammation in spondyloarthritis. Annals of the rheumatic
diseases, Dec. 23 2015;
Stebbings, S., Jenks, K., Treharne, G. J., García, J. A., Schultz, M., Highton, J., & Dudley-Brown, S. (2011).
Validation of the Dudley Inflammatory Bowel Symptom Questionnaire for the assessment of bowel
symptoms in axial SpA: prevalence of clinically relevant bowel symptoms and association with
disease activity. Rheumatology, ker359;
Stoll, M. L., Punaro, M., & Patel, A. S. (2011). Fecal calprotectin in children with the enthesitis-related
arthritis subtype of juvenile idiopathic arthritis. The Journal of rheumatology, 38(10), 2274-2275;
Bjarnason, I., Helgason, K. O., Geirsson, Á. J., Sigthorsson, G., Reynisdottir, I., Gudbjartsson, D., ... &
Thjodleifsson, B. (2003). Subclinical intestinal inflammation and sacroiliac changes in relatives of
patients with ankylosing spondylitis. Gastroenterology, 125(6), 1598-1605.
Klingberg, E., Strid, H., Ståhl, A., Deminger, A., Carlsten, H., Öhman, L., & Forsblad-d’Elia, H. (2017). A
longitudinal study of fecal calprotectin and the development of inflammatory bowel disease in
ankylosing spondylitis. Arthritis research & therapy, 19(1), 21.
Tayel, M., Megid, M. A., Nouh, H. H., & Rofaeil, B. (2014). AB0340 Fecal Calprotectin in Rheumatoid
Disease, and Its Relation to Disease State. Annals of the Rheumatic Diseases, 73(Suppl 2), 917-917.

[←2]
Van Praet, L., Van den Bosch, F. E., Jacques, P., Carron, P., Jans, L., Colman, R., ... & Cuvelier, C. (2013).
Microscopic gut inflammation in axial spondyloarthritis: a multiparametric predictive model. Annals
of the rheumatic diseases, 72(3), 414-417.
Van Praet, L., Jans, L., Carron, P., Jacques, P., Glorieus, E., Colman, R., ... & Van den Bosch, F. (2014).
Degree of bone marrow oedema in sacroiliac joints of patients with axial spondyloarthritis is linked
to gut inflammation and male sex: results from the GIANT cohort. Annals of the rheumatic diseases,
73(6), 1186-1189.
Duran, A., Kobak, S., Sen, N., Aktakka, S., Atabay, T., & Orman, M. (2016). Fecal calprotectin is
associated with disease activity in patients with ankylosing spondylitis. Bosnian Journal of Basic
Medical Sciences, 16(1), 71.
Tayel, M., Megid, M. A., Nouh, H. H., & Rofaeil, B. (2014). AB0340 Fecal Calprotectin in Rheumatoid
Disease, and Its Relation to Disease State. Annals of the Rheumatic Diseases, 73(Suppl 2), 917-917.
Stebbings, S., Jenks, K., Treharne, G. J., García, J. A., Schultz, M., Highton, J., & Dudley-Brown, S. (2011).
Validation of the Dudley Inflammatory Bowel Symptom Questionnaire for the assessment of bowel
symptoms in axial SpA: prevalence of clinically relevant bowel symptoms and association with
disease activity. Rheumatology, ker359;

[←3]
Viladomiu, M., Kivolowitz, C., Abdulhamid, A., Dogan, B., Victorio, D., Castellanos, J. G., ... & Chai, C.
(2017). IgA-coated E. coli enriched in Crohn’s disease spondyloarthritis promote TH17-dependent
inflammation. Science Translational Medicine, 9(376), eaaf9655;
Eppinga, H., Weiland, C. J. S., Thio, H. B., van der Woude, C. J., Nijsten, T. E., Peppelenbosch, M. P., &
 Konstantinov, S. R. (2016). Similar depletion of protective Faecalibacterium prausnitzii in psoriasis
and inflammatory bowel disease, but not in Hidradenitis suppurativa. Journal of Crohn's and Colitis,
10(9), 1067-1075;
Scher, J. U., Sczesnak, A., Longman, R. S., Segata, N., Ubeda, C., Bielski, C., … Littman, D. R. (2013).
Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. eLife, 2,
e01202.
Maeda, Y., Kurakawa, T., Umemoto, E., Motooka, D., Ito, Y., Gotoh, K., ... & Sakaguchi, N. (2016).
Dysbiosis contributes to arthritis development via activation of autoreactive T cells in the intestine.
Arthritis & Rheumatology, 68(11), 2646-2661.
Chen, J., Wright, K., Davis, J. M., Jeraldo, P., Marietta, E. V., Murray, J., ... & Taneja, V. (2016). An
expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis. Genome medicine,
8(1), 43.
Scher, J. U., Ubeda, C., Artacho, A., Attur, M., Isaac, S., Reddy, S. M., ... & Manasson, J. (2015).
Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic
arthritis, resembling dysbiosis in inflammatory bowel disease. Arthritis & rheumatology, 67(1), 128-
139.

[←4]
Mathew, J. L., Singh, S., & Sankar, J. (2015). Is antibiotic exposure associated with newly diagnosed
juvenile idiopathic arthritis?. Indian pediatrics, 52(10), 883-888.

[←5]
Kohn, D (2015, January 12). Joint Pain, from the Gut. The Atlantic

[←6]
Ghouri, Y. A., Richards, D. M., Rahimi, E. F., Krill, J. T., Jelinek, K. A., & DuPont, A. W. (2014). Systematic
review of randomized controlled trials of probiotics, prebiotics, and synbiotics in inflammatory
bowel disease. Clinical and experimental gastroenterology, 7, 473.

[←7]
Skoldstam, L., Hagfors, L., & Johansson, G. (2003). An experimental study of a Mediterranean diet
intervention for patients with rheumatoid arthritis. Annals of the Rheumatic Diseases, 62(3), 208–
214;
Abendroth, A., Michalsen, A., Luedtke, R., Rueffer, A., Musial, F., Dobos, G. J., & Langhorst, J. (2010).
Changes of intestinal microflora in patients with rheumatoid arthritis during fasting or a
Mediterranean diet. Forschende Komplementärmedizin/Research in Complementary Medicine,
17(6), 307-313;
McKellar, G., Morrison, E., McEntegart, A., Hampson, R., Tierney, A., Mackle, G., ... & Capell, H. A.
(2007). A pilot study of a Mediterranean-type diet intervention in female patients with rheumatoid
arthritis living in areas of social deprivation in Glasgow. Annals of the rheumatic diseases, 66(9),
1239-1243.
Preedy, V. R., & Watson, R. R. (Eds.). (2014). The Mediterranean Diet: An Evidence-Based Approach.
Academic press.
Barrea, L., Balato, N., Di Somma, C., Macchia, P. E., Napolitano, M., Savanelli, M. C., ... & Savastano, S.
(2015). Nutrition and psoriasis: is there any association between the severity of the disease and
adherence to the Mediterranean diet?. Journal of translational medicine, 13(1), 18.
Di Giuseppe, D., Crippa, A., Orsini, N., & Wolk, A. (2014). Fish consumption and risk of rheumatoid
 arthritis: a dose-response meta-analysis. Arthritis research & therapy, 16(5), 1.

[←8]
Dumas, J. A., Bunn, J. Y., Nickerson, J., Crain, K. I., Ebenstein, D. B., Tarleton, E. K., ... & Kien, C. L.
(2016). Dietary saturated fat and monounsaturated fat have reversible effects on brain function and
the secretion of pro-inflammatory cytokines in young women. Metabolism, 65(10), 1582-1588.
Kien, C. L., Bunn, J. Y., Fukagawa, N. K., Anathy, V., Matthews, D. E., Crain, K. I., ... & Poynter, M. E.
(2015). Lipidomic evidence that lowering the typical dietary palmitate to oleate ratio in humans
decreases the leukocyte production of proinflammatory cytokines and muscle expression of redox-
sensitive genes. The Journal of nutritional biochemistry, 26(12), 1599-1606.

[←9]
Rocha, D. M., Caldas, A. P., Oliveira, L. L., Bressan, J., & Hermsdorff, H. H. (2016). Saturated fatty acids
trigger TLR4-mediated inflammatory response. Atherosclerosis, 244, 211-215.
Reynolds, C. M., McGillicuddy, F. C., Harford, K. A., Finucane, O. M., Mills, K. H., & Roche, H. M. (2012).
Dietary saturated fatty acids prime the NLRP3 inflammasome via TLR4 in dendritic cells—
implications for diet-induced insulin resistance. Molecular nutrition & food research, 56(8), 1212-
1222.
Snodgrass, R. G., Huang, S., Choi, I. W., Rutledge, J. C., & Hwang, D. H. (2013). Inflammasome-mediated
secretion of IL-1β in human monocytes through TLR2 activation; modulation by dietary fatty acids.
The Journal of Immunology, 191(8), 4337-4347.

[←10]
Morris, Z. S., Wooding, S., & Grant, J. (2011). The answer is 17 years, what is the question:
understanding time lags in translational research. Journal of the Royal Society of Medicine, 104(12),
510-520.

[←11]
Proudman, S. M., James, M. J., Spargo, L. D., Metcalf, R. G., Sullivan, T. R., Rischmueller, M., ... &
Cleland, L. G. (2013). Fish oil in recent onset rheumatoid arthritis: a randomised, double-blind
controlled trial within algorithm-based drug use. Annals of the rheumatic diseases, annrheumdis-
2013.

[←12]
Meadows, S. (2013, February 1). The Boy with the Thorn in his Joints. The New York Times, Magazine.

[←13]
Mielants, H., De Vos, M., Goemaere, S., Schelstraete, K., Cuvelier, C., Goethals, K., ... & Veys, E. M.
(1991). Intestinal mucosal permeability in inflammatory rheumatic diseases. II. Role of disease. The
Journal of rheumatology, 18(3), 394-400.
Martínez-González O1, Cantero-Hinojosa J, Paule-Sastre P, Gómez-Magán JC, Salvatierra-Ríos D, Br J
Rheumatol. 1994 Jul;33(7):644-7. Intestinal permeability in patients with ankylosing spondylitis and
their healthy relatives
Picco, P., Gattorno, M., Marchese, N., Vignola, S., Sormani, M. P., Barabino, A., & Buoncompagni, A.
(2000). Increased gut permeability in juvenile chronic arthritides. A multivariate analysis of the
diagnostic parameters. Clinical and experimental rheumatology, 18(6), 773-778.
 Humbert P, Bidet A, Treffel P, Drobacheff C, Agache P. Intestinal permeability in patients with psoriasis.
J Dermatol Sci. 1991;2:324–6.

[←14]
Merga, Y., Campbell, B. J., & Rhodes, J. M. (2014). Mucosal barrier, bacteria and inflammatory bowel
disease: possibilities for therapy. Digestive diseases, 32(4), 475-483.

[←15]
Ciccia, F., Guggino, G., Rizzo, A., Saieva, L., Peralta, S., Giardina, A., ... & Triolo, G. (2015). Type 3 innate
lymphoid cells producing IL-17 and IL-22 are expanded in the gut, in the peripheral blood, synovial
fluid and bone marrow of patients with ankylosing spondylitis. Annals of the rheumatic diseases,
annrheumdis-2014
May, E., Märker–Hermann, E., Wittig, B. M., Zeitz, M., Zum Büschenfelde, K. H. M., & Duchmann, R.
(2000). Identical T-cell expansions in the colon mucosa and the synovium of a patient with
enterogenic spondyloarthropathy. Gastroenterology, 119(6), 1745-1755.
Fantini, M. C., Pallone, F., & Monteleone, G. (2009). Common immunologic mechanisms in
inflammatory bowel disease and spondylarthropathies. World J Gastroenterol, 15(20), 2472-2478;
Suurmond, J., Rivellese, F., Dorjee, A. L., Bakker, A. M., Rombouts, Y. J. P. C., Rispens, T., ... & Toes, R. E.
M. (2015). Toll-like receptor triggering augments activation of human mast cells by anti-citrullinated
protein antibodies. Annals of the rheumatic diseases, 74(10), 1915-1923

[←16]
Cypers, H., Varkas, G., Beeckman, S., Debusschere, K., Vogl, T., Roth, J., ... & De Vos, M. (2015).
Elevated calprotectin levels reveal bowel inflammation in spondyloarthritis. Annals of the rheumatic
diseases, Dec. 23 2015;
Stebbings, S., Jenks, K., Treharne, G. J., García, J. A., Schultz, M., Highton, J., & Dudley-Brown, S. (2011).
Validation of the Dudley Inflammatory Bowel Symptom Questionnaire for the assessment of bowel
symptoms in axial SpA: prevalence of clinically relevant bowel symptoms and association with
disease activity. Rheumatology, ker359;
Stoll, M. L., Punaro, M., & Patel, A. S. (2011). Fecal calprotectin in children with the enthesitis-related
arthritis subtype of juvenile idiopathic arthritis. The Journal of rheumatology, 38(10), 2274-2275;
Bjarnason, I., Helgason, K. O., Geirsson, Á. J., Sigthorsson, G., Reynisdottir, I., Gudbjartsson, D., ... &
Thjodleifsson, B. (2003). Subclinical intestinal inflammation and sacroiliac changes in relatives of
patients with ankylosing spondylitis. Gastroenterology, 125(6), 1598-1605.
Klingberg, E., Strid, H., Ståhl, A., Deminger, A., Carlsten, H., Öhman, L., & Forsblad-d’Elia, H. (2017). A
longitudinal study of fecal calprotectin and the development of inflammatory bowel disease in
ankylosing spondylitis. Arthritis research & therapy, 19(1), 21.
Tayel, M., Megid, M. A., Nouh, H. H., & Rofaeil, B. (2014). AB0340 Fecal Calprotectin in Rheumatoid
Disease, and Its Relation to Disease State. Annals of the Rheumatic Diseases, 73(Suppl 2), 917-917.

[←17]
Mielants, H., Veys, E. M., Cuvelier, C., & De Vos, M. (1988). Ileocolonoscopic findings in seronegative
spondylarthropathies. Rheumatology, 27(suppl 2), 95-105.

[←18]
Van Praet, L., Van den Bosch, F. E., Jacques, P., Carron, P., Jans, L., Colman, R., ... & Cuvelier, C. (2013).
 Microscopic gut inflammation in axial spondyloarthritis: a multiparametric predictive model. Annals
of the rheumatic diseases, 72(3), 414-417.
Cypers, H., Varkas, G., Beeckman, S., Debusschere, K., Vogl, T., Roth, J., ... & De Vos, M. (2015).
Elevated calprotectin levels reveal bowel inflammation in spondyloarthritis. Annals of the rheumatic
diseases, Dec. 23 2015;
Leirisalo-Repo, M., Turunen, U., Stenman, S., Helenius, P., & Seppälä, K. (1994). High frequency of silent
inflammatory bowel disease in spondylarthropathy. Arthritis & Rheumatology, 37(1), 23-31.
Scarpa R, Manguso F, D’Arienzo A, D’Armiento FP, Astarita C, Mazzacca G, et al. Microscopic
inflammatory changes in colon of patients with both active psoriasis and psoriatic arthritis without
bowel symptoms. J Rheumatol. 2000;27:1241–6.

[←19]
Li, W. Q., Han, J. L., Chan, A. T., & Qureshi, A. A. (2012). Psoriasis, psoriatic arthritis and increased risk
of incident Crohn's disease in US women. Annals of the rheumatic diseases, annrheumdis-2012.

[←20]
De Vos, Mielants, Cuvelier, C., Elewaut, A., & Veys, E. R. I. C. (1996). Long-term evolution of gut
inflammation in patients with spondyloarthropathy. Gastroenterology, 110(6), 1696-1703.

[←21]
Lucaciu, L., Ilies, M., Iuga, C., & Seicean, A. (2018). P136 Serum IL-17 and IL-23 levels can distinguish
between severe and non-severe inflammatory bowel disease. Journal of Crohn's and
Colitis, 12(supplement_1), S163-S163.
Kuwabara, T., Ishikawa, F., Kondo, M., & Kakiuchi, T. (2017). The role of IL-17 and related cytokines in
inflammatory autoimmune diseases. Mediators of inflammation, 2017.
Krueger, J. G., & Brunner, P. M. (2018). Interleukin-17 alters the biology of many cell types involved in
the genesis of psoriasis, systemic inflammation and associated comorbidities. Experimental
dermatology, 27(2), 115-123.
Sakkas, L. I., & Bogdanos, D. P. (2017). Are psoriasis and psoriatic arthritis the same disease? The IL-
23/IL-17 axis data. Autoimmunity reviews, 16(1), 10-15.
Poddubnyy, D., & Sieper, J. (2017). What is the best treatment target in axial spondyloarthritis: tumour
necrosis factor α, interleukin 17, or both?. Rheumatology.
Suurmond, J., Rivellese, F., Dorjee, A. L., Bakker, A. M., Rombouts, Y. J. P. C., Rispens, T., ... & Toes, R. E.
M. (2015). Toll-like receptor triggering augments activation of human mast cells by anti-citrullinated
protein antibodies. Annals of the rheumatic diseases, 74(10), 1915-1923.
Baricza, E., Marton, N., Királyhidi, P., Kovács, O. T., Kovácsné Székely, I., Lajkó, E., ... & Nagy, G. (2018).
Distinct In Vitro T-helper 17 Differentiation capacity of Peripheral naive T cells in rheumatoid and
Psoriatic arthritis. Frontiers in immunology, 9, 606.
Bazzazi, H., Aghaei, M., Memarian, A., Asgarian-Omran, H., Behnampour, N., & Yazdani, Y. (2018). Th1-
Th17 Ratio as a New Insight in Rheumatoid Arthritis Disease. Iranian Journal of Allergy, Asthma and
Immunology, 17(1), 68-77.

[←22]
Park, J. H., Jeong, S. Y., Choi, A. J., & Kim, S. J. (2015). Lipopolysaccharide directly stimulates Th17
differentiation in vitro modulating phosphorylation of RelB and NF-κB1. Immunology letters, 165(1),
10-19.
McAleer, J. P., Liu, B., Li, Z., Ngoi, S. M., Dai, J., Oft, M., & Vella, A. T. (2010). Potent intestinal Th17
 priming through peripheral lipopolysaccharide-based immunization. Journal of leukocyte
biology, 88(1), 21-31.
Dekita, M., Wu, Z., Ni, J., Zhang, X., Liu, Y., Yan, X., ... & Takahashi, I. (2017). Cathepsin S Is Involved in
Th17 Differentiation Through the Upregulation of IL-6 by Activating PAR-2 after Systemic Exposure
to Lipopolysaccharide from Porphyromonas gingivalis. Frontiers in pharmacology, 8, 470.
Chovanova, L., Vlcek, M., Krskova, K., Penesova, A., Radikova, Z., Rovensky, J., ... & Imrich, R. (2013).
Increased production of IL-6 and IL-17 in lipopolysaccharide-stimulated peripheral mononuclears
from patients with rheumatoid arthritis. Gen Physiol Biophys, 32(3), 395-404.
Supajatura, V., Ushio, H., Nakao, A., Okumura, K., Ra, C., & Ogawa, H. (2001). Protective roles of mast
cells against enterobacterial infection are mediated by Toll-like receptor 4. The Journal of
Immunology, 167(4), 2250-2256.
Abraham, S. N., & John, A. L. S. (2010). Mast cell-orchestrated immunity to pathogens. Nature Reviews
Immunology, 10(6), 440-452.
Suurmond, J., Rivellese, F., Dorjee, A. L., Bakker, A. M., Rombouts, Y. J. P. C., Rispens, T., ... & Toes, R. E.
M. (2015). Toll-like receptor triggering augments activation of human mast cells by anti-citrullinated
protein antibodies. Annals of the rheumatic diseases, 74(10), 1915-1923.

[←23]
Lee, G. R. (2018). The Balance of Th17 versus Treg Cells in Autoimmunity. International journal of
molecular sciences, 19(3), 730.
Lucaciu, L., Ilies, M., Iuga, C., & Seicean, A. (2018). P136 Serum IL-17 and IL-23 levels can distinguish
between severe and non-severe inflammatory bowel disease. Journal of Crohn's and
Colitis, 12(supplement_1), S163-S163.
Kuwabara, T., Ishikawa, F., Kondo, M., & Kakiuchi, T. (2017). The role of IL-17 and related cytokines in
inflammatory autoimmune diseases. Mediators of inflammation, 2017.
Krueger, J. G., & Brunner, P. M. (2018). Interleukin-17 alters the biology of many cell types involved in
the genesis of psoriasis, systemic inflammation and associated comorbidities. Experimental
dermatology, 27(2), 115-123.
Sakkas, L. I., & Bogdanos, D. P. (2017). Are psoriasis and psoriatic arthritis the same disease? The IL-
23/IL-17 axis data. Autoimmunity reviews, 16(1), 10-15.
Poddubnyy, D., & Sieper, J. (2017). What is the best treatment target in axial spondyloarthritis: tumour
necrosis factor α, interleukin 17, or both?. Rheumatology.
Suurmond, J., Rivellese, F., Dorjee, A. L., Bakker, A. M., Rombouts, Y. J. P. C., Rispens, T., ... & Toes, R. E.
M. (2015). Toll-like receptor triggering augments activation of human mast cells by anti-citrullinated
protein antibodies. Annals of the rheumatic diseases, 74(10), 1915-1923.
Baricza, E., Marton, N., Királyhidi, P., Kovács, O. T., Kovácsné Székely, I., Lajkó, E., ... & Nagy, G. (2018).
Distinct In Vitro T-helper 17 Differentiation capacity of Peripheral naive T cells in rheumatoid and
Psoriatic arthritis. Frontiers in immunology, 9, 606.
Bazzazi, H., Aghaei, M., Memarian, A., Asgarian-Omran, H., Behnampour, N., & Yazdani, Y. (2018). Th1-
Th17 Ratio as a New Insight in Rheumatoid Arthritis Disease. Iranian Journal of Allergy, Asthma and
Immunology, 17(1), 68-77.
Suurmond, J., Rivellese, F., Dorjee, A. L., Bakker, A. M., Rombouts, Y. J. P. C., Rispens, T., ... & Toes, R. E.
M. (2015). Toll-like receptor triggering augments activation of human mast cells by anti-citrullinated
protein antibodies. Annals of the rheumatic diseases, 74(10), 1915-1923.
Fotis, L., Shaikh, N., Baszis, K. W., Samson, C. M., Lev-Tzion, R., French, A. R., & Tarr, P. I. (2017).
Serologic evidence of gut-driven systemic inflammation in juvenile idiopathic arthritis. The Journal
of rheumatology, 44(11), 1624-1631
[←24]
Atarashi, K., Tanoue, T., Shima, T., Imaoka, A., Kuwahara, T., Momose, Y., ... & Taniguchi, T. (2011).
Induction of colonic regulatory T cells by indigenous Clostridium species. Science, 331(6015), 337-
341;
Frank, D. N., Amand, A. L. S., Feldman, R. A., Boedeker, E. C., Harpaz, N., & Pace, N. R. (2007).
Molecular-phylogenetic characterization of microbial community imbalances in human
inflammatory bowel diseases. Proceedings of the National Academy of Sciences, 104(34), 13780-
13785.
Gevers, D., Kugathasan, S., Denson, L. A., Vázquez-Baeza, Y., Van Treuren, W., Ren, B., ... & Morgan, X.
C. (2014). The treatment-naive microbiome in new-onset Crohn’s disease. Cell host & microbe,
15(3), 382-392.
Kang, S., Denman, S. E., Morrison, M., Yu, Z., Dore, J., Leclerc, M., & McSweeney, C. S. (2010). Dysbiosis
of fecal microbiota in Crohn's disease patients as revealed by a custom phylogenetic microarray.
Inflammatory bowel diseases, 16(12), 2034-2042.

[←25]
Kolho, K. L., Korpela, K., Jaakkola, T., Pichai, M. V., Zoetendal, E. G., Salonen, A., & De Vos, W. M.
(2015). Fecal microbiota in pediatric inflammatory bowel disease and its relation to inflammation.
The American journal of gastroenterology, 110(6), 921-930.

[←26]
Geirnaert, A., Calatayud, M., Grootaert, C., Laukens, D., Devriese, S., Smagghe, G., ... & Van de Wiele, T.
(2017). Butyrate-producing bacteria supplemented in vitro to Crohn’s disease patient microbiota
increased butyrate production and enhanced intestinal epithelial barrier integrity. Scientific
Reports, 7(1), 11450.

[←27]
Scher, J. U., Ubeda, C., Artacho, A., Attur, M., Isaac, S., Reddy, S. M., ... & Manasson, J. (2015).
Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic
arthritis, resembling dysbiosis in inflammatory bowel disease. Arthritis & rheumatology, 67(1), 128-
139.
Casellas, F., Borruel, N., Manichanh, C., Varela, E., Antolín, M., Torrejón, A., ... & MetaHIT Consortium.
(2014). OP022 Low microbial gene diversity and depletion of Akkermansia muciniphila is associated
with a relapsing course of ulcerative colitis. Journal of Crohn's and Colitis, 8(Supplement 1), S12-
S13.

[←28]
Vaahtovuo, J., Munukka, E., KORKEAMÄKI, M., Luukkainen, R., & Toivanen, P. (2008). Fecal microbiota
in early rheumatoid arthritis. The Journal of rheumatology, 35(8), 1500-1505.
Di Paola, M., Cavalieri, D., Albanese, D., Sordo, M., Pindo, M., Donati, C., ... & Lionetti, P. (2016).
Alteration of Fecal Microbiota Profiles in Juvenile Idiopathic Arthritis. Associations with HLA-B27
Allele and Disease Status. Frontiers in Microbiology, 7.
Eppinga, H., Weiland, C. J. S., Thio, H. B., van der Woude, C. J., Nijsten, T. E., Peppelenbosch, M. P., &
Konstantinov, S. R. (2016). Similar depletion of protective Faecalibacterium prausnitzii in psoriasis
and inflammatory bowel disease, but not in Hidradenitis suppurativa. Journal of Crohn's and Colitis,
10(9), 1067-1075.
Stoll, M. L., Kumar, R., Morrow, C. D., Lefkowitz, E. J., Cui, X., Genin, A., ... & Elson, C. O. (2014). Altered
 microbiota associated with abnormal humoral immune responses to commensal organisms in
enthesitis-related arthritis. Arthritis research & therapy, 16(6), 486.

[←29]
Gevers, D., Kugathasan, S., Denson, L. A., Vázquez-Baeza, Y., Van Treuren, W., Ren, B., ... & Morgan, X.
C. (2014). The treatment-naive microbiome in new-onset Crohn’s disease. Cell host & microbe,
15(3), 382-392.
Scher, J. U., Ubeda, C., Artacho, A., Attur, M., Isaac, S., Reddy, S. M., ... & Manasson, J. (2015).
Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic
arthritis, resembling dysbiosis in inflammatory bowel disease. Arthritis & rheumatology, 67(1), 128-
139.

[←30]
Stoll, M. L., Kumar, R., Morrow, C. D., Lefkowitz, E. J., Cui, X., Genin, A., ... & Elson, C. O. (2014). Altered
microbiota associated with abnormal humoral immune responses to commensal organisms in
enthesitis-related arthritis. Arthritis research & therapy, 16(6), 486.

[←31]
Di Paola, M., Cavalieri, D., Albanese, D., Sordo, M., Pindo, M., Donati, C., ... & Lionetti, P. (2016).
Alteration of Fecal Microbiota Profiles in Juvenile Idiopathic Arthritis. Associations with HLA-B27
Allele and Disease Status. Frontiers in microbiology, 7.

[←32]
Vaahtovuo, J., Munukka, E., KORKEAMÄKI, M., Luukkainen, R., & Toivanen, P. (2008). Fecal microbiota
in early rheumatoid arthritis. The Journal of rheumatology, 35(8), 1500-1505

[←33]
Reunanan (2015) Akkermansia muciniphila Adheres to Enterocytes and Strengthens the Integrity of the
Epithelial Cell Layer;
Atarashi, K., Tanoue, T., Shima, T., Imaoka, A., Kuwahara, T., Momose, Y., ... & Taniguchi, T. (2011).
Induction of colonic regulatory T cells by indigenous Clostridium species. Science, 331(6015), 337-
341.

[←34]
Atarashi, K., Tanoue, T., Shima, T., Imaoka, A., Kuwahara, T., Momose, Y., ... & Taniguchi, T. (2011).
Induction of colonic regulatory T cells by indigenous Clostridium species. Science, 331(6015), 337-
341

[←35]
Gri, G., Piconese, S., Frossi, B., Manfroi, V., Merluzzi, S., Tripodo, C., ... & Pucillo, C. E. (2008). CD4+
CD25+ regulatory T cells suppress mast cell degranulation and allergic responses through OX40-
OX40L interaction. Immunity, 29(5), 771-781;
Frossi, B., D'Incà, F., Crivellato, E., Sibilano, R., Gri, G., Mongillo, M., ... & Pucillo, C. E. (2011). Single-cell
dynamics of mast cell–CD4+ CD25+ regulatory T cell interactions. European journal of immunology,
41(7), 1872-1882.
[←36]
Smith, P. M., Howitt, M. R., Panikov, N., Michaud, M., Gallini, C. A., Bohlooly-y, M., ... & Garrett, W. S.
(2013). The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis.
Science, 341(6145), 569-573.

[←37]
Keijsers, R. R. M. C., van der Velden, H. M. J., van Erp, P. E. J., de Boer-van Huizen, R. T., Joosten, I.,
Koenen, H. J. P. M., & van de Kerkhof, P. C. M. (2013). Balance of Treg vs. T-helper cells in the
transition from symptomless to lesional psoriatic skin. British Journal of Dermatology, 168(6), 1294-
1302.

[←38]
Furusawa, Y., Obata, Y., Fukuda, S., Endo, T. A., Nakato, G., Takahashi, D., ... & Takahashi, M. (2013).
Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells.
Nature, 504(7480), 446-450.
Arpaia, N., Campbell, C., Fan, X., Dikiy, S., van der Veeken, J., Liu, H., ... & Rudensky, A. Y. (2013).
Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation.
Nature, 504(7480), 451-455.
Smith, P. M., Howitt, M. R., Panikov, N., Michaud, M., Gallini, C. A., Bohlooly-y, M., ... & Garrett, W. S.
(2013). The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis.
Science, 341(6145), 569-573.

[←39]
Sarrabayrouse, G., Bossard, C., Chauvin, J. M., Jarry, A., Meurette, G., Quévrain, E., ... & Altare, F.
(2014). CD4CD8αα lymphocytes, a novel human regulatory T cell subset induced by colonic bacteria
and deficient in patients with inflammatory bowel disease. PLoS Biol, 12(4), e1001833.
Omenetti, S., & Pizarro, T. T. (2015). The Treg/Th17 axis: a dynamic balance regulated by the gut
microbiome. Frontiers in immunology, 6, 639.

[←40]
Viladomiu, M., Kivolowitz, C., Abdulhamid, A., Dogan, B., Victorio, D., Castellanos, J. G., ... & Chai, C.
(2017). IgA-coated E. coli enriched in Crohn’s disease spondyloarthritis promote TH17-dependent
inflammation. Science Translational Medicine, 9(376), eaaf9655;
Eppinga, H., Weiland, C. J. S., Thio, H. B., van der Woude, C. J., Nijsten, T. E., Peppelenbosch, M. P., &
Konstantinov, S. R. (2016). Similar depletion of protective Faecalibacterium prausnitzii in psoriasis
and inflammatory bowel disease, but not in Hidradenitis suppurativa. Journal of Crohn's and Colitis,
10(9), 1067-1075;
Scher, J. U., Sczesnak, A., Longman, R. S., Segata, N., Ubeda, C., Bielski, C., … Littman, D. R. (2013).
Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. eLife, 2,
e01202.
Maeda, Y., Kurakawa, T., Umemoto, E., Motooka, D., Ito, Y., Gotoh, K., ... & Sakaguchi, N. (2016).
Dysbiosis contributes to arthritis development via activation of autoreactive T cells in the intestine.
Arthritis & Rheumatology, 68(11), 2646-2661.
Chen, J., Wright, K., Davis, J. M., Jeraldo, P., Marietta, E. V., Murray, J., ... & Taneja, V. (2016). An
expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis. Genome medicine,
8(1), 43.
Blankenberg-Sprenkels, S. H., Fielder, M., Feltkamp, T. E., Tiwana, H., Wilson, C., & Ebringer, A. (1998).
 Antibodies to Klebsiella pneumoniae in Dutch patients with ankylosing spondylitis and acute
anterior uveitis and to Proteus mirabilis in rheumatoid arthritis. The Journal of rheumatology, 25(4),
743-747.
Ramírez-Boscá, A., Navarro-López, V., Martínez-Andrés, A., Such, J., Francés, R., de la Parte, J. H., &
Asín-Llorca, M. (2015). Identification of bacterial DNA in the peripheral blood of patients with active
psoriasis. JAMA dermatology, 151(6), 670-671.

[←41]
Maeda, Y., Kurakawa, T., Umemoto, E., Motooka, D., Ito, Y., Gotoh, K., ... & Sakaguchi, N. (2016).
Dysbiosis contributes to arthritis development via activation of autoreactive T cells in the intestine.
Arthritis & Rheumatology, 68(11), 2646-2661;
Viladomiu, M., Kivolowitz, C., Abdulhamid, A., Dogan, B., Victorio, D., Castellanos, J. G., ... & Chai, C.
(2017). IgA-coated E. coli enriched in Crohn’s disease spondyloarthritis promote TH17-dependent
inflammation. Science Translational Medicine, 9(376), eaaf9655;
Shawki, A., & McCole, D. F. (2017). Mechanisms of Intestinal Epithelial Barrier Dysfunction by
Adherent-Invasive Escherichia coli. CMGH Cellular and Molecular Gastroenterology and Hepatology,
3(1), 41-50.
Kivolowitz, C., Abdulhamid, A., Victorio, D., Castellanos, J., Simpson, K., Scherl, E., & Longman, R.
(2016). O-006 Expansion of Immunologically-Relevant E. Coli in the Intestinal Microbiota of Patients
with IBD-Associated Spondyloarthritis Promotes Mucosal RORgt-Dependent Immunity.
Inflammatory bowel diseases, 22, S3.
Cosorich, I., Dalla-Costa, G., Sorini, C., Ferrarese, R., Messina, M. J., Dolpady, J., ... & Comi, G. (2017).
High frequency of intestinal TH17 cells correlates with microbiota alterations and disease activity in
multiple sclerosis. Science Advances, 3(7), e1700492.

[←42]
Agus, A., Massier, S., Darfeuille-Michaud, A., Billard, E., & Barnich, N. (2014). Understanding host-
adherent-invasive Escherichia coli interaction in Crohn’s disease: opening up new therapeutic
strategies. BioMed research international, 2014.

[←43]
Martinez-Medina, M., Aldeguer, X., Lopez-Siles, M., González-Huix, F., López-Oliu, C., Dahbi, G., ... &
Darfeuille-Michaud, A. (2009). Molecular diversity of Escherichia coli in the human gut: new
ecological evidence supporting the role of adherent-invasive E. coli (AIEC) in Crohn's disease.
Inflammatory bowel diseases, 15(6), 872-882.
Baumgart, M., Dogan, B., Rishniw, M., Weitzman, G., Bosworth, B., Yantiss, R., ... & Berg, D. (2007).
Culture independent analysis of ileal mucosa reveals a selective increase in invasive Escherichia coli
of novel phylogeny relative to depletion of Clostridiales in Crohn's disease involving the ileum. The
ISME journal, 1(5), 403-418.
Eaves-Pyles, T., Allen, C. A., Taormina, J., Swidsinski, A., Tutt, C. B., Jezek, G. E., ... & Torres, A. G.
(2008). Escherichia coli isolated from a Crohn's disease patient adheres, invades, and induces
inflammatory responses in polarized intestinal epithelial cells. International Journal of Medical
Microbiology, 298(5), 397-409.
Kotlowski, R., Bernstein, C. N., Sepehri, S., & Krause, D. O. (2007). High prevalence of Escherichia coli
belonging to the B2+ D phylogenetic group in inflammatory bowel disease. Gut, 56(5), 669-675.
Conte, M. P., Schippa, S., Zamboni, I., Penta, M., Chiarini, F., Seganti, L., ... & Cucchiara, S. (2006). Gut-
associated bacterial microbiota in paediatric patients with inflammatory bowel disease. Gut, 55(12),
1760-1767.
[←44]
Viladomiu, M., Kivolowitz, C., Abdulhamid, A., Dogan, B., Victorio, D., Castellanos, J. G., ... & Chai, C.
(2017). IgA-coated E. coli enriched in Crohn’s disease spondyloarthritis promote TH17-dependent
inflammation. Science Translational Medicine, 9(376), eaaf9655.
Kivolowitz, C., Abdulhamid, A., Victorio, D., Castellanos, J., Simpson, K., Scherl, E., & Longman, R.
(2016). O-006 Expansion of Immunologically-Relevant E. Coli in the Intestinal Microbiota of Patients
with IBD-Associated Spondyloarthritis Promotes Mucosal RORgt-Dependent Immunity.
Inflammatory bowel diseases, 22, S3.

[←45]
Viladomiu, M., Kivolowitz, C., Abdulhamid, A., Dogan, B., Victorio, D., Castellanos, J. G., ... & Chai, C.
(2017). IgA-coated E. coli enriched in Crohn’s disease spondyloarthritis promote TH17-dependent
inflammation. Science Translational Medicine, 9(376), eaaf9655.
Kivolowitz, C., Abdulhamid, A., Victorio, D., Castellanos, J., Simpson, K., Scherl, E., & Longman, R.
(2016). O-006 Expansion of Immunologically-Relevant E. Coli in the Intestinal Microbiota of Patients
with IBD-Associated Spondyloarthritis Promotes Mucosal RORgt-Dependent Immunity.
Inflammatory bowel diseases, 22, S3.

[←46]
Rashid, T., & Ebringer, A. (2007). Ankylosing spondylitis is linked to Klebsiella—the evidence. Clinical
rheumatology, 26(6), 858-864.

[←47]
Tani, Y., Tiwana, H., Hukuda, S., Nishioka, J., Fielder, M., Wilson, C., ... & Ebringer, A. (1997). Antibodies
to Klebsiella, Proteus, and HLA-B27 peptides in Japanese patients with ankylosing spondylitis and
rheumatoid arthritis. The Journal of rheumatology, 24(1), 109-114.

[←48]
Blankenberg-Sprenkels, S. H., Fielder, M., Feltkamp, T. E., Tiwana, H., Wilson, C., & Ebringer, A. (1998).
Antibodies to Klebsiella pneumoniae in Dutch patients with ankylosing spondylitis and acute
anterior uveitis and to Proteus mirabilis in rheumatoid arthritis. The Journal of rheumatology, 25(4),
743-747.

[←49]
Tiwana, H., Wilson, C., Walmsley, R. S., Wakefield, A. J., Smith, M. S. N., Cox, N. L., ... & Ebringer, A.
(1997). Antibody responses to gut bacteria in ankylosing spondylitis, rheumatoid arthritis, Crohn's
disease and ulcerative colitis. Rheumatology international, 17(1), 11-16.

[←50]
Puccetti, A., Dolcino, M., Tinazzi, E., Moretta, F., D’Angelo, S., Olivieri, I., & Lunardi, C. (2017).
Antibodies Directed against a Peptide Epitope of a Klebsiella pneumoniae-Derived Protein Are
Present in Ankylosing Spondylitis. PloS one, 12(1), e0171073.

[←51]
Puccetti, A., Dolcino, M., Tinazzi, E., Moretta, F., D’Angelo, S., Olivieri, I., & Lunardi, C. (2017).
 Antibodies Directed against a Peptide Epitope of a Klebsiella pneumoniae-Derived Protein Are
Present in Ankylosing Spondylitis. PloS one, 12(1), e0171073.

[←52]
Christopoulos, G., Christopoulou, V., Routsias, J. G., Babionitakis, A., Antoniadis, C., & Vaiopoulos, G.
(2017). Greek rheumatoid arthritis patients have elevated levels of antibodies against antigens from
Proteus mirabilis. Clinical rheumatology, 36(3), 527-535.
Rashid, T., Jayakumar, K. S., Binder, A., Ellis, S., Cunningham, P., & Ebringer, A. (2007). Rheumatoid
arthritis patients have elevated antibodies to cross-reactive and non cross-reactive antigens from
Proteus microbes. Clinical and experimental rheumatology, 25(2), 259.
Tani, Y., Tiwana, H., Hukuda, S., Nishioka, J., Fielder, M., Wilson, C., ... & Ebringer, A. (1997). Antibodies
to Klebsiella, Proteus, and HLA-B27 peptides in Japanese patients with ankylosing spondylitis and
rheumatoid arthritis. The Journal of rheumatology, 24(1), 109-114.
Newkirk, M. M., Goldbach-Mansky, R., Senior, B. W., Klippel, J., Schumacher Jr, H. R., & El-Gabalawy, H.
S. (2005). Elevated levels of IgM and IgA antibodies to Proteus mirabilis and IgM antibodies to
Escherichia coli are associated with early rheumatoid factor (RF)-positive rheumatoid arthritis.
Rheumatology, 44(11), 1433-1441.

[←53]
Pyleris, E., Giamarellos-Bourboulis, E. J., Tzivras, D., Koussoulas, V., Barbatzas, C., & Pimentel, M.
(2012). The prevalence of overgrowth by aerobic bacteria in the small intestine by small bowel
culture: relationship with irritable bowel syndrome. Digestive diseases and sciences, 57(5), 1321-
1329;
Dukowicz, A. C., Lacy, B. E., & Levine, G. M. (2007). Small intestinal bacterial overgrowth: a
comprehensive review. Gastroenterology & hepatology, 3(2), 112.

[←54]
Ely, P. H. (1980). The bowel bypass syndrome: A response to bacterial peptidoglycanss. Journal of the
American Academy of Dermatology, 2(6), 473-487.
Zhao, H., Zhao, L., Shi, W., Luo, H., Duan, L., You, Y., ... & Zuo, X. (2016). Is it bowel-associated
dermatosis-arthritis syndrome induced by small intestinal bacteria overgrowth?. SpringerPlus, 5(1),
1551.
Bhangle, S. D., Kramer, N., & Rosenstein, E. D. (2009). Spondyloarthropathy after ampullary carcinoma
resection:“post-Whipple” disease. JCR: Journal of Clinical Rheumatology, 15(5), 241-243.

[←55]
Fisch, C., Schiller, P., Harr, T., & Maclachlan, D. (2001). First presentation of intestinal bypass syndrome
18 yr after initial surgery. Rheumatology, 40(3), 351-353.

[←56]
Fisch, C., Schiller, P., Harr, T., & Maclachlan, D. (2001). First presentation of intestinal bypass syndrome
18 yr after initial surgery. Rheumatology, 40(3), 351-353; Slater, G. H., Kerlin, P., Georghiou, P. R., &
Fielding, G. A. (2004). Bowel-associated dermatosis-arthritis syndrome after biliopancreatic
diversion. Obesity surgery, 14(1), 133-135.
Zhao, H., Zhao, L., Shi, W., Luo, H., Duan, L., You, Y., ... & Zuo, X. (2016). Is it bowel-associated
dermatosis-arthritis syndrome induced by small intestinal bacteria overgrowth?. SpringerPlus, 5(1),
 1551.

[←57]
Ojetti, V., De Simone, C., Aguilar Sanchez, J., Capizzi, R., Migneco, A., Guerriero, C., ... & Gasbarrini, A.
(2006). Malabsorption in psoriatic patients: cause or consequence?. Scandinavian journal of
gastroenterology, 41(11), 1267-1271.
Peslyak, M., Gumayunova, N., Nesterov, A., & Potaturkina-Nesterova, N. (2012). Small intestine
microflora at psoriasis. Its possible role in pathogenesis. In 3rd World Psoriasis & Psoriatic Arthritis
Conference.
Drago, F., Ciccarese, G., Indemini, E., Savarino, V., & Parodi, A. (2017). Psoriasis and small intestine
bacterial overgrowth. International journal of dermatology.

[←58]
Henriksson, A. E., Blomquist, L., Nord, C. E., Midtvedt, T., & Uribe, A. (1993). Small intestinal bacterial
overgrowth in patients with rheumatoid arthritis. Annals of the rheumatic diseases, 52(7), 503.

[←59]
Orchard, T. R., & Jewell, D. P. (1999). The importance of ileocaecal integrity in the arthritic
complications of Crohn's disease. Inflammatory bowel diseases, 5(2), 92-97.

[←60]
Pimentel, M., Wallace, D., Hallegua, D., Chow, E., Kong, Y., Park, S., & Lin, H. C. (2004). A link between
irritable bowel syndrome and fibromyalgia may be related to findings on lactulose breath testing.
Annals of the rheumatic diseases, 63(4), 450-452.

[←61]
Peslyak, M., Gumayunova, N., Nesterov, A., & Potaturkina-Nesterova, N. (2012). Small
intestine microflora at psoriasis. Its possible role in pathogenesis. In 3rd World Psoriasis &
Psoriatic Arthritis Conference.

[←62]
Ramírez-Boscá, A., Navarro-López, V., Martínez-Andrés, A., Such, J., Francés, R., de la Parte, J. H., &
Asín-Llorca, M. (2015). Identification of bacterial DNA in the peripheral blood of patients with active
psoriasis. JAMA dermatology, 151(6), 670-671.

[←63]
Ramírez-Boscá, A., Navarro-López, V., Martínez-Andrés, A., Such, J., Francés, R., de la Parte, J. H., &
Asín-Llorca, M. (2015). Identification of bacterial DNA in the peripheral blood of patients with active
psoriasis. JAMA dermatology, 151(6), 670-671.

[←64]
Drago, F., Ciccarese, G., Indemini, E., Savarino, V., & Parodi, A. (2018). Psoriasis and small intestine
bacterial overgrowth. International journal of dermatology, 57(1), 112-113.
[←65]
Mäki-Ikola, O., Hällgren, R., Kanerud, L., Feltelius, N., Knutsson, L., & Granfors, K. (1997). Enhanced
jejunal production of antibodies to Klebsiella and other Enterobacteria in patients with ankylosing
spondylitis and rheumatoid arthritis. Annals of the rheumatic diseases, 56(7), 421-425.

[←66]
Fotis, L., Shaikh, N., Baszis, K. W., Samson, C. M., Lev-Tzion, R., French, A. R., & Tarr, P. I. (2017).
Serologic evidence of gut-driven systemic inflammation in juvenile idiopathic arthritis. The Journal
of rheumatology, 44(11), 1624-1631.
Fialho, A., Fialho, A., Thota, P., McCullough, A. J., & Shen, B. (2016). Small Intestinal Bacterial
Overgrowth Is Associated with Non-Alcoholic Fatty Liver Disease. Journal of Gastrointestinal & Liver
Diseases, 25(2).
Bauer, Tilman M., et al. "Small intestinal bacterial overgrowth in human cirrhosis is associated with
systemic endotoxemia." The American journal of gastroenterology 97.9 (2002): 2364-2370

[←67]
Dukowicz, A. C., Lacy, B. E., & Levine, G. M. (2007). Small intestinal bacterial overgrowth: a
comprehensive review. Gastroenterology & hepatology, 3(2), 112;
Pimentel, M., Chow, E. J., & Lin, H. C. (2000). Eradication of small intestinal bacterial overgrowth
reduces symptoms of irritable bowel syndrome. The American journal of gastroenterology, 95(12),
3503-3506.

[←68]
Drago, F., Ciccarese, G., Indemini, E., Savarino, V., & Parodi, A. (2018). Psoriasis and small intestine
bacterial overgrowth. International journal of dermatology, 57(1), 112-113.

[←69]
Lauritano, E. C., Gabrielli, M., Scarpellini, E., Lupascu, A., Novi, M., Sottili, S., ... & Gasbarrini, G. (2008).
Small intestinal bacterial overgrowth recurrence after antibiotic therapy. The American journal of
gastroenterology, 103(8), 2031

[←70]
Gudjonsson, J. E., Thorarinsson, A. M., Sigurgeirsson, B., Kristinsson, K. G., & Valdimarsson, H. (2003).
Streptococcal throat infections and exacerbation of chronic plaque psoriasis: a prospective study.
British journal of dermatology, 149(3), 530-534.
Thorleifsdottir, R. H., Sigurdardottir, S. L., Sigurgeirsson, B., Olafsson, J. H., Sigurdsson, M. I., Petersen,
H., ... & Valdimarsson, H. (2012). Improvement of psoriasis after tonsillectomy is associated with a
decrease in the frequency of circulating T cells that recognize streptococcal determinants and
homologous skin determinants. The Journal of Immunology, 188(10), 5160-5165.
Johnston, A., Gudjonsson, J. E., Sigmundsdottir, H., Love, T. J., & Valdimarsson, H. (2004). Peripheral
blood T cell responses to keratin peptides that share sequences with streptococcal M proteins are
largely restricted to skin-homing CD8+ T cells. Clinical & Experimental Immunology, 138(1), 83-93.

[←71]
El-Rachkidy, R. G., Hales, J. M., Freestone, P. P., Young, H. S., Griffiths, C. E., & Camp, R. D. (2007).
 Increased blood levels of IgG reactive with secreted Streptococcus pyogenes proteins in chronic
plaque psoriasis. Journal of Investigative Dermatology, 127(6), 1337-1342.
Rantakokko, K., Rimpiläinen, M., Uksila, J., Jansen, C., Luukkainen, R., & Toivanen, P. (1997). Antibodies
to streptococcal cell wall in psoriatic arthritis and cutaneous psoriasis. Clinical and experimental
rheumatology, 15(4), 399-404.

[←72]
McFadden, J., Valdimarsson, H., & Fry, L. (1991). Cross-reactivity between streptococcal M surface
antigen and human skin. British Journal of Dermatology, 125(5), 443-447.
Swerlick, R. A., Cunningham, M. W., & Hall, N. K. (1986). Monoclonal antibodies cross-reactive with
group A streptococci and normal and psoriatic human skin. Journal of investigative dermatology,
87(3), 367-371.

[←73]
Weisenseel, P., Laumbacher, B., Besgen, P., Ludolph-Hauser, D., Herzinger, T., Roecken, M., ... & Prinz,
J. C. (2002). Streptococcal infection distinguishes different types of psoriasis. Journal of medical
genetics, 39(10), 767-768

[←74]
Thorleifsdottir, R. H., Sigurdardottir, S. L., Sigurgeirsson, B., Olafsson, J. H., Sigurdsson, M. I., Petersen,
H., ... & Valdimarsson, H. (2012). Improvement of psoriasis after tonsillectomy is associated with a
decrease in the frequency of circulating T cells that recognize streptococcal determinants and
homologous skin determinants. The Journal of Immunology, 188(10), 5160-5165.

[←75]
Thorleifsdottir, R. H., Sigurdardottir, S. L., Sigurgeirsson, B., Olafsson, J. H., Sigurdsson, M. I., Petersen,
H., ... & Valdimarsson, H. (2012). Improvement of psoriasis after tonsillectomy is associated with a
decrease in the frequency of circulating T cells that recognize streptococcal determinants and
homologous skin determinants. The Journal of Immunology, 188(10), 5160-5165.

[←76]
Allen, H. B., Jadeja, S., Allawh, R. M., & Goyal, K. (2018). Psoriasis, chronic tonsillitis, and biofilms:
Tonsillar pathologic findings supporting a microbial hypothesis. ENT: Ear, Nose & Throat Journal,
97(3).

[←77]
Di Pierro, F., Colombo, M., Zanvit, A., Risso, P., & Rottoli, A. S. (2014). Use of Streptococcus salivarius
K12 in the prevention of streptococcal and viral pharyngotonsillitis in children. Drug, healthcare and
patient safety, 6, 15.

[←78]
Mankia, K., Cheng, Z., Do, T., Kang, J., Hunt, L., Meade, J., ... & Devine, D. (2018). OP0352 An increased
prevalence of periodontal disease, porphyromonas gingivalis and aggregatibacter
actinomycetemcomitans in anti-ccp positive individuals at-risk of inflammatory arthritis.
 Kriebel, K., Hieke, C., Müller-Hilke, B., Nakata, M., & Kreikemeyer, B. (2018). Oral biofilms from
symbiotic to pathogenic interactions and associated disease–Connection of Periodontitis and
Rheumatic arthritis by peptidylarginine deiminase. Frontiers in microbiology, 9, 53.
Rosenstein, E. D., Greenwald, R. A., Kushner, L. J., & Weissmann, G. (2004). Hypothesis: the humoral
immune response to oral bacteria provides a stimulus for the development of rheumatoid
arthritis. Inflammation, 28(6), 311-318.

[←79]
Gleńska-Olender, J., Durlik, K., Konieczna, I., Kowalska, P., Gawęda, J., & Kaca, W. (2017). Detection of
human antibodies binding with smooth and rough LPSs from Proteus mirabilis O3 strains S1959,
R110, R45. Antonie van Leeuwenhoek, 110(11), 1435-1443.
Ebringer, A., & Rashid, T. (2006). Rheumatoid arthritis is an autoimmune disease triggered by Proteus
urinary tract infection. Journal of Immunology Research, 13(1), 41-48.

[←80]
Ebringer, A., & Rashid, T. (2014). Rheumatoid arthritis is caused by a Proteus urinary tract infection.
Apmis, 122(5), 363-368.

[←81]
Schaffer, J. N., & Pearson, M. M. (2015). Proteus mirabilis and urinary tract infections. Microbiology
spectrum, 3(5).

[←82]
Viladomiu, M., Kivolowitz, C., Abdulhamid, A., Dogan, B., Victorio, D., Castellanos, J. G., ... & Chai, C.
(2017). IgA-coated E. coli enriched in Crohn’s disease spondyloarthritis promote TH17-dependent
inflammation. Science Translational Medicine, 9(376), eaaf9655;
Ramírez-Boscá, A., Navarro-López, V., Martínez-Andrés, A., Such, J., Francés, R., de la Parte, J. H., &
Asín-Llorca, M. (2015). Identification of bacterial DNA in the peripheral blood of patients with active
psoriasis. JAMA dermatology, 151(6), 670-671
Scher, J. U., Sczesnak, A., Longman, R. S., Segata, N., Ubeda, C., Bielski, C., … Littman, D. R. (2013).
Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. eLife, 2,
e01202.
Maeda, Y., Kurakawa, T., Umemoto, E., Motooka, D., Ito, Y., Gotoh, K., ... & Sakaguchi, N. (2016).
Dysbiosis contributes to arthritis development via activation of autoreactive T cells in the intestine.
Arthritis & Rheumatology, 68(11), 2646-2661.
Chen, J., Wright, K., Davis, J. M., Jeraldo, P., Marietta, E. V., Murray, J., ... & Taneja, V. (2016). An
expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis. Genome medicine,
8(1), 43.

[←83]
Meadows, S. (2013, February 1). The Boy with the Thorn in his Joints. The New York Times, Magazine.

[←84]
Kohn, D (2015, January 12). Joint Pain, from the Gut. The Atlantic
[←85]
Horton, D. B., Scott, F. I., Haynes, K., Putt, M. E., Rose, C. D., Lewis, J. D., & Strom, B. L. (2015).
Antibiotic exposure and juvenile idiopathic arthritis: a case–control study. Pediatrics, peds-2015

[←86]
Marra, F., Marra, C. A., Richardson, K., Lynd, L. D., Kozyrskyj, A., Patrick, D. M., ... & FitzGerald, J. M.
(2009). Antibiotic use in children is associated with increased risk of asthma. Pediatrics, 123(3),
1003-1010.

[←87]
Ungaro, R., Bernstein, C. N., Gearry, R., Hviid, A., Kolho, K. L., Kronman, M. P., ... & Atreja, A. (2014).
Antibiotics associated with increased risk of new-onset Crohn’s disease but not ulcerative colitis: a
meta-analysis. The American journal of gastroenterology, 109(11), 1728-1738.

[←88]
Zaura, E., Brandt, B. W., de Mattos, M. J. T., Buijs, M. J., Caspers, M. P., Rashid, M. U., ... & Coates, A. R.
(2015). Same exposure but two radically different responses to antibiotics: Resilience of the salivary
microbiome versus long-term microbial shifts in feces. MBio, 6(6), e01693-15.

[←89]
Song, H. J., Shim, K. N., Jung, S. A., Choi, H. J., Lee, M. A., Ryu, K. H., ... & Yoo, K. (2008). Antibiotic-
associated diarrhea: candidate organisms other than Clostridium difficile. The Korean journal of
internal medicine, 23(1), 9.
Högenauer, C., Hammer, H. F., Krejs, G. J., & Reisinger, C. (1998). Mechanisms and management of
antibiotic-associated diarrhea. Clinical infectious diseases, 27(4), 702-710.

[←90]
Hanson, L., VandeVusse, L., Jermé, M., Abad, C. L., & Safdar, N. (2016). Probiotics for Treatment and
Prevention of Urogenital Infections in Women: A Systematic Review. Journal of Midwifery &
Women’s Health, 61(3), 339-355.

[←91]
Zhang, L., Huang, Y., Zhou, Y., Buckley, T., & Wang, H. H. (2013). Antibiotic administration routes
significantly influence the levels of antibiotic resistance in gut microbiota. Antimicrobial agents and
chemotherapy, 57(8), 3659-3666.

[←92]
FSIS RESIDUE VIOLATION INFORMATION SYSTEM, December 6, 2016. Available online at
www.fsis.usda.gov

[←93]
FSIS RESIDUE VIOLATION INFORMATION SYSTEM, December 6, 2016. Available online at
www.fsis.usda.gov

 Chapter 2. Rebalancing the Microbiome with Probiotics

[←94]
Canani, R. B., Sangwan, N., Stefka, A. T., Nocerino, R., Paparo, L., Aitoro, R., ... & Nagler, C. R. (2016).
Lactobacillus rhamnosus GG-supplemented formula expands butyrate-producing bacterial strains in
food allergic infants. The ISME journal, 10(3), 742-750.

[←95]
Falony, G., Vlachou, A., Verbrugghe, K., & De Vuyst, L. (2006). Cross-feeding between Bifidobacterium
longum BB536 and acetate-converting, butyrate-producing colon bacteria during growth on
oligofructose. Applied and environmental microbiology, 72(12), 7835-7841.

[←96]
Rios-Covian, D., Gueimonde, M., Duncan, S. H., Flint, H. J., & Clara, G. (2015). Enhanced butyrate
formation by cross-feeding between Faecalibacterium prausnitzii and Bifidobacterium adolescentis.
FEMS microbiology letters, 362(21), fnv176.
Rivière, A., Gagnon, M., Weckx, S., Roy, D., & De Vuyst, L. (2015). Mutual cross-feeding interactions
between Bifidobacterium longum subsp. longum NCC2705 and Eubacterium rectale ATCC 33656
explain the bifidogenic and butyrogenic effects of arabinoxylan oligosaccharides. Applied and
environmental microbiology, 81(22), 7767-7781.
Rivière, A., Gagnon, M., Weckx, S., Roy, D., & De Vuyst, L. (2015). Mutual cross-feeding interactions
between Bifidobacterium longum subsp. longum NCC2705 and Eubacterium rectale ATCC 33656
explain the bifidogenic and butyrogenic effects of arabinoxylan oligosaccharides. Applied and
environmental microbiology, 81(22), 7767-7781.

[←97]
Falony, G., Vlachou, A., Verbrugghe, K., & De Vuyst, L. (2006). Cross-feeding between Bifidobacterium
longum BB536 and acetate-converting, butyrate-producing colon bacteria during growth on
oligofructose. Applied and environmental microbiology, 72(12), 7835-7841.
Sugahara, H., Odamaki, T., Fukuda, S., Kato, T., Xiao, J. Z., Abe, F., ... & Ohno, H. (2015). Probiotic
Bifidobacterium longum alters gut luminal metabolism through modification of the gut microbial
community. Scientific reports, 5, 13548.
Rios-Covian, D., Gueimonde, M., Duncan, S. H., Flint, H. J., & Clara, G. (2015). Enhanced butyrate
formation by cross-feeding between Faecalibacterium prausnitzii and Bifidobacterium adolescentis.
FEMS microbiology letters, 362(21), fnv176.
Quagliariello, A., Aloisio, I., Bozzi Cionci, N., Luiselli, D., D’Auria, G., Martinez-Priego, L., ... & Di Gioia, D.
(2016). Effect of Bifidobacterium breve on the Intestinal Microbiota of Coeliac Children on a Gluten
Free Diet: A Pilot Study. Nutrients, 8(10), 660.

[←98]
Leahy, S. C., Higgins, D. G., Fitzgerald, G. F., & Sinderen, D. V. (2005). Getting better with bifidobacteria.
Journal of Applied Microbiology, 98(6), 1303-1315.

[←99]
 Ishibashi, N., Yaeshima, T., & Hayasawa, H. (1997). Bifidobacteria: their significance in human intestinal
health. Mal J Nutr, 3, 149-159.

[←100]
Rios-Covian, D., Gueimonde, M., Duncan, S. H., Flint, H. J., & Clara, G. (2015). Enhanced butyrate
formation by cross-feeding between Faecalibacterium prausnitzii and Bifidobacterium adolescentis.
FEMS microbiology letters, 362(21), fnv176.
Rivière, A., Gagnon, M., Weckx, S., Roy, D., & De Vuyst, L. (2015). Mutual cross-feeding interactions
between Bifidobacterium longum subsp. longum NCC2705 and Eubacterium rectale ATCC 33656
explain the bifidogenic and butyrogenic effects of arabinoxylan oligosaccharides. Applied and
environmental microbiology, 81(22), 7767-7781.

[←101]
Trosvik, P., & Muinck, E. J. (2015). Ecology of bacteria in the human gastrointestinal tract—
identification of keystone and foundation taxa. Microbiome, 3(1), 44.

[←102]
Mogna, L., Del Piano, M., Deidda, F., Nicola, S., Soattini, L., Debiaggi, R., ... & Mogna, G. (2012).
Assessment of the in vitro inhibitory activity of specific probiotic bacteria against different
Escherichia coli strains. Journal of clinical gastroenterology, 46, S29-S32.
Lemoli, E., Trabattoni, D., Parisotto, S., Borgonovo, L., Toscano, M., Rizzardini, G., ... & Piconi, S. (2012).
Probiotics reduce gut microbial translocation and improve adult atopic dermatitis. Journal of clinical
gastroenterology, 46, S33-S40.
Gibson, G. R., & Wang, X. (1994). Regulatory effects of bifidobacteria on the growth of other colonic
bacteria. Journal of Applied Bacteriology, 77(4), 412-420.
Aloisio, I., Santini, C., Biavati, B., Dinelli, G., Cencič, A., Chingwaru, W., ... & Di Gioia, D. (2012).
Characterization of Bifidobacterium spp. strains for the treatment of enteric disorders in newborns.
Applied microbiology and biotechnology, 96(6), 1561-1576.

[←103]
Bin-Nun, A., Bromiker, R., Wilschanski, M., Kaplan, M., Rudensky, B., Caplan, M., & Hammerman, C.
(2005). Oral probiotics prevent necrotizing enterocolitis in very low birth weight neonates. The
Journal of pediatrics, 147(2), 192-196.
Lievin, V., Peiffer, I., Hudault, S., Rochat, F., Brassart, D., Neeser, J. R., & Servin, A. L. (2000).
Bifidobacterium strains from resident infant human gastrointestinal microflora exert antimicrobial
activity. Gut, 47(5), 646-652.
Viswanathan, S., Lau, C., Akbari, H., Hoyen, C., & Walsh, M. C. (2016). Survey and evidence based
review of probiotics used in very low birth weight preterm infants within the United States. Journal
of Perinatology.

[←104]
Athalye-Jape, G., Rao, S., & Patole, S. (2016). Lactobacillus reuteri DSM 17938 as a probiotic for
preterm neonates: a strain-specific systematic review. Journal of parenteral and enteral nutrition,
40(6), 783-794.
Savino, F., Cordisco, L., Tarasco, V., Palumeri, E., Calabrese, R., Oggero, R., ... & Matteuzzi, D. (2010).
Lactobacillus reuteri DSM 17938 in infantile colic: a randomized, double-blind, placebo-controlled
 trial. Pediatrics, 126(3), e526-e533.

[←105]
Gutierrez-Castrellon, P., Lopez-Velazquez, G., Diaz-Garcia, L., Jimenez-Gutierrez, C., Mancilla-Ramirez,
J., Estevez-Jimenez, J., & Parra, M. (2014). Diarrhea in preschool children and Lactobacillus reuteri: a
randomized controlled trial. Pediatrics, 133(4), e904-e909

[←106]
Ojetti, V., Petruzziello, C., Migneco, A., Gnarra, M., Gasbarrini, A., & Franceschi, F. (2017). Effect of
Lactobacillus reuteri (DSM 17938) on methane production in patients affected by functional
constipation: a retrospective study. Eur Rev Med Pharmacol Sci, 21(7), 1702-1708.

[←107]
Morrow, L. E., Kollef, M. H., & Casale, T. B. (2010). Probiotic prophylaxis of ventilator-associated
pneumonia: a blinded, randomized, controlled trial. American journal of respiratory and critical care
medicine, 182(8), 1058-1064.
McFarland, L. V. (2015). Probiotics for the primary and secondary prevention of C. difficile infections:
a meta-analysis and systematic review. Antibiotics, 4(2), 160-178.

[←108]
Canani, R. B., Cirillo, P., Terrin, G., Cesarano, L., Spagnuolo, M. I., De Vincenzo, A., ... & Guarino, A.
(2007). Probiotics for treatment of acute diarrhoea in children: randomised clinical trial of five
different preparations. Bmj, 335(7615), 340.

[←109]
McFarland, L. V. (2015). Probiotics for the primary and secondary prevention of C. difficile infections: a
meta-analysis and systematic review. Antibiotics, 4(2), 160-178.
Scaldaferri, F., Gerardi, V., Mangiola, F., Lopetuso, L. R., Pizzoferrato, M., Petito, V., ... & Gasbarrini, A.
(2016). Role and mechanisms of action of Escherichia coli Nissle 1917 in the maintenance of
remission in ulcerative colitis patients: an update. World journal of gastroenterology, 22(24), 5505

[←110]
Auclair, J., Frappier, M., & Millette, M. (2015). Lactobacillus acidophilus CL1285, Lactobacillus casei
LBC80R, and Lactobacillus rhamnosus CLR2 (Bio-K+): characterization, manufacture, mechanisms of
action, and quality control of a specific probiotic combination for primary prevention of Clostridium
difficile infection. Clinical Infectious Diseases, 60(suppl_2), S135-S143.

[←111]
Beausoleil, M., Fortier, N.A., Guinette, S., L'Ecuyer, A., Savoie, M., Weiss, K., Lachaine, J., and Franco,
M. (2004) Effect of a Lactobacillus acidophilusand casei-fermented milk in the primary prevention of
antibiotic-associated diarrhea (lactic trial) : a randomized, double-blind, placebo-controlled trial.
In 69thAnnual Scientific Meeting and Post-graduate Course, November 2004. Orlando, FL: American
College of Gastroenterology.
[←112]
Gao, X. W., Mubasher, M., Fang, C. Y., Reifer, C., & Miller, L. E. (2010). Dose–response efficacy of a
proprietary probiotic formula of Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R for
antibiotic-associated diarrhea and Clostridium difficile-associated diarrhea prophylaxis in adult
patients. The American journal of gastroenterology, 105(7), 1636.

[←113]
Song, H. J., Shim, K. N., Jung, S. A., Choi, H. J., Lee, M. A., Ryu, K. H., ... & Yoo, K. (2008). Antibiotic-
associated diarrhea: candidate organisms other than Clostridium difficile. The Korean journal of
internal medicine, 23(1), 9.
Högenauer, C., Hammer, H. F., Krejs, G. J., & Reisinger, C. (1998). Mechanisms and management of
antibiotic-associated diarrhea. Clinical infectious diseases, 27(4), 702-710

[←114]
Millette, M., Luquet, F. M., & Lacroix, M. (2007). In vitro growth control of selected pathogens by
Lactobacillus acidophilus-and Lactobacillus casei-fermented milk. Letters in applied
microbiology, 44(3), 314-319.

[←115]
Reddy, N. R., & Pierson, M. D. (1994). Reduction in antinutritional and toxic components in plant foods
by fermentationa. Food Research International, 27(3), 281-290.

[←116]
Nazareth, S., Lebwohl, B., Voyksner, J. S., & Green, P. H. (2015). 108 Widespread Contamination of
Probiotics With Gluten, Detected by Liquid Chromatography-Mass
Spectrometry. Gastroenterology, 148(4), S-28.

[←117]
Millette, M., Nguyen, A., Amine, K. M., & Lacroix, M. (2013). Gastrointestinal survival of bacteria in
commercial probiotic products. International Journal of Probiotics & Prebiotics, 8(4), 149.

[←118]
Scaldaferri, F., Gerardi, V., Mangiola, F., Lopetuso, L. R., Pizzoferrato, M., Petito, V., ... & Gasbarrini, A.
(2016). Role and mechanisms of action of Escherichia coli Nissle 1917 in the maintenance of
remission in ulcerative colitis patients: an update. World journal of gastroenterology, 22(24), 5505.
Sonnenborn, U., & Schulze, J. (2009). The non-pathogenic Escherichia coli strain Nissle 1917–features
of a versatile probiotic. Microbial Ecology in Health and Disease, 21(3-4), 122-158.

[←119]
Kruis, W., Frič, P., Pokrotnieks, J., Lukáš, M., Fixa, B., Kaščák, M., ... & Wolff, C. (2004). Maintaining
remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with
standard mesalazine. Gut, 53(11), 1617-1623.
Rembacken, B. J., Snelling, A. M., Hawkey, P. M., Chalmers, D. M., & Axon, A. T. R. (1999). Non-
pathogenic Escherichia coli versus mesalazine for the treatment of ulcerative colitis: a randomised
trial. The Lancet, 354(9179), 635-639.
[←120]
Malchow HA. Crohn’s disease and Escherichia coli. A new approach in therapy to maintain remission of
colonic Crohn’s disease? J Clin Gastroenterol (1997) 25(4):653–8.10.

[←121]
Reissbrodt R, Hammes WP, dal Bello F, Prager R, Fruth A, Hantke K, Rakin A, Starcic-Erjavec M, Williams
PH. Inhibition of growth of Shiga toxin-producing Escherichia coli by nonpathogenic Escherichia
coli. FEMS Microbiol Lett. 2009;290:62–69.
Lasaro MA, Salinger N, Zhang J, Wang Y, Zhong Z, Goulian M, Zhu J. F1C fimbriae play an important role
in biofilm formation and intestinal colonization by the Escherichia coli commensal strain Nissle
1917. Appl Environ Microbiol. 2009;75:246–251
Boudeau J, Glasser AL, Neut C, et al. Invasive ability of Escherichia coli strains isolated from ileal
mucosa in Crohn's disease. Gastroenterology2000; 118(S2): A1847.
Darfeuille-Michaud A, Neut C, Barnich N, et al.Presence of adherent Escherichia coli strains in ileal
mucosa of patients with Crohn's disease. Gastroenterology 1998; 115(6): 1405–13.
Lederman E, Neut C, Desreumaux P, et al. Bacterial overgrowth in the neoterminal ileum after
ileocolonic resection for Crohn's disease. Gastroenterology 1997; 112: A1023
Boudeau J, Glasser AL, Masseret E, Joly B, Darfeuille-Michaud A. Invasive ability of an Escherichia coli
strain isolated from the ileal mucosa of a patient with Crohn's disease. Infect Immun 1999; 67(9):
4499–509.
Swidsinski, A., Swidsinski, S., Godzun, A., Orthner, M., & Lochs, H. (2000). Therapy with E. coli Nissle
reduces concentrations of mucosa associated colonic flora in patients with ulcerative colitis.
Gastroenterology, 118(4), A1138.

[←122]
Boudeau, J., Glasser, A. L., Julien, S., Colombel, J. F., & Darfeuille-Michaud, A. (2003). Inhibitory effect
of probiotic Escherichia coli strain Nissle 1917 on adhesion to and invasion of intestinal epithelial
cells by adherent–invasive E. coli strains isolated from patients with Crohn's disease. Alimentary
pharmacology & therapeutics, 18(1), 45-56.
Huebner, C., Ding, Y., Petermann, I., Knapp, C., & Ferguson, L. R. (2011). The probiotic Escherichia coli
Nissle 1917 reduces pathogen invasion and modulates cytokine expression in Caco-2 cells infected
with Crohn's disease-associated E. coli LF82. Applied and environmental microbiology, 77(7), 2541-
2544.

[←123]
Hancock, V., Dahl, M., & Klemm, P. (2010). Probiotic Escherichia coli strain Nissle 1917 outcompetes
intestinal pathogens during biofilm formation. Journal of medical microbiology, 59(4), 392-399.

[←124]
Altenhoefer, A., Oswald, S., Sonnenborn, U., Enders, C., Schulze, J., Hacker, J., & Oelschlaeger, T. A.
(2004). The probiotic Escherichia coli strain Nissle 1917 interferes with invasion of human intestinal
epithelial cells by different enteroinvasive bacterial pathogens. FEMS Immunology & Medical
Microbiology, 40(3), 223-229.
Storm, D. W., Koff, S. A., Horvath, D. J., Li, B., & Justice, S. S. (2011). In vitro analysis of the bactericidal
activity of Escherichia coli Nissle 1917 against pediatric uropathogens. The Journal of urology,
186(4), 1678-1683.
[←125]
Lodinová-Žádníková, R., & Sonnenborn, U. (1997). Effect of preventive administration of a
nonpathogenic Escherichia coli strain on the colonization of the intestine with microbial pathogens
in newborn infants. Neonatology, 71(4), 224-232.

[←126]
Kamada, N., Maeda, K., Inoue, N., Hisamatsu, T., Okamoto, S., Hong, K. S., ... & Hibi, T. (2008).
Nonpathogenic Escherichia coli strain Nissle 1917 inhibits signal transduction in intestinal epithelial
cells. Infection and immunity, 76(1), 214-220.
Splichalova, A., Trebichavsky, I., Rada, V., Vlkova, E., Sonnenborn, U., & Splichal, I. (2011). Interference
of Bifidobacterium choerinum or Escherichia coli Nissle 1917 with Salmonella Typhimurium in
gnotobiotic piglets correlates with cytokine patterns in blood and intestine. Clinical & Experimental
Immunology, 163(2), 242-249
Swidsinski, A., Swidsinski, S., Godzun, A., Orthner, M., & Lochs, H. (2000). Therapy with E. coli Nissle
reduces concentrations of mucosa associated colonic flora in patients with ulcerative
colitis. Gastroenterology, 118(4), A1138.

[←127]
FDA Memorandum to Medical Futures, Inc., Re: 75-Day Premarket Notification of New Dietary
Ingredients, E.coli Nissle 1917. Dated November 16, 2011.

[←128]
McFarland, L. V. (2010). Systematic review and meta-analysis of Saccharomyces boulardii in adult
patients. World journal of gastroenterology: WJG, 16(18), 2202.

[←129]
McFarland, L. V. (2010). Systematic review and meta-analysis of Saccharomyces boulardii in adult
patients. World journal of gastroenterology: WJG, 16(18), 2202.

[←130]
Lewis SJ, Potts LF, Barry RE. The lack of therapeutic effect of Saccharomyces boulardii in the prevention
of antibiotic-related diarrhoea in elderly patients. J Infect. 1998;36:171–174.
Cremonini F, Di Caro S, Covino M, Armuzzi A, Gabrielli M, Santarelli L, Nista EC, Cammarota G,
Gasbarrini G, Gasbarrini A. Effect of different probiotic preparations on anti-helicobacter pylori
therapy-related side effects: a parallel group, triple blind, placebo-controlled study. Am J
Gastroenterol. 2002;97:2744–2749.
Can M, Beşirbellioglu BA, Avci IY, Beker CM, Pahsa A. Prophylactic Saccharomyces boulardii in the
prevention of antibiotic-associated diarrhea: a prospective study. Med Sci Monit. 2006;12:PI19–
PI22.
Bravo MV, Bunout D, Leiva L, de la Maza MP, Barrera G, de la Maza J, Hirsch S. [Effect of probiotic
Saccharomyces boulardii on prevention of antibiotic-associated diarrhea in adult outpatients with
amoxicillin treatment] Rev Med Chil. 2008;136:981–988.
Adam J, Barret C, Barret-Bellet A, Benedetti E, Calendini A, Darchen P, Galibert JM, Guerci P, Guiot G,
Haechler M, et al. Controlled double-blind clinical trials of Ultra-Levure: multi centre study by 25
physicians in 388 cases. Gazette Medicale de France. 1977;84:2072–2078
Cindoruk M, Erkan G, Karakan T, Dursun A, Unal S. Efficacy and safety of Saccharomyces boulardii in
 the 14-day triple anti-Helicobacter pylori therapy: a prospective randomized placebo-controlled
double-blind study. Helicobacter. 2007;12:309–316.
Duman DG, Bor S, Ozütemiz O, Sahin T, Oğuz D, Iştan F, Vural T, Sandkci M, Işksal F, Simşek I, et al.
Efficacy and safety of Saccharomyces boulardii in prevention of antibiotic-associated diarrhoea due
to Helicobacterpylori eradication. Eur J Gastroenterol Hepatol. 2005;17:1357–1361
McFarland LV, Surawicz CM, Greenberg RN, Elmer GW, Moyer KA, Melcher SA, Bowen KE, Cox JL.
Prevention of beta-lactam-associated diarrhea by Saccharomyces boulardii compared with
placebo. Am J Gastroenterol. 1995;90:439–448.
McFarland, L. V. (2010). Systematic review and meta-analysis of Saccharomyces boulardii in adult
patients. World journal of gastroenterology: WJG, 16(18), 2202.
Monteiro E, Fernandes JP, Vieira MR, Correia JP, Caetano JM, Ribeiro T, Antunes AB, Noronha R, Batista
F, Reis L, et al. [Double blind clinical trial on the use of ultra-levure in the prophylaxis of antibiotic
induced gastro-intestinal and mucocutaneous disorders] Acta Med Port. 1981;3:143–145.
Surawicz CM, Elmer GW, Speelman P, McFarland LV, Chinn J, van Belle G. Prevention of antibiotic-
associated diarrhea by Saccharomyces boulardii: a prospective
study. Gastroenterology. 1989;96:981–988.

[←131]
Kabbani, T. A., Pallav, K., Dowd, S. E., Villafuerte-Galvez, J., Vanga, R. R., Castillo, N. E., ... & Kelly, C. P.
(2017). Prospective randomized controlled study on the effects of Saccharomyces boulardii CNCM I-
745 and amoxicillin-clavulanate or the combination on the gut microbiota of healthy
volunteers. Gut microbes, 8(1), 17-32.

[←132]
Hochter W, Chase D, Hagenhoff G. Saccharomyces boulardii in acute adult diarrhea: efficacy and
tolerability of treatment. Munch Med Wschr. 1990;132:188–192.
Besirbellioglu BA, Ulcay A, Can M, Erdem H, Tanyuksel M, Avci IY, Araz E, Pahsa A. Saccharomyces
boulardii and infection due to Giardia lamblia. Scand J Infect Dis. 2006;38:479–481
Mansour-Ghanaei F, Dehbashi N, Yazdanparast K, Shafaghi A. Efficacy of saccharomyces boulardii with
antibiotics in acute amoebiasis. World J Gastroenterol. 2003;9:1832–1833
Buts JP, Corthier G, Delmee M. Saccharomyces boulardii for Clostridium difficile-associated
enteropathies in infants. J Pediatr Gastroenterol Nutr. 1993;16:419–425.
Surawicz CM, McFarland LV, Elmer G, Chinn J. Treatment of recurrent Clostridium difficile colitis with
vancomycin and Saccharomyces boulardii. Am J Gastroenterol. 1989;84:1285–1287.
Hassett J, Meyers S, McFarland L, Mulligan ME. Recurrent Clostridium difficile infection in a patient
with selective IgG1 deficiency treated with intravenous immune globulin and Saccharomyces
boulardii. Clin Infect Dis. 1995;20 Suppl 2:S266–S268
Popoola J, Swann A, Warwick G. Clostridium difficile in patients with renal failure - management of an
outbreak using biotherapy. Nephrol Dial Transplant. 2000;15:571–574

[←133]
Hochter W, Chase D, Hagenhoff G. Saccharomyces boulardii in acute adult diarrhea: efficacy and
tolerability of treatment. Munch Med Wschr. 1990;132:188–192.
Dinleyici, E. C., Kara, A., Dalgic, N., Kurugol, Z., Arica, V., Metin, O., ... & Bulut, S. (2015). Saccharomyces
boulardii CNCM I-745 reduces the duration of diarrhoea, length of emergency care and hospital stay
in children with acute diarrhoea. Beneficial microbes, 6(4), 415-421.
[←134]
Ducluzeau, R., & Bensaada, M. (1982). Comparative effect of a single or continuous administration of"
Saccharomyces boulardii" on the establishment of various strains of" candida" in the digestive tract
of gnotobiotic mice. In Annales de microbiologie (Vol. 133, No. 3, pp. 491-501).
Zbinden R, Bonczi E, Altwegg M. Inhibition of Saccharomyces boulardii (nom. inval.) on cell invasion of
Salmonella typhimurium and Yersinia enterocolitica. Micro Ecol Health Dis. 1999;11:158–162.
Altwegg M, Schnack J, Zbinden R. Influence of Saccharomyces boulardii on Aeromonas hemolysin. Med
Microbiol Lett. 1995;4:417–425.

[←135]
Buts JP, Dekeyser N, Stilmant C, Delem E, Smets F, Sokal E. Saccharomyces boulardii produces in rat
small intestine a novel protein phosphatase that inhibits Escherichia coli endotoxin by
dephosphorylation. Pediatr Res. 2006;60:24–29
Castagliuolo I, Riegler MF, Valenick L, LaMont JT, Pothoulakis C. Saccharomyces boulardii protease
inhibits the effects of Clostridium difficile toxins A and B in human colonic mucosa. Infect
Immun. 1999;67:302–307.
Vidon N, Huchet B, Rambaud JC. Effect of S. boulardii on water and sodium secretions induced by
cholera toxin. Gastroenterol Clin Biol. 1986;10:1–4.
Czerucka D, Rampal P. Effect of Saccharomyces boulardii on cAMP- and Ca2+ -dependent Cl- secretion
in T84 cells. Dig Dis Sci. 1999;44:2359–2368

[←136]
Ducluzeau, R., & Bensaada, M. (1982). Comparative effect of a single or continuous administration of"
Saccharomyces boulardii" on the establishment of various strains of" candida" in the digestive tract
of gnotobiotic mice. In Annales de microbiologie (Vol. 133, No. 3, pp. 491-501).

[←137]
Krasowska, A., Murzyn, A., Dyjankiewicz, A., Łukaszewicz, M., & Dziadkowiec, D. (2009). The
antagonistic effect of Saccharomyces boulardii on Candida albicans filamentation, adhesion and
biofilm formation. FEMS yeast research, 9(8), 1312-1321.
Murzyn, A., Krasowska, A., Stefanowicz, P., Dziadkowiec, D., & Łukaszewicz, M. (2010). Capric acid
secreted by S. boulardii inhibits C. albicans filamentous growth, adhesion and biofilm
formation. PloS one, 5(8), e12050.
Jawhara S, Poulain D. Saccharomyces boulardii decreases inflammation and intestinal colonization by
Candida albicans in a mouse model of chemically-induced colitis. Med Mycol. 2007;45(8):691–700

[←138]
Kumamoto, C. A. (2011). Inflammation and gastrointestinal Candida colonization. Current opinion in
microbiology, 14(4), 386-391.

[←139]
Sokol, H., Leducq, V., Aschard, H., Pham, H. P., Jegou, S., Landman, C., ... & Cosnes, J. (2016). Fungal
microbiota dysbiosis in IBD. Gut, gutjnl-2015.
Liguori, G., Lamas, B., Richard, M. L., Brandi, G., Da Costa, G., Hoffmann, T. W., ... & Campieri, M.
(2015). Fungal dysbiosis in mucosa-associated microbiota of Crohn’s disease patients. Journal of
Crohn's and Colitis, 10(3), 296-305.
[←140]
Kumamoto, C. A. (2011). Inflammation and gastrointestinal Candida colonization. Current opinion in
microbiology, 14(4), 386-391.

[←141]
Garcia Vilela E, De Lourdes De Abreu Ferrari M, Oswaldo Da Gama Torres H, Guerra Pinto A, Carolina
Carneiro Aguirre A, Paiva Martins F, Marcos Andrade Goulart E, Sales Da Cunha A. Influence of
Saccharomyces boulardii on the intestinal permeability of patients with Crohn's disease in
remission. Scand J Gastroenterol. 2008;43:842–848.

[←142]
Guslandi, M., Mezzi, G., Sorghi, M., & Testoni, P. A. (2000). Saccharomyces boulardii in maintenance
treatment of Crohn’s disease. Digestive diseases and sciences, 45(7), 1462-1464.

[←143]
Plein K, Hotz J. Therapeutic effects of Saccharomyces boulardii on mild residual symptoms in a stable
phase of Crohn's disease with special respect to chronic diarrhea--a pilot study. Z
Gastroenterol. 1993;31:129–134.

[←144]
Lherm, T., Monet, C., Nougière, B., Soulier, M., Larbi, D., Le Gall, C., ... & Malbrunot, C. (2002). Seven
cases of fungemia with Saccharomyces boulardii in critically ill patients. Intensive care
medicine, 28(6), 797-801.

[←145]
Kwak, D. S., Jun, D. W., Seo, J. G., Chung, W. S., Park, S. E., Lee, K. N., ... & Choi, H. S. (2014). Short-term
probiotic therapy alleviates small intestinal bacterial overgrowth, but does not improve intestinal
permeability in chronic liver disease. European journal of gastroenterology & hepatology, 26(12),
1353-1359.

[←146]
Soifer, L. O., Peralta, D., Dima, G., & Besasso, H. (2010). Comparative clinical efficacy of a probiotic vs.
an antibiotic in the treatment of patients with intestinal bacterial overgrowth and chronic
abdominal functional distension: a pilot study. Acta gastroenterologica Latinoamericana, 40(4),
323-327

[←147]
Gabrielli M, Lauritano EC, Scarpellini E, Lupascu A, Ojetti V, Gasbarrini G, Silveri NG, Gasbarrini A.
Bacillus clausii as a treatment of small intestinal bacterial overgrowth. Am J
Gastroenterol. 2009;104:1327–1328.
Khalighi, A. R., Khalighi, M. R., Behdani, R., Jamali, J., Khosravi, A., Kouhestani, S., ... & Khalighi, N.
(2014). Evaluating the efficacy of probiotic on treatment in patients with small intestinal bacterial
overgrowth (SIBO)-A pilot study. The Indian journal of medical research, 140(5), 604.
Barrett, J. S., Canale, K. E., Gearry, R. B., Irving, P. M., & Gibson, P. R. (2008). Probiotic effects on
intestinal fermentation patterns in patients with irritable bowel syndrome. World journal of
 gastroenterology: WJG, 14(32), 5020.

[←148]
Uribarri, J., Oh, M. S., & Carroll, H. J. (1998). D-lactic acidosis: a review of clinical presentation,
biochemical features, and pathophysiologic mechanisms. MEDICINE-BALTIMORE-, 77, 73-82

[←149]
Sheedy, J. R., Wettenhall, R. E., Scanlon, D., Gooley, P. R., Lewis, D. P., Mcgregor, N., ... & De Meirleir, K.
L. (2009). Increased d-lactic acid intestinal bacteria in patients with chronic fatigue syndrome. in
vivo, 23(4), 621-628.

[←150]
Bures, J., Cyrany, J., Kohoutova, D., Förstl, M., Rejchrt, S., Kvetina, J., ... & Kopacova, M. (2010). Small
intestinal bacterial overgrowth syndrome. World journal of gastroenterology: WJG, 16(24), 2978.
Yamaguchi, N., Sugita, R., Miki, A., Takemura, N., Kawabata, J., Watanabe, J., & Sonoyama, K. (2006).
Gastrointestinal Candida colonisation promotes sensitisation against food antigens by affecting the
mucosal barrier in mice. Gut, 55(7), 954-960.

[←151]
Canani, R. B., Costanzo, M. D., Leone, L., Pedata, M., Meli, R., & Calignano, A. (2011). Potential
beneficial effects of butyrate in intestinal and extraintestinal diseases. World J Gastroenterol,
17(12), 1519-1528.
Plöger, S., Stumpff, F., Penner, G. B., Schulzke, J. D., Gäbel, G., Martens, H., ... & Aschenbach, J. R.
(2012). Microbial butyrate and its role for barrier function in the gastrointestinal tract. Annals of the
New York Academy of Sciences, 1258(1), 52-59.
Willemsen, L. E. M., Koetsier, M. A., Van Deventer, S. J. H., & Van Tol, E. A. F. (2003). Short chain fatty
acids stimulate epithelial mucin 2 expression through differential effects on prostaglandin E1 and E2
production by intestinal myofibroblasts. Gut, 52(10), 1442-1447.
Burger-van Paassen, N., Vincent, A., Puiman, P. J., Van Der Sluis, M., Bouma, J., Boehm, G., ... & Renes,
I. B. (2009). The regulation of intestinal mucin MUC2 expression by short-chain fatty acids:
implications for epithelial protection. Biochemical Journal, 420(2), 211-219.
Kripke, S. A., Fox, A. D., Berman, J. M., Settle, R. G., & Rombeau, J. L. (1989). Stimulation of intestinal
mucosal growth with intracolonic infusion of short-chain fatty acids. Journal of Parenteral and
Enteral Nutrition, 13(2), 109-116.
Johansson, M. E., Gustafsson, J. K., Holmén-Larsson, J., Jabbar, K. S., Xia, L., Xu, H., ... & Hansson, G. C.
(2013). Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis
models and patients with ulcerative colitis. Gut, gutjnl-2012

[←152]
Canani, R. B., Costanzo, M. D., Leone, L., Pedata, M., Meli, R., & Calignano, A. (2011). Potential
beneficial effects of butyrate in intestinal and extraintestinal diseases. World J Gastroenterol,
17(12), 1519-1528.
Plöger, S., Stumpff, F., Penner, G. B., Schulzke, J. D., Gäbel, G., Martens, H., ... & Aschenbach, J. R.
(2012). Microbial butyrate and its role for barrier function in the gastrointestinal tract. Annals of the
New York Academy of Sciences, 1258(1), 52-59.
Willemsen, L. E. M., Koetsier, M. A., Van Deventer, S. J. H., & Van Tol, E. A. F. (2003). Short chain fatty
 acids stimulate epithelial mucin 2 expression through differential effects on prostaglandin E1 and E2
production by intestinal myofibroblasts. Gut, 52(10), 1442-1447.
Burger-van Paassen, N., Vincent, A., Puiman, P. J., Van Der Sluis, M., Bouma, J., Boehm, G., ... & Renes,
I. B. (2009). The regulation of intestinal mucin MUC2 expression by short-chain fatty acids:
implications for epithelial protection. Biochemical Journal, 420(2), 211-219.
Kripke, S. A., Fox, A. D., Berman, J. M., Settle, R. G., & Rombeau, J. L. (1989). Stimulation of intestinal
mucosal growth with intracolonic infusion of short-chain fatty acids. Journal of Parenteral and
Enteral Nutrition, 13(2), 109-116.
Hsieh, C. Y., Osaka, T., Moriyama, E., Date, Y., Kikuchi, J., & Tsuneda, S. (2015). Strengthening of the
intestinal epithelial tight junction by Bifidobacterium bifidum. Physiological reports, 3(3), e12327.
Ewaschuk, J. B., Diaz, H., Meddings, L., Diederichs, B., Dmytrash, A., Backer, J., ... & Madsen, K. L.
(2008). Secreted bioactive factors from Bifidobacterium infantis enhance epithelial cell barrier
function. American Journal of Physiology-Gastrointestinal and Liver Physiology, 295(5), G1025-
G1034.
Suzuki, T., Yoshida, S., & Hara, H. (2008). Physiological concentrations of short-chain fatty acids
immediately suppress colonic epithelial permeability. British journal of nutrition, 100(02), 297-305;

[←153]
Ewaschuk, J. B., Diaz, H., Meddings, L., Diederichs, B., Dmytrash, A., Backer, J., ... & Madsen, K. L.
(2008). Secreted bioactive factors from Bifidobacterium infantis enhance epithelial cell barrier
function. American Journal of Physiology-Gastrointestinal and Liver Physiology, 295(5), G1025-
G1034.
Ohland, C. L., & MacNaughton, W. K. (2010). Probiotic bacteria and intestinal epithelial barrier
function. American Journal of Physiology-Gastrointestinal and Liver Physiology, 298(6), G807-G819.
Hsieh, C. Y., Osaka, T., Moriyama, E., Date, Y., Kikuchi, J., & Tsuneda, S. (2015). Strengthening of the
intestinal epithelial tight junction by Bifidobacterium bifidum. Physiological reports, 3(3), e12327.
Zyrek, A. A., Cichon, C., Helms, S., Enders, C., Sonnenborn, U., & Schmidt, M. A. (2007). Molecular
mechanisms underlying the probiotic effects of Escherichia coli Nissle 1917 involve ZO-2 and PKCζ
redistribution resulting in tight junction and epithelial barrier repair. Cellular microbiology, 9(3),
804-816.
Ukena, S. N., Singh, A., Dringenberg, U., Engelhardt, R., Seidler, U., Hansen, W., ... & Suerbaum, S.
(2007). Probiotic Escherichia coli Nissle 1917 inhibits leaky gut by enhancing mucosal integrity. PloS
one, 2(12), e1308

[←154]
Ohland, C. L., & MacNaughton, W. K. (2010). Probiotic bacteria and intestinal epithelial barrier
function. American Journal of Physiology-Gastrointestinal and Liver Physiology, 298(6), G807-G819.
Bron, P. A., Kleerebezem, M., Brummer, R. J., Cani, P. D., Mercenier, A., MacDonald, T. T., ... & Wells, J.
M. (2017). Can probiotics modulate human disease by impacting intestinal barrier function?. British
Journal of Nutrition, 117(1), 93-107.
Ewaschuk, J. B., Diaz, H., Meddings, L., Diederichs, B., Dmytrash, A., Backer, J., ... & Madsen, K. L.
(2008). Secreted bioactive factors from Bifidobacterium infantis enhance epithelial cell barrier
function. American Journal of Physiology-Gastrointestinal and Liver Physiology, 295(5), G1025-
G1034.
Mack, D. R., Ahrné, S., Hyde, L., Wei, S., & Hollingsworth, M. A. (2003). Extracellular MUC3 mucin
secretion follows adherence of Lactobacillus strains to intestinal epithelial cells in vitro. Gut, 52(6),
827-833
Zyrek, A. A., Cichon, C., Helms, S., Enders, C., Sonnenborn, U., & Schmidt, M. A. (2007). Molecular
 mechanisms underlying the probiotic effects of Escherichia coli Nissle 1917 involve ZO-2 and PKCζ
redistribution resulting in tight junction and epithelial barrier repair. Cellular microbiology, 9(3),
804-816.
Ukena, S. N., Singh, A., Dringenberg, U., Engelhardt, R., Seidler, U., Hansen, W., ... & Suerbaum, S.
(2007). Probiotic Escherichia coli Nissle 1917 inhibits leaky gut by enhancing mucosal integrity. PloS
one, 2(12), e1308.
Karczewski, J., Troost, F. J., Konings, I., Dekker, J., Kleerebezem, M., Brummer, R. J. M., & Wells, J. M.
(2010). Regulation of human epithelial tight junction proteins by Lactobacillus plantarum in vivo and
protective effects on the epithelial barrier. American Journal of Physiology-Gastrointestinal and
Liver Physiology, 298(6), G851-G859.
Yan, F., Cao, H., Cover, T. L., Washington, M. K., Shi, Y., Liu, L., ... & Polk, D. B. (2011). Colon-specific
delivery of a probiotic-derived soluble protein ameliorates intestinal inflammation in mice through
an EGFR-dependent mechanism. The Journal of clinical investigation, 121(6), 2242-2253.

[←155]
Sagar, S., Vos, A. P., Morgan, M. E., Garssen, J., Georgiou, N. A., Boon, L., ... & Folkerts, G. (2014). The
combination of Bifidobacterium breve with non-digestible oligosaccharides suppresses airway
inflammation in a murine model for chronic asthma. Biochimica et Biophysica Acta (BBA)-Molecular
Basis of Disease, 1842(4), 573-583.
Drago, L., De Vecchi, E., Gabrieli, A., De Grandi, R., & Toscano, M. (2015). Immunomodulatory effects of
Lactobacillus salivarius LS01 and Bifidobacterium breve BR03, alone and in combination, on
peripheral blood mononuclear cells of allergic asthmatics. Allergy, asthma & immunology research,
7(4), 409-413.
Jeon, S. G., Kayama, H., Ueda, Y., Takahashi, T., Asahara, T., Tsuji, H., ... & Okumura, R. (2012). Probiotic
Bifidobacterium breve induces IL-10-producing Tr1 cells in the colon. PLoS Pathog, 8(5), e1002714.
Khokhlova, E. V., Smeianov, V. V., Efimov, B. A., Kafarskaia, L. I., Pavlova, S. I., & Shkoporov, A. N.
(2012). Anti-inflammatory properties of intestinal Bifidobacterium strains isolated from healthy
infants. Microbiology and immunology, 56(1), 27-39.
Zheng, B., van Bergenhenegouwen, J., Overbeek, S., van de Kant, H. J., Garssen, J., Folkerts, G., ... &
Kraneveld, A. D. (2014). Bifidobacterium breve attenuates murine dextran sodium sulfate-induced
colitis and increases regulatory T cell responses. PloS one, 9(5), e95441
Konieczna, P., Groeger, D., Ziegler, M., Frei, R., Ferstl, R., Shanahan, F., ... & O'mahony, L. (2011).
Bifidobacterium infantis 35624 administration induces Foxp3 T regulatory cells in human peripheral
blood: potential role for myeloid and plasmacytoid dendritic cells. Gut, gutjnl-2011
Groeger, D., O’Mahony, L., Murphy, E. F., Bourke, J. F., Dinan, T. G., Kiely, B., ... & Quigley, E. M. (2013).
Bifidobacterium infantis 35624 modulates host inflammatory processes beyond the gut. Gut
microbes, 4(4), 325-339.
Kwon, H. K., Lee, C. G., So, J. S., Chae, C. S., Hwang, J. S., Sahoo, A., ... & Im, S. H. (2010). Generation of
regulatory dendritic cells and CD4+ Foxp3+ T cells by probiotics administration suppresses immune
disorders. Proceedings of the National Academy of Sciences, 107(5), 2159-2164.
Thomas, S., Metzke, D., Schmitz, J., Dörffel, Y., & Baumgart, D. C. (2011). Anti-inflammatory effects of
Saccharomyces boulardii mediated by myeloid dendritic cells from patients with Crohn's disease
and ulcerative colitis. American Journal of Physiology-Gastrointestinal and Liver Physiology, 301(6),
G1083-G1092.
Spaiser, S. J., Culpepper, T., Nieves Jr, C., Ukhanova, M., Mai, V., Percival, S. S., ... & Langkamp-Henken,
B. (2015). Lactobacillus gasseri KS-13, Bifidobacterium bifidum G9-1, and Bifidobacterium longum
MM-2 ingestion induces a less inflammatory cytokine profile and a potentially beneficial shift in gut
microbiota in older adults: a randomized, double-blind, placebo-controlled, crossover study. Journal
of the American College of Nutrition, 34(6), 459-469
 Mizuta, M., Yamamoto, S., Inokawa, H.,... & Xiao, J. Z. (2016). Perioperative supplementation with
bifidobacteria improves postoperative nutritional recovery, inflammatory response, and fecal
microbiota in patients undergoing colorectal surgery: a prospective, randomized clinical trial.
Bioscience of microbiota, food and health, 35(2), 77-87.

[←156]
Sagar, S., Vos, A. P., Morgan, M. E., Garssen, J., Georgiou, N. A., Boon, L., ... & Folkerts, G. (2014). The
combination of Bifidobacterium breve with non-digestible oligosaccharides suppresses airway
inflammation in a murine model for chronic asthma. Biochimica et Biophysica Acta (BBA)-Molecular
Basis of Disease, 1842(4), 573-583.
Drago, L., De Vecchi, E., Gabrieli, A., De Grandi, R., & Toscano, M. (2015). Immunomodulatory effects of
Lactobacillus salivarius LS01 and Bifidobacterium breve BR03, alone and in combination, on
peripheral blood mononuclear cells of allergic asthmatics. Allergy, asthma & immunology research,
7(4), 409-413.
Jeon, S. G., Kayama, H., Ueda, Y., Takahashi, T., Asahara, T., Tsuji, H., ... & Okumura, R. (2012). Probiotic
Bifidobacterium breve induces IL-10-producing Tr1 cells in the colon. PLoS Pathog, 8(5), e1002714.
Khokhlova, E. V., Smeianov, V. V., Efimov, B. A., Kafarskaia, L. I., Pavlova, S. I., & Shkoporov, A. N.
(2012). Anti-inflammatory properties of intestinal Bifidobacterium strains isolated from healthy
infants. Microbiology and immunology, 56(1), 27-39.
Zheng, B., van Bergenhenegouwen, J., Overbeek, S., van de Kant, H. J., Garssen, J., Folkerts, G., ... &
Kraneveld, A. D. (2014). Bifidobacterium breve attenuates murine dextran sodium sulfate-induced
colitis and increases regulatory T cell responses. PloS one, 9(5), e95441
Konieczna, P., Groeger, D., Ziegler, M., Frei, R., Ferstl, R., Shanahan, F., ... & O'mahony, L. (2011).
Bifidobacterium infantis 35624 administration induces Foxp3 T regulatory cells in human peripheral
blood: potential role for myeloid and plasmacytoid dendritic cells. Gut, gutjnl-2011
Groeger, D., O’Mahony, L., Murphy, E. F., Bourke, J. F., Dinan, T. G., Kiely, B., ... & Quigley, E. M. (2013).
Bifidobacterium infantis 35624 modulates host inflammatory processes beyond the gut. Gut
microbes, 4(4), 325-339.
Kwon, H. K., Lee, C. G., So, J. S., Chae, C. S., Hwang, J. S., Sahoo, A., ... & Im, S. H. (2010). Generation of
regulatory dendritic cells and CD4+ Foxp3+ T cells by probiotics administration suppresses immune
disorders. Proceedings of the National Academy of Sciences, 107(5), 2159-2164.

[←157]
Van der Aa, L. B., Van Aalderen, W. M. C., Heymans, H. S. A., Henk Sillevis Smitt, J., Nauta, A. J.,
Knippels, L. M. J., ... & Sprikkelman, A. B. (2011). Synbiotics prevent asthma-like symptoms in infants
with atopic dermatitis. Allergy, 66(2), 170-177.
Abramson, S. L. (2011). Synbiotics Prevent Asthma-Like Symptoms in Infants With Atopic Dermatitis.
Pediatrics, 128(Supplement 3), S138-S138.
Van De Pol, M. A., Lutter, R., Smids, B. S., Weersink, E. J., & Van Der Zee, J. S. (2011). Synbiotics reduce
allergen-induced T-helper 2 response and improve peak expiratory flow in allergic asthmatics.
Allergy, 66(1), 39-47.
Lemoli, E., Trabattoni, D., Parisotto, S., Borgonovo, L., Toscano, M., Rizzardini, G., ... & Piconi, S. (2012).
Probiotics reduce gut microbial translocation and improve adult atopic dermatitis. Journal of clinical
gastroenterology, 46, S33-S40.
Kruis, W., Frič, P., Pokrotnieks, J., Lukáš, M., Fixa, B., Kaščák, M., ... & Wolff, C. (2004). Maintaining
remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with
standard mesalazine. Gut, 53(11), 1617-1623.
Rembacken, B. J., Snelling, A. M., Hawkey, P. M., Chalmers, D. M., & Axon, A. T. R. (1999). Non-
 pathogenic Escherichia coli versus mesalazine for the treatment of ulcerative colitis: a randomised
trial. The Lancet, 354(9179), 635-639
Miraglia, D. G. M., Maiello, N., Decimo, F., Fusco, N., D'Agostino, B., Sullo, N., ... & Marseglia, G. L.
(2012). Airways allergic inflammation and L. reuterii treatment in asthmatic children. Journal of
biological regulators and homeostatic agents, 26(1 Suppl), S35-40.
Tamaki, H., Nakase, H., Inoue, S., Kawanami, C., Itani, T., Ohana, M., ... & Noda, T. (2016). Efficacy of
probiotic treatment with Bifidobacterium longum 536 for induction of remission in active ulcerative
colitis: A randomized, double-blinded, placebo-controlled multicenter trial. Digestive Endoscopy,
28(1), 67-74.
del Campo, R., Garriga, M., Pérez-Aragón, A., Guallarte, P., Lamas, A., Máiz, L., ... & Baquero, F. (2014).
Improvement of digestive health and reduction in proteobacterial populations in the gut microbiota
of cystic fibrosis patients using a Lactobacillus reuteri probiotic preparation: a double blind
prospective study. Journal of Cystic Fibrosis, 13(6), 716-722.

[←158]
Lucaciu, L., Ilies, M., Iuga, C., & Seicean, A. (2018). P136 Serum IL-17 and IL-23 levels can distinguish
between severe and non-severe inflammatory bowel disease. Journal of Crohn's and
Colitis, 12(supplement_1), S163-S163.
Kuwabara, T., Ishikawa, F., Kondo, M., & Kakiuchi, T. (2017). The role of IL-17 and related cytokines in
inflammatory autoimmune diseases. Mediators of inflammation, 2017.
Krueger, J. G., & Brunner, P. M. (2018). Interleukin-17 alters the biology of many cell types involved in
the genesis of psoriasis, systemic inflammation and associated comorbidities. Experimental
dermatology, 27(2), 115-123.
Sakkas, L. I., & Bogdanos, D. P. (2017). Are psoriasis and psoriatic arthritis the same disease? The IL-
23/IL-17 axis data. Autoimmunity reviews, 16(1), 10-15.
Poddubnyy, D., & Sieper, J. (2017). What is the best treatment target in axial spondyloarthritis: tumour
necrosis factor α, interleukin 17, or both?. Rheumatology.

[←159]
Tan, T. G., Sefik, E., Geva-Zatorsky, N., Kua, L., Naskar, D., Teng, F., ... & Kasper, D. L. (2016). Identifying
species of symbiont bacteria from the human gut that, alone, can induce intestinal Th17 cells in
mice. Proceedings of the National Academy of Sciences, 201617460.
Cosorich, I., Dalla-Costa, G., Sorini, C., Ferrarese, R., Messina, M. J., Dolpady, J., ... & Comi, G. (2017).
High frequency of intestinal TH17 cells correlates with microbiota alterations and disease activity in
multiple sclerosis. Science Advances, 3(7), e1700492.
Curtis, M. M., & Way, S. S. (2009). Interleukin-17 in host defence against bacterial, mycobacterial and
fungal pathogens. Immunology, 126(2), 177-185.

[←160]
Indrio, F., Riezzo, G., Tafuri, S., Ficarella, M., Carlucci, B., Bisceglia, M., ... & Francavilla, R. (2017).
Probiotic supplementation in preterm: Feeding intolerance and hospital cost. Nutrients, 9(9), 965.
Savino, F., Garro, M., Montanari, P., Galliano, I., & Bergallo, M. (2018). Crying Time and RORγ/FOXP3
Expression in Lactobacillus reuteri DSM17938-Treated Infants with Colic: A Randomized Trial. The
Journal of pediatrics, 192, 171-177.
Miraglia, D. G. M., Maiello, N., Decimo, F., Fusco, N., D'Agostino, B., Sullo, N., ... & Marseglia, G. L.
(2012). Airways allergic inflammation and L. reuterii treatment in asthmatic children. Journal of
biological regulators and homeostatic agents, 26(1 Suppl), S35-40.
Tanabe, S., Kinuta, Y., & Saito, Y. (2008). Bifidobacterium infantis suppresses proinflammatory
 interleukin-17 production in murine splenocytes and dextran sodium sulfate-induced intestinal
inflammation. International journal of molecular medicine, 22(2), 181-185.
Ghadimi, D., Helwig, U., Schrezenmeir, J., Heller, K. J., & Vrese, M. (2012). Epigenetic imprinting by
commensal probiotics inhibits the IL-23/IL-17 axis in an in vitro model of the intestinal mucosal
immune system. Journal of leukocyte biology, 92(4), 895-911.

[←161]
Consoli, M. L. D., da Silva, R. S., Nicoli, J. R., Bruña-Romero, O., da Silva, R. G., de Vasconcelos
Generoso, S., & Correia, M. I. T. (2016). Randomized clinical trial: impact of oral administration of
Saccharomyces boulardii on gene expression of intestinal cytokines in patients undergoing colon
resection. Journal of Parenteral and Enteral Nutrition, 40(8), 1114-1121.
López, P., Gueimonde, M., Margolles, A., & Suárez, A. (2010). Distinct Bifidobacterium strains drive
different immune responses in vitro. International journal of food microbiology, 138(1-2), 157-165.
Jeon, S. G., Kayama, H., Ueda, Y., Takahashi, T., Asahara, T., Tsuji, H., ... & Okumura, R. (2012). Probiotic
Bifidobacterium breve induces IL-10-producing Tr1 cells in the colon. PLoS pathogens, 8(5),
e1002714.

[←162]
López, P., González-Rodríguez, I., Gueimonde, M., Margolles, A., & Suárez, A. (2011). Immune response
to Bifidobacterium bifidum strains support Treg/Th17 plasticity. PloS one, 6(9), e24776.
López, P., Gueimonde, M., Margolles, A., & Suárez, A. (2010). Distinct Bifidobacterium strains drive
different immune responses in vitro. International journal of food microbiology, 138(1-2), 157-165.

[←163]
Curtis, M. M., & Way, S. S. (2009). Interleukin-17 in host defence against bacterial, mycobacterial and
fungal pathogens. Immunology, 126(2), 177-185.
Tan, T. G., Sefik, E., Geva-Zatorsky, N., Kua, L., Naskar, D., Teng, F., ... & Kasper, D. L. (2016). Identifying
species of symbiont bacteria from the human gut that, alone, can induce intestinal Th17 cells in
mice. Proceedings of the National Academy of Sciences, 201617460
Cosorich, I., Dalla-Costa, G., Sorini, C., Ferrarese, R., Messina, M. J., Dolpady, J., ... & Comi, G.
(2017). High frequency of intestinal TH17 cells correlates with microbiota alterations and disease
activity in multiple sclerosis. Science Advances, 3(7), e1700492.

[←164]
López, P., González-Rodríguez, I., Gueimonde, M., Margolles, A., & Suárez, A. (2011). Immune response
to Bifidobacterium bifidum strains support Treg/Th17 plasticity. PloS one, 6(9), e24776.
López, P., Gueimonde, M., Margolles, A., & Suárez, A. (2010). Distinct Bifidobacterium strains drive
different immune responses in vitro. International journal of food microbiology, 138(1-2), 157-165.

[←165]
Kwon, H. K., Lee, C. G., So, J. S., Chae, C. S., Hwang, J. S., Sahoo, A., ... & Im, S. H. (2010). Generation of
regulatory dendritic cells and CD4+ Foxp3+ T cells by probiotics administration suppresses immune
disorders. Proceedings of the National Academy of Sciences, 107(5), 2159-2164.

[←166]
Llana, M. N., Sarnacki, S. H., Castañeda, M. D. R. A., Bernal, M. I., Giacomodonato, M. N., & Cerquetti,
 M. C. (2013). Consumption of Lactobacillus casei fermented milk prevents Salmonella reactive
arthritis by modulating IL-23/IL-17 expression. PLoS One, 8(12), e82588.

[←167]
Sun, D., Luo, F., Xing, J. C., Zhang, F., Xu, J. Z., & Zhang, Z. H. (2018). 1, 25 (OH) 2 D3 inhibited Th17 cells
differentiation via regulating the NF-κB activity and expression of IL-17. Cell proliferation, e12461-
e12461.
Marinho, A., Carvalho, C., Boleixa, D., Bettencourt, A., Leal, B., Guimarães, J., ... & Costa, P. P. (2017).
Vitamin D supplementation effects on FoxP3 expression in T cells and FoxP3+/IL-17A ratio and
clinical course in systemic lupus erythematosus patients: a study in a Portuguese
cohort. Immunologic research, 65(1), 197-206.
Tejón, G., Manríquez, V., De Calisto, J., Flores-Santibáñez, F., Hidalgo, Y., Crisóstomo, N., ... &
Rosemblatt, M. (2015). Vitamin A impairs the reprogramming of Tregs into IL-17-producing cells
during intestinal inflammation. BioMed research international, 2015.
Tang, J., Zhou, R. U., Luger, D., Zhu, W., Silver, P. B., Grajewski, R. S., ... & Caspi, R. R. (2009). Calcitriol
suppresses antiretinal autoimmunity through inhibitory effects on the Th17 effector response. The
Journal of Immunology, 182(8), 4624-4632.
Chen, X., Su, W., Wan, T., Yu, J., Zhu, W., Tang, F., ... & Zheng, S. G. (2017). Sodium butyrate regulates
Th17/Treg cell balance to ameliorate uveitis via the Nrf2/HO-1 pathway. Biochemical
pharmacology, 142, 111-119.
Zhu, C., Song, K., Shen, Z., Quan, Y., Tan, B., Luo, W., ... & Wang, X. (2018). Roseburia intestinalis
inhibits interleukin-17 excretion and promotes regulatory T cells differentiation in colitis. Molecular
medicine reports, 17(6), 7567-7574.
Kim, J. Y., Lim, K., Kim, K. H., Kim, J. H., Choi, J. S., & Shim, S. C. (2018). N-3 polyunsaturated fatty acids
restore Th17 and Treg balance in collagen antibody-induced arthritis. PloS one, 13(3), e0194331.

[←168]
Gezginc, Y., Akyol, I., Kuley, E., & Özogul, F. (2013). Biogenic amines formation in Streptococcus
thermophilus isolated from home-made natural yogurt. Food chemistry, 138(1), 655-662.

[←169]
Priyadarshani, D., Mesthri, W., & Rakshit, S. K. (2011). Screening selected strains of probiotic lactic acid
bacteria for their ability to produce biogenic amines (histamine and tyramine). International journal
of food science & technology, 46(10), 2062-2069.

[←170]
Cifone, M. G., Cinque, B., La Torre, C., Lombardi, F., Palumbo, P., van den Rest, M. E., ... & Donelli, G.
(2017). Complexities and pitfalls in the production of multispecies probiotics: the paradigmatic case
of VSL# 3 formulation and visbiome. In The Microbiota in Gastrointestinal Pathophysiology (pp. 171-
178).

[←171]
Barcik, W., Pugin, B., Westermann, P., Perez, N. R., Ferstl, R., Wawrzyniak, M., ... & Akdis, C. A. (2016).
Histamine-secreting microbes are increased in the gut of adult asthma patients. Journal of Allergy
and Clinical Immunology, 138(5), 1491-1494.
Özoğul, F. (2004). Production of biogenic amines by Morganella morganii, Klebsiella pneumoniae and
 Hafnia alvei using a rapid HPLC method. European Food Research and Technology, 219(5), 465-469.
Pugin, B., Barcik, W., Westermann, P., Heider, A., Wawrzyniak, M., Hellings, P., ... & O’Mahony, L.
(2017). A wide diversity of bacteria from the human gut produces and degrades biogenic amines.
Microbial ecology in health and disease, 28(1), 1353881.

[←172]
Matsumoto, N., Riley, S., Fraser, D., Al-Assaf, S., Ishimura, E., Wolever, T., ... & Phillips, A. O. (2006).
Butyrate modulates TGF-β1 generation and function: Potential renal benefit for Acacia (sen)
SUPERGUM™(gum arabic)?. Kidney international, 69(2), 257-265.
Daguet, D., Pinheiro, I., Verhelst, A., Possemiers, S., & Marzorati, M. (2015). Acacia gum improves the
gut barrier functionality in vitro. AGRO FOOD INDUSTRY HI-TECH, 26(4), 29-33.
Calame, W., Weseler, A. R., Viebke, C., Flynn, C., & Siemensma, A. D. (2008). Gum arabic establishes
prebiotic functionality in healthy human volunteers in a dose-dependent manner. British journal of
nutrition, 100(06), 1269-1275.
Marzorati, M., Qin, B., Hildebrand, F., Klosterbuer, A., Roughead, Z., Roessle, C., ... & Possemiers, S.
(2015). Addition of acacia gum to a FOS/inulin blend improves its fermentation profile in the
Simulator of the Human Intestinal Microbial Ecosystem (SHIME®). Journal of Functional Foods, 16,
211-222.
Cherbut, C., Michel, C., Raison, V., Kravtchenko, T., & Severine, M. (2003). Acacia gum is a bifidogenic
dietary fibre with high digestive tolerance in healthy humans. Microbial Ecology in Health and
Disease, 15(1), 43-50.
Wyatt, G. M., Bayliss, C. E., & Holcroft, J. D. (1986). A change in human faecal flora in response to
inclusion of gum arabic in the diet. British Journal of Nutrition, 55(2), 261-266.

[←173]
Calame, W., Weseler, A. R., Viebke, C., Flynn, C., & Siemensma, A. D. (2008). Gum arabic establishes
prebiotic functionality in healthy human volunteers in a dose-dependent manner. British journal of
nutrition, 100(06), 1269-1275.
Marzorati, M., Qin, B., Hildebrand, F., Klosterbuer, A., Roughead, Z., Roessle, C., ... & Possemiers, S.
(2015). Addition of acacia gum to a FOS/inulin blend improves its fermentation profile in the
Simulator of the Human Intestinal Microbial Ecosystem (SHIME®). Journal of Functional Foods, 16,
211-222.
Cherbut, C., Michel, C., Raison, V., Kravtchenko, T., & Severine, M. (2003). Acacia gum is a bifidogenic
dietary fibre with high digestive tolerance in healthy humans. Microbial Ecology in Health and
Disease, 15(1), 43-50.
Wyatt, G. M., Bayliss, C. E., & Holcroft, J. D. (1986). A change in human faecal flora in response to
inclusion of gum arabic in the diet. British Journal of Nutrition, 55(2), 261-266.

[←174]
Van Laere, K. M., Hartemink, R., Bosveld, M., Schols, H. A., & Voragen, A. G. (2000). Fermentation of
plant cell wall derived polysaccharides and their corresponding oligosaccharides by intestinal
bacteria. Journal of Agricultural and Food Chemistry, 48(5), 1644-1652.

[←175]
Cherbut, C., Michel, C., Raison, V., Kravtchenko, T., & Severine, M. (2003). Acacia gum is a bifidogenic
dietary fibre with high digestive tolerance in healthy humans. Microbial Ecology in Health and
Disease, 15(1), 43-50.
 Calame, W., Weseler, A. R., Viebke, C., Flynn, C., & Siemensma, A. D. (2008). Gum arabic establishes
prebiotic functionality in healthy human volunteers in a dose-dependent manner. British journal of
nutrition, 100(06), 1269-1275.

[←176]
Min, Y. W., Park, S. U., Jang, Y. S., Kim, Y. H., Rhee, P. L., Ko, S. H., ... & Chang, D. K. (2012). Effect of
composite yogurt enriched with acacia fiber and Bifidobacterium lactis. World Journal of
Gastroenterology: WJG, 18(33), 4563.
Bliss, D. Z., Jung, H. J., Savik, K., Lowry, A., LeMoine, M., Jensen, L., ... & Schaffer, K. (2001).
Supplementation with dietary fiber improves fecal incontinence. Nursing research, 50(4), 203-213.

[←177]
Macfarlane, G. T., Steed, H., & Macfarlane, S. (2008). Bacterial metabolism and health-related effects
of galacto-oligosaccharides and other prebiotics. Journal of applied microbiology, 104(2), 305-344.

[←178]
Davis, L. M., Martínez, I., Walter, J., Goin, C., & Hutkins, R. W. (2011). Barcoded pyrosequencing reveals
that consumption of galactooligosaccharides results in a highly specific bifidogenic response in
humans. PLoS One, 6(9), e25200.
Fanaro, S., Marten, B., Bagna, R., Vigi, V., Fabris, C., Peña-Quintana, L., ... & Schrezenmeir, J. (2009).
Galacto-oligosaccharides are bifidogenic and safe at weaning: a double-blind randomized
multicenter study. Journal of pediatric gastroenterology and nutrition, 48(1), 82-88.
Azcarate-Peril, M. A., Ritter, A. J., Savaiano, D., Monteagudo-Mera, A., Anderson, C., Magness, S. T., &
Klaenhammer, T. R. (2017). Impact of short-chain galactooligosaccharides on the gut microbiome of
lactose-intolerant individuals. Proceedings of the National Academy of Sciences, 201606722.

[←179]
Knol, J., Boehm, G., Lidestri, M., Negretti, F., Jelinek, J., Agosti, M., ... & Mosca, F. (2005). Increase of
faecal bifidobacteria due to dietary oligosaccharides induces a reduction of clinically relevant
pathogen germs in the faeces of formula-fed preterm infants. Acta Paediatrica, 94(s449), 31-33.

[←180]
Azcarate-Peril, M. A., Ritter, A. J., Savaiano, D., Monteagudo-Mera, A., Anderson, C., Magness, S. T., &
Klaenhammer, T. R. (2017). Impact of short-chain galactooligosaccharides on the gut microbiome of
lactose-intolerant individuals. Proceedings of the National Academy of Sciences, 201606722.

[←181]
Scher, J. U., Sczesnak, A., Longman, R. S., Segata, N., Ubeda, C., Bielski, C., ... & Huttenhower, C. (2013).
Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. elife, 2.

[←182]
Macfarlane, G. T., Steed, H., & Macfarlane, S. (2008). Bacterial metabolism and health-related effects
of galacto-oligosaccharides and other prebiotics. Journal of applied microbiology, 104(2), 305-344.

[←183]
 Ohashi, Y., Sumitani, K., Tokunaga, M., Ishihara, N., Okubo, T., & Fujisawa, T. (2015). Consumption of
partially hydrolysed guar gum stimulates Bifidobacteria and butyrate-producing bacteria in the
human large intestine. Beneficial microbes, 6(4), 451-455.
Okubo, T., Ishihara, N., Takahashi, H., Fujisawa, T., Mujo, K., Yamamoto, T., & Mitsuoka, T. (1994).
Effects of partially hydrolyzed guar gum intake on human intestinal microflora and its metabolism.
Bioscience, biotechnology, and biochemistry, 58(8), 1364-1369.

[←184]
Noack, J., Timm, D., Hospattankar, A., & Slavin, J. (2013). Fermentation profiles of wheat dextrin, inulin
and partially hydrolyzed guar gum using an in vitro digestion pretreatment and in vitro batch
fermentation system model. Nutrients, 5(5), 1500-1510.

[←185]
McDonald, D. E., Pethick, D. W., Pluske, J. R., & Hampson, D. J. (1999). Adverse effects of soluble non-
starch polysaccharide (guar gum) on piglet growth and experimental colibacillosis immediately after
weaning. Research in veterinary science, 67(3), 245-250.
Vulevic, J., Rastall, R. A., & Gibson, G. R. (2004). Developing a quantitative approach for determining
the in vitro prebiotic potential of dietary oligosaccharides. FEMS microbiology letters, 236(1), 153-
159.

[←186]
Giannini, E. G., Mansi, C., Dulbecco, P., & Savarino, V. (2006). Role of partially hydrolyzed guar gum in
the treatment of irritable bowel syndrome. Nutrition, 22(3), 334-342.
Parisi, G. C., Zilli, M., Miani, M. P., Carrara, M., Bottona, E., Verdianelli, G., ... & Tonon, A. (2002). High-
fiber diet supplementation in patients with irritable bowel syndrome (IBS): a multicenter,
randomized, open trial comparison between wheat bran diet and partially hydrolyzed guar gum
(PHGG). Digestive diseases and sciences, 47(8), 1697-1704.
Furnari, M., Parodi, A., Gemignani, L., Giannini, E. G., Marenco, S., Savarino, E., ... & Savarino, V. (2010).
Clinical trial: the combination of rifaximin with partially hydrolysed guar gum is more effective than
rifaximin alone in eradicating small intestinal bacterial overgrowth. Alimentary pharmacology &
therapeutics, 32(8), 1000-1006.

[←187]
Dr. Allyson Siebecker, interview with Dr. Michael Ruscio, February 2016,
https://drruscio.com/prebiotics-fodmaps-treating-sibo-episode-51/

[←188]
Fernandez-Banares, F., Hinojosa, J., Sanchez-Lombrana, J. L., Navarro, E., Martinez-Salmeron, J. F.,
Garcia-Puges, A., ... & Gine, J. J. (1999). Randomized clinical trial of Plantago ovata seeds (dietary
fiber) as compared with mesalamine in maintaining remission in ulcerative colitis. The American
journal of gastroenterology, 94(2), 427-433.
Nordgaard, I., Hove, H., Clausen, M. R., & Mortensen, P. B. (1996). Colonic production of butyrate in
patients with previous colonic cancer during long-term treatment with dietary fibre (Plantago ovata
seeds). Scandinavian journal of gastroenterology, 31(10), 1011-1020.
Hayden, U. L., Mcguirk, S. M., West, S. E., & Carey, H. V. (1998). Psyllium improves fecal consistency
and prevents enhanced secretory responses in jejunal tissues of piglets infected with ETEC.
 Digestive diseases and sciences, 43(11), 2536-2541.
Yakoob, J., Jafri, W., Mehmood, M. H., Abbas, Z., & Tariq, K. (2017). Cytokine changes in gastric and
colonic epithelial cell in response to Planta ovata extract. Journal of Complementary and Integrative
Medicine.
Rodrı ́guez-Cabezas, M. E., Galvez, J., Camuesco, D., Lorente, M. D., Concha, A., Mar nez-Augus n, O., ...
& Zarzuelo, A. (2003). Intestinal anti-inflammatory activity of dietary fiber (Plantago ovata seeds) in
HLA-B27 transgenic rats. Clinical nutrition, 22(5), 463-471.
Van Laere, K. M., Hartemink, R., Bosveld, M., Schols, H. A., & Voragen, A. G. (2000). Fermentation of
plant cell wall derived polysaccharides and their corresponding oligosaccharides by intestinal
bacteria. Journal of Agricultural and Food Chemistry, 48(5), 1644-1652.

[←189]
Dewulf, E. M., Cani, P. D., Claus, S. P., Fuentes, S., Puylaert, P. G., Neyrinck, A. M., ... & Delzenne, N. M.
(2012). Insight into the prebiotic concept: lessons from an exploratory, double blind intervention
study with inulin-type fructans in obese women. Gut, gutjnl-2012.
Furrie, E., Macfarlane, S., Kennedy, A., Cummings, J. H., Walsh, S. V., O’neil, D. A., & Macfarlane, G. T.
(2005). Synbiotic therapy (Bifidobacterium longum/Synergy 1) initiates resolution of inflammation
in patients with active ulcerative colitis: a randomised controlled pilot trial. Gut, 54(2), 242-249.
Lindsay, J. O., Whelan, K., Stagg, A. J., Gobin, P., Al-Hassi, H. O., Rayment, N., ... & Forbes, A. (2006).
Clinical, microbiological, and immunological effects of fructo-oligosaccharide in patients with
Crohn’s disease. Gut, 55(3), 348-355.
Fujimori S., Gudis K., Mitsui K., et al. A randomized controlled trial on the efficacy of synbiotic versus
probiotic or prebiotic treatment to improve the quality of life in patients with ulcerative colitis.
Nutrition. 2009;25(5):520–525. doi: 10.1016/j.nut.2008.11.017
Casellas, F., Borruel, N., Torrejon, A., Varela, E., Antolin, M., Guarner, F., & MALAGELADA, J. R. (2007).
Oral oligofructose-enriched inulin supplementation in acute ulcerative colitis is well tolerated and
associated with lowered faecal calprotectin. Alimentary pharmacology & therapeutics, 25(9), 1061-
1067

[←190]
Hartemink, R., Van Laere, K. M. J., & Rombouts, F. M. (1997). Growth of enterobacteria on fructo-
oligosaccharides. Journal of Applied Microbiology, 83(3), 367-374.
Loh, G., Eberhard, M., Brunner, R. M., Hennig, U., Kuhla, S., Kleessen, B., & Metges, C. C. (2006). Inulin
alters the intestinal microbiota and short-chain fatty acid concentrations in growing pigs regardless
of their basal diet. The Journal of nutrition, 136(5), 1198-1202.
Rycroft, C. E., Jones, M. R., Gibson, G. R., & Rastall, R. A. (2001). A comparative in vitro evaluation of
the fermentation properties of prebiotic oligosaccharides. Journal of applied microbiology, 91(5),
878-887.

 Chapter 3. Additional Strategies to Combat Bacterial
Overgrowth

[←191]
Lauritano, E. C., Gabrielli, M., Scarpellini, E., Lupascu, A., Novi, M., Sottili, S., ... & Gasbarrini, G. (2008).
Small intestinal bacterial overgrowth recurrence after antibiotic therapy. The American journal of
gastroenterology, 103(8), 2031

[←192]
Drago, F., Ciccarese, G., Indemini, E., Savarino, V., & Parodi, A. (2018). Psoriasis and small intestine
bacterial overgrowth. International journal of dermatology, 57(1), 112-113.

[←193]
Cedars Sinai Patient Handout.
http://www.siboinfo.com/uploads/5/4/8/4/5484269/low_fermentation_diet.pdf

[←194]
Urdaneta, V., & Casadesús, J. (2017). interactions between Bacteria and Bile Salts in the
Gastrointestinal and Hepatobiliary Tracts. Frontiers in medicine, 4, 163.
Lorenzo-Zúñiga, V., Bartoli, R., Planas, R., Hofmann, A. F., Viñado, B., Hagey, L. R., ... &
Gassull, M. A. (2003). Oral bile acids reduce bacterial overgrowth, bacterial translocation,
and endotoxemia in cirrhotic rats. Hepatology, 37(3), 551-557.

[←195]
Cahill, C. J., Pain, J. A., & Bailey, M. E. (1987). Bile salts, endotoxin and renal function in
obstructive jaundice. Surgery, gynecology & obstetrics, 165(6), 519-522.
Cahill, C. J. (1983). Prevention of postoperative renal failure in patients with obstructive
jaundice—the role of bile salts. British journal of surgery, 70(10), 590-595.
Lorenzo-Zúñiga, V., Bartoli, R., Planas, R., Hofmann, A. F., Viñado, B., Hagey, L. R., ... & Gassull, M. A.
(2003). Oral bile acids reduce bacterial overgrowth, bacterial translocation, and endotoxemia in
cirrhotic rats. Hepatology, 37(3), 551-557.
Kocsar, L. T., Bertok, L., & Varteresz, V. (1969). Effect of bile acids on the intestinal absorption of
endotoxin in rats. Journal of bacteriology, 100(1), 220-223.

[←196]
Gyurcsovics, K., & Bertók, L. (2003). Pathophysiology of psoriasis: coping endotoxins with bile acid
therapy. Pathophysiology, 10(1), 57-61.
Ely, P. H. (2018). Is psoriasis a bowel disease? Successful treatment with bile acids and bioflavonoids
suggest it is. Clinics in Dermatology.

[←197]
Madisch, A., Vinson, B. R., Abdel-Aziz, H., Kelber, O., Nieber, K., Kraft, K., & Storr, M. (2017).
 Modulation of gastrointestinal motility beyond metoclopramide and domperidone. Wiener
Medizinische Wochenschrift, 167(7-8), 160-168.

[←198]
Ottillinger, B., Storr, M., Malfertheiner, P., & Allescher, H. D. (2013). STW 5 (Iberogast®)—a safe and
effective standard in the treatment of functional gastrointestinal disorders. Wiener Medizinische
Wochenschrift, 163(3-4), 65-72.

[←199]
Ottillinger, B., Storr, M., Malfertheiner, P., & Allescher, H. D. (2013). STW 5 (Iberogast®)—a safe and
effective standard in the treatment of functional gastrointestinal disorders. Wiener Medizinische
Wochenschrift, 163(3-4), 65-72.

[←200]
Chen, P. W., Jheng, T. T., Shyu, C. L., & Mao, F. C. (2013). Antimicrobial potential for the combination of
bovine lactoferrin or its hydrolysate with lactoferrin-resistant probiotics against foodborne
pathogens. Journal of dairy science, 96(3), 1438-1446.
Bellamy, W., Takase, M., Wakabayashi, H., Kawase, K., & Tomita, M. (1992). Antibacterial spectrum of
lactoferricin B, a potent bactericidal peptide derived from the N-terminal region of bovine
lactoferrin. Journal of Applied Microbiology, 73(6), 472-479.
Yuan, Y., Wu, Q., Cheng, G., Liu, X., Liu, S., Luo, J., ... & Dong, X. (2015). Recombinant human lactoferrin
enhances the efficacy of triple therapy in mice infected with Helicobacter pylori. International
journal of molecular medicine, 36(2), 363-368
Griffiths, E. A., Duffy, L. C., Schanbacher, F. L., Dryja, D., Leavens, A., Neiswander, R. L., ... & Ogra, P.
(2003). In vitro growth responses of bifidobacteria and enteropathogens to bovine and human
lactoferrin. Digestive diseases and sciences, 48(7), 1324-1332.

[←201]
Griffiths, E. A., Duffy, L. C., Schanbacher, F. L., Dryja, D., Leavens, A., Neiswander, R. L., ... & Ogra, P.
(2003). In vitro growth responses of bifidobacteria and enteropathogens to bovine and human
lactoferrin. Digestive diseases and sciences, 48(7), 1324-1332.

[←202]
Bertuccini, L., Costanzo, M., Iosi, F., Tinari, A., Terruzzi, F., Stronati, L., ... & Superti, F. (2014).
Lactoferrin prevents invasion and inflammatory response following E. coli strain LF82 infection in
experimental model of Crohn's disease. Digestive and Liver Disease, 46(6), 496-504.
Ammons, M. C., & Copié, V. (2013). Mini-review: Lactoferrin: a bioinspired, anti-biofilm therapeutic.
Biofouling, 29(4), 443-455.

[←203]
Chen, P. W., Liu, Z. S., Kuo, T. C., Hsieh, M. C., & Li, Z. W. (2017). Prebiotic effects of bovine
lactoferrin on specific probiotic bacteria. BioMetals, 30(2), 237-248.
Oda, H., Wakabayashi, H., Yamauchi, K., & Abe, F. (2014). Lactoferrin and
bifidobacteria. Biometals, 27(5), 915-922.
[←204]
Oda, H., Wakabayashi, H., Yamauchi, K., & Abe, F. (2014). Lactoferrin and bifidobacteria. Biometals,
27(5), 915-922.
Akin, I. M., Atasay, B., Dogu, F., Okulu, E., Arsan, S., Karatas, H. D., ... & Turmen, T. (2014). Oral
lactoferrin to prevent nosocomial sepsis and necrotizing enterocolitis of premature neonates and
effect on T-regulatory cells. Am J Perinatol, 31(12), 1111-1120.

[←205]
Abubakar, E. M. M. (2009). Efficacy of crude extracts of garlic (Allium sativum Linn.) against nosocomial
Escherichia coli, Staphylococcus aureus, Streptococcus pneumoniea and Pseudomonas
aeruginosa. Journal of Medicinal Plants Research, 3(4), 179-185.

[←206]
Ankri, S., & Mirelman, D. (1999). Antimicrobial properties of allicin from garlic. Microbes and
infection, 1(2), 125-129.
Gebreyohannes, G., & Gebreyohannes, M. (2013). Medicinal values of garlic: A review. International
Journal of Medicine and Medical Sciences, 5(9), 401-408.
Ranjbar-Omid, M., Arzanlou, M., Amani, M., Shokri Al-Hashem, S. K., Amir Mozafari, N., & Peeri
Doghaheh, H. (2015). Allicin from garlic inhibits the biofilm formation and urease activity of Proteus
mirabilis in vitro. FEMS microbiology letters, 362(9).
Ruiz, R., García, M. P., Lara, A., & Rubio, L. A. (2010). Garlic derivatives (PTS and PTS-O) differently
affect the ecology of swine faecal microbiota in vitro. Veterinary microbiology, 144(1-2), 110-117.

[←207]
Yin, M. C., Chang, H. C., & Tsao, S. M. (2002). Inhibitory effects of aqueous garlic extract, garlic oil and
four diallyl sulphides against four enteric pathogens. Journal of Food and Drug Analysis, 10(2).
Saravanan, P., Ramya, V., Sridhar, H., Balamurugan, V., & Umamaheswari, S. (2010). Antibacterial
activity of Allium sativum L. on pathogenic bacterial strains. Global veterinaria, 4(5), 519-522.

[←208]
Khodavandi, A., Alizadeh, F., Harmal, N. S., Sidik, S. M., Othman, F., Sekawi, Z., ... & Chong, P. P. (2011).
Comparison between efficacy of allicin and fluconazole against Candida albicans in vitro and in a
systemic candidiasis mouse model. FEMS microbiology letters, 315(2), 87-93.
Khodavandi, A., Alizadeh, F., Aala, F., Sekawi, Z., & Chong, P. P. (2010). In vitro investigation of
antifungal activity of allicin alone and in combination with azoles against Candida
species. Mycopathologia, 169(4), 287-295.
Gebreyohannes, G., & Gebreyohannes, M. (2013). Medicinal values of garlic: A review. International
Journal of Medicine and Medical Sciences, 5(9), 401-408.

[←209]
Ruiz, R., García, M. P., Lara, A., & Rubio, L. A. (2010). Garlic derivatives (PTS and PTS-O) differently
affect the ecology of swine faecal microbiota in vitro. Veterinary microbiology, 144(1-2), 110-117.
Filocamo, A., Nueno-Palop, C., Bisignano, C., Mandalari, G., & Narbad, A. (2012). Effect of garlic powder
on the growth of commensal bacteria from the gastrointestinal tract. Phytomedicine, 19(8-9), 707-
711.
Booyens, J., & Thantsha, M. S. (2013). Antibacterial effect of hydrosoluble extracts of garlic (Allium
 sativum) against Bifidobacterium spp. and Lactobacillus acidophilus. African Journal of Microbiology
Research, 7(8), 669-677.

[←210]
Liu, S., He, L., Jiang, Q., Duraipandiyan, V., Al-Dhabi, N. A., Liu, G., ... & Yin, Y. (2018). Effect of Dietary α-
ketoglutarate and Allicin Supplementation on the Cecal Microbial Community Composition and
Diversity in Growing Pigs. Journal of the Science of Food and Agriculture.
Busquet, M., Calsamiglia, S., Ferret, A., Cardozo, P. W., & Kamel, C. (2005). Effects of cinnamaldehyde
and garlic oil on rumen microbial fermentation in a dual flow continuous culture. Journal of Dairy
Science, 88(7), 2508-2516.

[←211]
Lan, J., Zhao, Y., Dong, F., Yan, Z., Zheng, W., Fan, J., & Sun, G. (2015). Meta-analysis of the effect and
safety of berberine in the treatment of type 2 diabetes mellitus, hyperlipemia and
hypertension. Journal of ethnopharmacology, 161, 69-81.

[←212]
Zhang, X., Zhao, Y., Zhang, M., Pang, X., Xu, J., Kang, C., ... & Li, X. (2012). Structural changes of gut
microbiota during berberine-mediated prevention of obesity and insulin resistance in high-fat diet-
fed rats. PloS one, 7(8), e42529.
Kong, W. J., Xing, X. Y., Xiao, X. H., Zhao, Y. L., Wei, J. H., Wang, J. B., ... & Yang, M. H. (2012). Effect of
berberine on Escherichia coli, Bacillus subtilis, and their mixtures as determined by isothermal
microcalorimetry. Applied microbiology and biotechnology, 96(2), 503-510.
Han, J., Lin, H., & Huang, W. (2011). Modulating gut microbiota as an anti-diabetic mechanism of
berberine. Medical science monitor: international medical journal of experimental and clinical
research, 17(7), RA164.

[←213]
Rabbani, G. H., Butler, T., Knight, J., Sanyal, S. C., & Alam, K. (1987). Randomized controlled trial of
berberine sulfate therapy for diarrhea due to enterotoxigenic Escherichia coli and Vibrio cholerae.
Journal of infectious diseases, 155(5), 979-984.
Zorić, N., Kosalec, I., Tomić, S., Bobnjarić, I., Jug, M., Vlainić, T., & Vlainić, J. (2017). Membrane of
Candida albicans as a target of berberine. BMC complementary and alternative medicine, 17(1),
268.
Dhamgaye S, Devaux F, Vandeputte P, Khandelwal NK, Sanglard D, Mukhopadhyay G, Prasad R.
Molecular mechanisms of action of herbal antifungal alkaloid berberine in Candida albicans. PloS
ONE. 2014. doi:10.1371/journal.pone.0104554.
da Silva AR, de Andrade Neto JB, da Silva CR, Campos RDS, Costa Silva RA, Freitas DD, do Nascimento
FBSA, de Andrade LND, Sampaio LS, Grangeiro TB, Magalhães HIF, Cavalcanti BC, de Moraes MO,
Nobre Júnior HV. Berberine antifungal activity in fluconazole-resistant pathogenic yeasts: action
mechanism evaluated by flow cytometry and biofilm growth inhibition in Candida spp. Antimicrob
Agents Chemother. 2016. doi:10.1128/AAC.01846-15.

[←214]
Wang, L. L., Guo, H. H., Huang, S., Feng, C. L., Han, Y. X., & Jiang, J. D. (2017). Comprehensive evaluation
of SCFA production in the intestinal bacteria regulated by berberine using gas-chromatography
 combined with polymerase chain reaction. Journal of Chromatography B, 1057, 70-80.
Zhu, L., Zhang, D., Zhu, H., Zhu, J., Weng, S., Dong, L., ... & Shen, X. (2018). Berberine treatment
increases Akkermansia in the gut and improves high-fat diet-induced atherosclerosis in Apoe−/−
mice. Atherosclerosis, 268, 117-126.
Xu, J. H., Liu, X. Z., Pan, W., & Zou, D. J. (2017). Berberine protects against diet-induced obesity through
regulating metabolic endotoxemia and gut hormone levels. Molecular medicine reports, 15(5),
2765-2787
Zhang, X., Zhao, Y., Zhang, M., Pang, X., Xu, J., Kang, C., ... & Li, X. (2012). Structural changes of gut
microbiota during berberine-mediated prevention of obesity and insulin resistance in high-fat diet-
fed rats. PloS one, 7(8), e42529.

[←215]
Yue, M., Xia, Y., Shi, C., Guan, C., Li, Y., Liu, R., ... & Dai, Y. (2017). Berberine ameliorates collagen-
induced arthritis in rats by suppressing Th17 cell responses via inducing cortistatin in the gut. The
FEBS journal, 284(17), 2786-2801.
Wang, X., He, X., Zhang, C. F., Guo, C. R., Wang, C. Z., & Yuan, C. S. (2017). Anti-arthritic effect of
berberine on adjuvant-induced rheumatoid arthritis in rats. Biomedicine & Pharmacotherapy, 89,
887-893.
Yue, J., Xu, J., Li, H., Wang, J., Zheng, N., Yao, H., ... & Qin, L. (2018). THU0078 Berberine ameliorates
bone erosions in collagen-induced arthritis rat models via suppressing the expression of il-17a.

[←216]
Qin, X., Guo, B. T., Wan, B., Fang, L., Lu, L., Wu, L., ... & Zhang, J. Z. (2010). Regulation of Th1 and Th17
cell differentiation and amelioration of experimental autoimmune encephalomyelitis by natural
product compound berberine. The Journal of Immunology, 0903853.
Yang, Y., Qi, J., Wang, Q., Du, L., Zhou, Y., Yu, H., ... & Yang, P. (2013). Berberine suppresses Th17 and
dendritic cell responses. Investigative ophthalmology & visual science, 54(4), 2516-2522.
Yang, Y., Wang, Q., Xie, M., Liu, P., Qi, X., Liu, X., & Li, Z. (2017). Berberine exerts an anti-inflammatory
role in ocular Behcet's disease. Molecular medicine reports, 15(1), 97-102.

[←217]
Guo, Y., Chen, Y., Tan, Z. R., Klaassen, C. D., & Zhou, H. H. (2012). Repeated administration of berberine
inhibits cytochromes P450 in humans. European journal of clinical pharmacology, 68(2), 213-217.
https://www.rxlist.com/berberine/supplements.htm

[←218]
Lan, J., Zhao, Y., Dong, F., Yan, Z., Zheng, W., Fan, J., & Sun, G. (2015). Meta-analysis of the effect and
safety of berberine in the treatment of type 2 diabetes mellitus, hyperlipemia and
hypertension. Journal of ethnopharmacology, 161, 69-81.

[←219]
Williams, D. W., Kuriyama, T., Silva, S., Malic, S., & Lewis, M. A. (2011). Candida biofilms and oral
candidosis: treatment and prevention. Periodontology 2000, 55(1), 250-265.
Harriott, M. M., Lilly, E. A., Rodriguez, T. E., Fidel Jr, P. L., & Noverr, M. C. (2010). Candida albicans
forms biofilms on the vaginal mucosa. Microbiology, 156(12), 3635-3644.
Ganguly, S., & Mitchell, A. P. (2011). Mucosal biofilms of Candida albicans. Current opinion in
 microbiology, 14(4), 380-385.

Chapter 4. A Microbiome-Restoring Diet

[←220]
Hou, J. K., Abraham, B., & El-Serag, H. (2011). Dietary intake and risk of developing inflammatory bowel
disease: a systematic review of the literature. The American journal of gastroenterology, 106(4),
563.
Penagini, F., Dilillo, D., Borsani, B., Cococcioni, L., Galli, E., Bedogni, G., ... & Zuccotti, G. V. (2016).
Nutrition in Pediatric Inflammatory Bowel Disease: From Etiology to Treatment. A Systematic
Review. Nutrients, 8(6), 334.
Minami, Y., Hirabayashi, Y., Nagata, C., Ishii, T., Harigae, H., & Sasaki, T. (2011). Intakes of vitamin B6
and dietary fiber and clinical course of systemic lupus erythematosus: a prospective study of
Japanese female patients. Journal of epidemiology, 21(4), 246-254.
Trompette, A., Gollwitzer, E. S., Yadava, K., Sichelstiel, A. K., Sprenger, N., Ngom-Bru, C., ... & Marsland,
B. J. (2014). Gut microbiota metabolism of dietary fiber influences allergic airway disease and
hematopoiesis. Nature medicine, 20(2), 159-166.
Reif, S., Klein, I., Lubin, F., Farbstein, M., Hallak, A., & Gilat, T. (1997). Pre-illness dietary factors in
inflammatory bowel disease. Gut, 40(6), 754-760.

[←221]
De Filippo, C., Cavalieri, D., Di Paola, M., Ramazzotti, M., Poullet, J. B., Massart, S., ... & Lionetti, P.
(2010). Impact of diet in shaping gut microbiota revealed by a comparative study in children from
Europe and rural Africa. Proceedings of the National Academy of Sciences, 107(33), 14691-14696.

[←222]
O’Keefe, S. J. D., Li, J. V., Lahti, L., Ou, J., Carbonero, F., Mohammed, K., … Zoetendal, E. G. (2015). Fat,
Fiber and Cancer Risk in African Americans and Rural Africans. Nature Communications, 6, 6342.
http://doi.org/10.1038/ncomms7342

[←223]
Hou, J. K., Abraham, B., & El-Serag, H. (2011). Dietary intake and risk of developing inflammatory bowel
disease: a systematic review of the literature. The American journal of gastroenterology, 106(4),
563.
Penagini, F., Dilillo, D., Borsani, B., Cococcioni, L., Galli, E., Bedogni, G., ... & Zuccotti, G. V. (2016).
Nutrition in Pediatric Inflammatory Bowel Disease: From Etiology to Treatment. A Systematic
Review. Nutrients, 8(6), 334.
Minami, Y., Hirabayashi, Y., Nagata, C., Ishii, T., Harigae, H., & Sasaki, T. (2011). Intakes of vitamin B6
and dietary fiber and clinical course of systemic lupus erythematosus: a prospective study of
Japanese female patients. Journal of epidemiology, 21(4), 246-254.
Trompette, A., Gollwitzer, E. S., Yadava, K., Sichelstiel, A. K., Sprenger, N., Ngom-Bru, C., ... & Marsland,
B. J. (2014). Gut microbiota metabolism of dietary fiber influences allergic airway disease and
hematopoiesis. Nature medicine, 20(2), 159-166.
Reif, S., Klein, I., Lubin, F., Farbstein, M., Hallak, A., & Gilat, T. (1997). Pre-illness dietary factors in
inflammatory bowel disease. Gut, 40(6), 754-760.
[←224]
Ajani, U. A., Ford, E. S., & Mokdad, A. H. (2004). Dietary fiber and C-reactive protein: findings from
national health and nutrition examination survey data. The Journal of nutrition, 134(5), 1181-1185.
Ma, Y., Hébert, J. R., Li, W., Bertone-Johnson, E. R., Olendzki, B., Pagoto, S. L., ... & Griffith, J. A. (2008).
Association between dietary fiber and markers of systemic inflammation in the Women's Health
Initiative Observational Study. Nutrition, 24(10), 941-949.

[←225]
Ma, Y., Hébert, J. R., Li, W., Bertone-Johnson, E. R., Olendzki, B., Pagoto, S. L., ... & Griffith,
J. A. (2008). Association between dietary fiber and markers of systemic inflammation in the
Women's Health Initiative Observational Study. Nutrition, 24(10), 941-949.

[←226]
Holscher, H. D. (2017). Dietary fiber and prebiotics and the gastrointestinal microbiota. Gut
Microbes, 8(2), 172-184.

[←227]
Lupton, J. R. (2004). Microbial degradation products influence colon cancer risk: the butyrate
controversy. The Journal of nutrition, 134(2), 479-482.

[←228]
Dominianni, C., Sinha, R., Goedert, J. J., Pei, Z., Yang, L., Hayes, R. B., & Ahn, J. (2015). Sex, body mass
index, and dietary fiber intake influence the human gut microbiome. PloS one, 10(4), e0124599.

[←229]
Tanaka: relationship of Enhanced Butyrate Production by Colonic Butyrate-Producing Bacteria to
Immunomodulatory Effects in Normal Mice Fed an Insoluble Fraction o fBrassica rapa L.

[←230]
Waldecker, M., Kautenburger, T., Daumann, H., Veeriah, S., Will, F., Dietrich, H., ... & Schrenk, D.
(2008). Histone-deacetylase inhibition and butyrate formation: Fecal slurry incubations with apple
pectin and apple juice extracts. Nutrition, 24(4), 366-374.

[←231]
Anhê, F. F., Varin, T. V., Le Barz, M., Desjardins, Y., Levy, E., Roy, D., & Marette, A. (2015). Gut
Microbiota Dysbiosis in Obesity-Linked Metabolic Diseases and Prebiotic Potential of Polyphenol-
Rich Extracts. Current Obesity Reports, 389–400;
Roopchand, D. E., Carmody, R. N., Kuhn, P., Moskal, K., Rojas-Silva, P., Turnbaugh, P. J., & Raskin, I.
(2015). Dietary Polyphenols Promote Growth of the Gut Bacterium Akkermansia muciniphila and
Attenuate High-Fat Diet–Induced Metabolic Syndrome. Diabetes, 64(8), 2847-2858.
Henning, S. M., Summanen, P. H., Lee, R. P., Yang, J., Finegold, S. M., Heber, D., & Li, Z. (2017).
Pomegranate ellagitannins stimulate the growth of Akkermansia muciniphila in vivo. Anaerobe, 43,
56-60.
[←232]
de Vos, W. M. (2017). Microbe profile: Akkermansia muciniphila: a conserved intestinal symbiont that
acts as the gatekeeper of our mucosa. Microbiology, 163(5), 646-648.

[←233]

Castaldo G., Galdo G., Rotondi Aufiero F., Cereda E. Very low-calorie ketogenic diet may allow restoring
response to systemic therapy in relapsing plaque psoriasis. Obes. Res. Clin. Pract. 2015
Ebringer, A., & Wilson, C. (1996). The use of a low starch diet in the treatment of patients suffering
from ankylosing spondylitis. Clinical rheumatology, 15(1), 62-66

[←234]
http://www.phoenixhelix.com/2013/11/03/charles-story/

[←235]
Fletcher, A. A. (1922). Chronic Arthritis—Some Phases in its Etiology and Treatment. Canadian Medical
Association journal, 12(9), 633.

[←236]
Pemberton, R., & TOMPKINS, E. H. (1920). Studies on Arthritis in the Army Based on Four Hundred
Cases: II. Observations on the Basal Metabolism. Archives of Internal Medicine, 25(3), 241-242.

[←237]
Fletcher, A. A. (1922). Chronic Arthritis—Some Phases in its Etiology and Treatment. Canadian Medical
Association journal, 12(9), 633.

[←238]
Ebringer, A., & Wilson, C. (1996). The use of a low starch diet in the treatment of patients suffering
from ankylosing spondylitis. Clinical rheumatology, 15(1), 62-66

[←239]
Rashid, T., & Ebringer, A. (2007). Ankylosing spondylitis is linked to Klebsiella—the evidence. Clinical
rheumatology, 26(6), 858-864.

[←240]
Ebringer, A., & Wilson, C. (1996). The use of a low starch diet in the treatment of patients suffering
from ankylosing spondylitis. Clinical rheumatology, 15(1), 62-66

[←241]
Ebringer, A., & Wilson, C. (1996). The use of a low starch diet in the treatment of patients suffering
from ankylosing spondylitis. Clinical rheumatology, 15(1), 62-66

[←242]
 Ochuba, G. U., & von Riesen, V. L. (1980). Fermentation of polysaccharides by Klebsielleae and other
facultative bacilli. Applied and environmental microbiology, 39(5), 988-992.

[←243]
Puccetti, A., Dolcino, M., Tinazzi, E., Moretta, F., D’Angelo, S., Olivieri, I., & Lunardi, C. (2017).
Antibodies Directed against a Peptide Epitope of a Klebsiella pneumoniae-Derived Protein Are
Present in Ankylosing Spondylitis. PloS one, 12(1), e0171073.

[←244]
Puccetti, A., Dolcino, M., Tinazzi, E., Moretta, F., D’Angelo, S., Olivieri, I., & Lunardi, C. (2017).
Antibodies Directed against a Peptide Epitope of a Klebsiella pneumoniae-Derived Protein Are
Present in Ankylosing Spondylitis. PloS one, 12(1), e0171073.

[←245]
Castaldo, G., Galdo, G., Aufiero, F. R., & Cereda, E. (2016). Very low-calorie ketogenic diet may allow
restoring response to systemic therapy in relapsing plaque psoriasis. Obesity research & clinical
practice, 10(3), 348-352.
Suskind, D. L., Wahbeh, G., Cohen, S. A., Damman, C. J., Klein, J., Braly, K., ... & Lee, D. (2016). Patients
Perceive Clinical Benefit with the Specific Carbohydrate Diet for Inflammatory Bowel Disease.
Digestive diseases and sciences, 61(11), 3255-3260.
Kakodkar, S., Farooqui, A. J., Mikolaitis, S. L., & Mutlu, E. A. (2015). The specific carbohydrate diet for
inflammatory bowel disease: a case series. Journal of the Academy of Nutrition and Dietetics,
115(8), 1226-1232.
Khandalavala, B. N., & Nirmalraj, M. C. (2015). Resolution of severe ulcerative colitis with the specific
carbohydrate diet. Case reports in gastroenterology, 9(2), 291-295
Obih, C., Wahbeh, G., Lee, D., Braly, K., Giefer, M., Shaffer, M. L., ... & Suskind, D. L. (2016). Specific
carbohydrate diet for pediatric inflammatory bowel disease in clinical practice within an academic
IBD center. Nutrition, 32(4), 418-425;
Suskind, D. L., Wahbeh, G., Gregory, N., Vendettuoli, H., & Christie, D. (2014). Nutritional therapy in
pediatric Crohn disease: the specific carbohydrate diet. Journal of pediatric gastroenterology and
nutrition, 58(1), 87-91.
Cohen, S. A., Gold, B. D., Oliva, S., Lewis, J., Stallworth, A., Koch, B., ... & Mason, D. (2014). Clinical and
mucosal improvement with specific carbohydrate diet in pediatric Crohn disease. Journal of
pediatric gastroenterology and nutrition, 59(4), 516-521.
Burgis, J. C., Nguyen, K., Park, K. T., & Cox, K. (2016). Response to strict and liberalized specific
carbohydrate diet in pediatric Crohn’s disease. World journal of gastroenterology, 22(6), 2111

[←246]
Viladomiu, M., Kivolowitz, C., Abdulhamid, A., Dogan, B., Victorio, D., Castellanos, J. G., ... & Chai, C.
(2017). IgA-coated E. coli enriched in Crohn’s disease spondyloarthritis promote TH17-dependent
inflammation. Science Translational Medicine, 9(376), eaaf9655.
Kivolowitz, C., Abdulhamid, A., Victorio, D., Castellanos, J., Simpson, K., Scherl, E., & Longman, R.
(2016). O-006 Expansion of Immunologically-Relevant E. Coli in the Intestinal Microbiota of Patients
with IBD-Associated Spondyloarthritis Promotes Mucosal RORgt-Dependent Immunity.
Inflammatory bowel diseases, 22, S3.
[←247]
Nickerson, K. P., Chanin, R., & McDonald, C. (2015). Deregulation of intestinal anti-microbial defense by
the dietary additive, maltodextrin. Gut microbes, 6(1), 78-83.

[←248]
Dr. Allyson Siebecker (2014), SIBO Specific Food Guide.
http://www.siboinfo.com/uploads/5/4/8/4/5484269/sibo_specific_diet_food_guide_sept_2014.pdf

[←249]
Penagini, F., Dilillo, D., Borsani, B., Cococcioni, L., Galli, E., Bedogni, G., ... & Zuccotti, G. V. (2016).
Nutrition in Pediatric Inflammatory Bowel Disease: From Etiology to Treatment. A Systematic
Review. Nutrients, 8(6), 334.
Burgis, J. C., Nguyen, K., Park, K. T., & Cox, K. (2016). Response to strict and liberalized specific
carbohydrate diet in pediatric Crohn’s disease. World journal of gastroenterology, 22(6), 2111.

[←250]
Suskind, D. L., Wahbeh, G., Cohen, S. A., Damman, C. J., Klein, J., Braly, K., ... & Lee, D. (2016). Patients
Perceive Clinical Benefit with the Specific Carbohydrate Diet for Inflammatory Bowel Disease.
Digestive diseases and sciences, 61(11), 3255-3260.
Kakodkar, S., Farooqui, A. J., Mikolaitis, S. L., & Mutlu, E. A. (2015). The specific carbohydrate diet for
inflammatory bowel disease: a case series. Journal of the Academy of Nutrition and Dietetics,
115(8), 1226-1232.
Khandalavala, B. N., & Nirmalraj, M. C. (2015). Resolution of severe ulcerative colitis with the specific
carbohydrate diet. Case reports in gastroenterology, 9(2), 291-295
Obih, C., Wahbeh, G., Lee, D., Braly, K., Giefer, M., Shaffer, M. L., ... & Suskind, D. L. (2016). Specific
carbohydrate diet for pediatric inflammatory bowel disease in clinical practice within an academic
IBD center. Nutrition, 32(4), 418-425;
Suskind, D. L., Wahbeh, G., Gregory, N., Vendettuoli, H., & Christie, D. (2014). Nutritional therapy in
pediatric Crohn disease: the specific carbohydrate diet. Journal of pediatric gastroenterology and
nutrition, 58(1), 87-91.
Cohen, S. A., Gold, B. D., Oliva, S., Lewis, J., Stallworth, A., Koch, B., ... & Mason, D. (2014). Clinical and
mucosal improvement with specific carbohydrate diet in pediatric Crohn disease. Journal of
pediatric gastroenterology and nutrition, 59(4), 516-521.
Burgis, J. C., Nguyen, K., Park, K. T., & Cox, K. (2016). Response to strict and liberalized specific
carbohydrate diet in pediatric Crohn’s disease. World journal of gastroenterology, 22(6), 2111.

[←251]
Suskind, D. (2016). Nutrition in Immune Balance (NIMBAL) Therapy: Using Diet to Treat Inflammatory
Bowel Disease. Seattle, Washington. Nimbal Publishing .

[←252]
Suskind, D. L., Cohen, S. A., Brittnacher, M. J., Wahbeh, G., Lee, D., Shaffer, M. L., ... & Giefer, M.
(2017). Clinical and Fecal Microbial Changes With Diet Therapy in Active Inflammatory Bowel
Disease. Journal of Clinical Gastroenterology.
[←253]
Walters, S. S., Quiros, A., Rolston, M., Grishina, I., Li, J., Fenton, A., ... & Nieves, R. (2014). Analysis of
gut microbiome and diet modification in patients with Crohn’s disease. SOJ Microbiol Infect Dis,
2(3), 1-13.

[←254]
James, M. J., Gibson, R. A., & Cleland, L. G. (2000). Dietary polyunsaturated fatty acids and
inflammatory mediator production. The American journal of clinical nutrition, 71(1), 343s-348s.
Sperling, R. I. (1991). Effects of Dietary Fish Oil on Leukocyte Leukotriene and PAF Generation and on
Neutrophil Chemotaxis1. In Health Effects of Omega 3 Polyunsaturated Fatty Acids in Seafoods (pp.
391-400). Karger Publishers.
Barrea L., Balato N., Di Somma C., Macchia P.E., Napolitano M., Savanelli M.C., Esposito K., Colao A.,
Savastano S. Nutrition and psoriasis: Is there any association between the severity of the disease
and adherence to the Mediterranean diet? J. Transl. Med. 2015;13:18. doi: 10.1186/s12967-014-
0372-1.)
Hayashi, H., Satoi, K., Sato-Mito, N., Kaburagi, T., Yoshino, H., Higaki, M., ... & Sato, K. (2012).
Nutritional status in relation to adipokines and oxidative stress is associated with disease activity in
patients with rheumatoid arthritis. Nutrition, 28(11), 1109-1114.
Skoldstam, L., Hagfors, L., & Johansson, G. (2003). An experimental study of a Mediterranean diet
intervention for patients with rheumatoid arthritis. Annals of the Rheumatic Diseases, 62(3), 208–
214. http://doi.org/10.1136/ard.62.3.208
Guida, B., Napoleone, A., Trio, R., Nastasi, A., Balato, N., Laccetti, R., & Cataldi, M. (2014). Energy-
restricted, n-3 polyunsaturated fatty acids-rich diet improves the clinical response to immuno-
modulating drugs in obese patients with plaque-type psoriasis: a randomized control clinical trial.
Clinical Nutrition, 33(3), 399-405.
Hansen, G. V. O., Nielsen, L., Kluger, E., Thysen, M., Emmertsen, H., Stengaard-Pedersen, K., ... &
Andersen, P. W. (1996). Nutritional status of Danish rheumatoid arthritis patients and effects of a
diet adjusted in energy intake, fish-meal, and antioxidants. Scandinavian journal of rheumatology,
25(5), 325-333.

[←255]
Barrea L., Balato N., Di Somma C., Macchia P.E., Napolitano M., Savanelli M.C., Esposito K., Colao A.,
Savastano S. Nutrition and psoriasis: Is there any association between the severity of the disease
and adherence to the Mediterranean diet? J. Transl. Med. 2015;13:18. doi: 10.1186/s12967-014-
0372-1.)
Hayashi, H., Satoi, K., Sato-Mito, N., Kaburagi, T., Yoshino, H., Higaki, M., ... & Sato, K. (2012).
Nutritional status in relation to adipokines and oxidative stress is associated with disease activity in
patients with rheumatoid arthritis. Nutrition, 28(11), 1109-1114.
Skoldstam, L., Hagfors, L., & Johansson, G. (2003). An experimental study of a Mediterranean diet
intervention for patients with rheumatoid arthritis. Annals of the Rheumatic Diseases, 62(3), 208–
214. http://doi.org/10.1136/ard.62.3.208
Guida, B., Napoleone, A., Trio, R., Nastasi, A., Balato, N., Laccetti, R., & Cataldi, M. (2014). Energy-
restricted, n-3 polyunsaturated fatty acids-rich diet improves the clinical response to immuno-
modulating drugs in obese patients with plaque-type psoriasis: a randomized control clinical trial.
Clinical Nutrition, 33(3), 399-405.
Hansen, G. V. O., Nielsen, L., Kluger, E., Thysen, M., Emmertsen, H., Stengaard-Pedersen, K., ... &
Andersen, P. W. (1996). Nutritional status of Danish rheumatoid arthritis patients and effects of a
diet adjusted in energy intake, fish-meal, and antioxidants. Scandinavian journal of rheumatology,
 25(5), 325-333.

[←256]
Serra-Majem, L., Ribas, L., García, A., Pérez-Rodrigo, C., & Aranceta, J. (2003). Nutrient adequacy and
Mediterranean Diet in Spanish school children and adolescents. European journal of clinical
nutrition, 57, S35-S39.
Castro-Quezada, I., Román-Viñas, B., & Serra-Majem, L. (2014). The Mediterranean diet and nutritional
adequacy: a review. Nutrients, 6(1), 231-248.

[←257]
Agarwal, S., Reider, C., Brooks, J. R., & Fulgoni III, V. L. (2015). Comparison of prevalence of inadequate
nutrient intake based on body weight status of adults in the United States: an analysis of NHANES
2001–2008. Journal of the American College of Nutrition, 34(2), 126-134.
Rosanoff, A., Weaver, C. M., & Rude, R. K. (2012). Suboptimal magnesium status in the United States:
are the health consequences underestimated?. Nutrition reviews, 70(3), 153-164.

[←258]
Rosanoff, A., Weaver, C. M., & Rude, R. K. (2012). Suboptimal magnesium status in the United States:
are the health consequences underestimated?. Nutrition reviews, 70(3), 153-164.
Dibaba, D. T., Xun, P., & He, K. (2014). Dietary magnesium intake is inversely associated with serum C-
reactive protein levels: meta-analysis and systematic review. European journal of clinical nutrition,
68(4), 510.
King, D. E. (2009). Inflammation and elevation of C-reactive protein: does magnesium play a key role?.
Magnesium Research, 22(2), 57-59.
Almoznino-Sarafian, D., Berman, S., Mor, A., Shteinshnaider, M., Gorelik, O., Tzur, I., ... & Cohen, N.
(2007). Magnesium and C-reactive protein in heart failure: an anti-inflammatory effect of
magnesium administration?. European journal of nutrition, 46(4), 230-237.
Kim, D. J., Xun, P., Liu, K., Loria, C., Yokota, K., Jacobs, D. R., & He, K. (2010). Magnesium intake in
relation to systemic inflammation, insulin resistance, and the incidence of diabetes. Diabetes care,
33(12), 2604-2610.
Chacko, S. A., Song, Y., Nathan, L., Tinker, L., De Boer, I. H., Tylavsky, F., ... & Liu, S. (2010). Relations of
dietary magnesium intake to biomarkers of inflammation and endothelial dysfunction in an
ethnically diverse cohort of postmenopausal women. Diabetes care, 33(2), 304-310.
Song, Y., Li, T. Y., van Dam, R. M., Manson, J. E., & Hu, F. B. (2007). Magnesium intake and plasma
concentrations of markers of systemic inflammation and endothelial dysfunction in women. The
American journal of clinical nutrition, 85(4), 1068-1074.
Nielsen, F. H., Johnson, L. K., & Zeng, H. (2010). Magnesium supplementation improves indicators of
low magnesium status and inflammatory stress in adults older than 51 years with poor quality
sleep. Magnesium Research, 23(4), 158-168.
Chacko, S. A., Sul, J., Song, Y., Li, X., LeBlanc, J., You, Y., ... & Liu, S. (2011). Magnesium
supplementation, metabolic and inflammatory markers, and global genomic and proteomic
profiling: a randomized, double-blind, controlled, crossover trial in overweight individuals. The
American journal of clinical nutrition, 93(2), 463-473.

[←259]
Murr, C., Pilz, S., Grammer, T. B., Kleber, M. E., Böhm, B. O., März, W., & Fuchs, D. (2012). Low serum
zinc levels in patients undergoing coronary angiography correlate with immune activation and
 inflammation. Journal of Trace Elements in Medicine and Biology, 26(1), 26-30;
De Paula, R. C., Aneni, E. C., Costa, A. P. R., Figueiredo, V. N., Moura, F. A., Freitas, W. M., ... & Blaha,
M. (2014). Low zinc levels is associated with increased inflammatory activity but not with
atherosclerosis, arteriosclerosis or endothelial dysfunction among the very elderly. BBA clinical, 2,
1-6.

[←260]
Preedy, V. R., & Watson, R. R. (Eds.). (2014). The Mediterranean Diet: An Evidence-Based Approach.
Academic press.

[←261]
Hagfors, L., Leanderson, P., Sköldstam, L., Andersson, J., & Johansson, G. (2003). Antioxidant intake,
plasma antioxidants and oxidative stress in a randomized, controlled, parallel, Mediterranean
dietary intervention study on patients with rheumatoid arthritis. Nutrition journal, 2(1), 5.
Kolomvotsou, A. I., Rallidis, L. S., Mountzouris, K. C., Lekakis, J., Koutelidakis, A., Efstathiou, S., ... &
Zampelas, A. (2013). Adherence to Mediterranean diet and close dietetic supervision increase total
dietary antioxidant intake and plasma antioxidant capacity in subjects with abdominal obesity.
European journal of nutrition, 52(1), 37-48.
Razquin, C., Martinez, J. A., Martinez-Gonzalez, M. A., Mitjavila, M. T., Estruch, R., & Marti, A. (2009). A
3 years follow-up of a Mediterranean diet rich in virgin olive oil is associated with high plasma
antioxidant capacity and reduced body weight gain. European journal of clinical nutrition, 63(12),
1387-1393.

[←262]
Quiñonez-Flores, C. M., González-Chávez, S. A., Del Río Nájera, D., & Pacheco-Tena, C. (2016). Oxidative
Stress Relevance in the Pathogenesis of the Rheumatoid Arthritis: A Systematic Review. BioMed
Research International, 2016.
Mateen, S., Moin, S., Khan, A. Q., Zafar, A., & Fatima, N. (2016). Increased Reactive Oxygen Species
Formation and Oxidative Stress in Rheumatoid Arthritis. PloS one, 11(4), e0152925.

[←263]
Bae, S. C., Kim, S. J., & Sung, M. K. (2003). Inadequate antioxidant nutrient intake and altered plasma
antioxidant status of rheumatoid arthritis patients. Journal of the American College of Nutrition,
22(4), 311-315.

[←264]

Quiñonez-Flores, C. M., González-Chávez, S. A., Del Río Nájera, D., & Pacheco-Tena, C. (2016). Oxidative
Stress Relevance in the Pathogenesis of the Rheumatoid Arthritis: A Systematic Review. BioMed
Research International, 2016.
Datta, S., Kundu, S., Ghosh, P., De, S., Ghosh, A., & Chatterjee, M. (2014). Correlation of oxidant status
with oxidative tissue damage in patients with rheumatoid arthritis. Clinical rheumatology, 33(11),
1557-1564.
Wolters M. (2005) Diet and psoriasis: experimental data and clinical evidence. Br J Dermatol. 153:706–
714
Vijayakumar, D., Suresh, K., & Manoharan, S. (2006). Lipid peroxidation and antioxidant status in blood
 of rheumatoid arthritis patients. Indian Journal of Clinical Biochemistry, 21(1), 105-105.
Wolters M. (2005) Diet and psoriasis: experimental data and clinical evidence. Br J Dermatol. 153:706–
714
Kundu, S., Ghosh, P., Datta, S., Ghosh, A., Chattopadhyay, S., & Chatterjee, M. (2012). Oxidative stress
as a potential biomarker for determining disease activity in patients with rheumatoid arthritis. Free
radical research, 46(12), 1482-1489.
Mateen, S., Moin, S., Khan, A. Q., Zafar, A., & Fatima, N. (2016). Increased Reactive Oxygen Species
Formation and Oxidative Stress in Rheumatoid Arthritis. PloS one, 11(4), e0152925
Lin, X., & Huang, T. (2016). Oxidative stress in psoriasis and potential therapeutic use of antioxidants.
Free radical research, 50(6), 585-595.
Wang, L., Gao, L., Jin, D., Wang, P., Yang, B., Deng, W., ... & Shen, H. (2015). The Relationship of Bone
Mineral Density to Oxidant/Antioxidant Status and Inflammatory and Bone Turnover Markers in a
Multicenter Cross-Sectional Study of Young Men with Ankylosing Spondylitis. Calcified tissue
international, 97(1), 12-22.
Datta, S., Kundu, S., Ghosh, P., De, S., Ghosh, A., & Chatterjee, M. (2014). Correlation of oxidant status
with oxidative tissue damage in patients with rheumatoid arthritis. Clinical rheumatology, 33(11),
1557-1564.

[←265]
Root, M. M., McGinn, M. C., Nieman, D. C., Henson, D. A., Heinz, S. A., Shanely, R. A., ... & Jin, F. (2012).
Combined fruit and vegetable intake is correlated with improved inflammatory and oxidant status
from a cross-sectional study in a community setting. Nutrients, 4(1), 29-41;
Linos, A., Kaklamani, V. G., Kaklamani, E., Koumantaki, Y., Giziaki, E., Papazoglou, S., & Mantzoros, C. S.
(1999). Dietary factors in relation to rheumatoid arthritis: a role for olive oil and cooked
vegetables?. The American journal of clinical nutrition, 70(6), 1077-1082.
Valtueña, S., Pellegrini, N., Franzini, L., Bianchi, M. A., Ardigo, D., Del Rio, D., ... & Brighenti, F. (2008).
Food selection based on total antioxidant capacity can modify antioxidant intake, systemic
inflammation, and liver function without altering markers of oxidative stress. The American journal
of clinical nutrition, 87(5), 1290-1297.
Mier-Cabrera, J., Aburto-Soto, T., Burrola-Méndez, S., Jiménez-Zamudio, L., Tolentino, M. C.,
Casanueva, E., & Hernández-Guerrero, C. (2009). Women with endometriosis improved their
peripheral antioxidant markers after the application of a high antioxidant diet. Reproductive Biology
and Endocrinology, 7(1), 54.

[←266]
Dragsted, L. O., Pedersen, A., Hermetter, A., Basu, S., Hansen, M., Haren, G. R., ... & Jakobsen, J. (2004).
The 6-a-day study: effects of fruit and vegetables on markers of oxidative stress and antioxidative
defense in healthy nonsmokers. The American journal of clinical nutrition, 79(6), 1060-1072.
Dauchet, L., Péneau, S., Bertrais, S., Vergnaud, A. C., Estaquio, C., Kesse-Guyot, E., ... & Hercberg, S.
(2008). Relationships between different types of fruit and vegetable consumption and serum
concentrations of antioxidant vitamins. British journal of nutrition, 100(03), 633-641.
Zino, S., Skeaff, M., Williams, S., & Mann, J. (1997). Randomised controlled trial of effect of fruit and
vegetable consumption on plasma concentrations of lipids and antioxidants. Bmj, 314(7097), 1787.

[←267]
Jiang, Y., Wu, S. H., Shu, X. O., Xiang, Y. B., Ji, B. T., Milne, G. L., ... & Yang, G. (2014). Cruciferous
vegetable intake is inversely correlated with circulating levels of proinflammatory markers in
women. Journal of the Academy of Nutrition and Dietetics, 114(5), 700-708.
[←268]
Jiang, Y., Wu, S. H., Shu, X. O., Xiang, Y. B., Ji, B. T., Milne, G. L., ... & Yang, G. (2014). Cruciferous
vegetable intake is inversely correlated with circulating levels of proinflammatory markers in
women. Journal of the Academy of Nutrition and Dietetics, 114(5), 700-708.

[←269]
Lu, B., Rho, Y. H., Cui, J., Iannaccone, C. K., Frits, M. L., Karlson, E. W., & Shadick, N. A. (2014).
Associations of smoking and alcohol consumption with disease activity and functional status in
rheumatoid arthritis. The Journal of rheumatology, 41(1), 24-30.
Lu, B., Solomon, D. H., Costenbader, K. H., Keenan, B. T., Chibnik, L. B., & Karlson, E. W. (2010). Alcohol
consumption and markers of inflammation in women with preclinical rheumatoid arthritis. Arthritis
& Rheumatism, 62(12), 3554-3559.
Di Giuseppe, D., Alfredsson, L., Bottai, M., Askling, J., & Wolk, A. (2012). Long term alcohol intake and
risk of rheumatoid arthritis in women: a population based cohort study. Bmj, 345, e4230.

[←270]
Purohit, V., Bode, J. C., Bode, C., Brenner, D. A., Choudhry, M. A., Hamilton, F., ... & Swanson, C. (2008).
Alcohol, intestinal bacterial growth, intestinal permeability to endotoxin, and medical
consequences: summary of a symposium. Alcohol, 42(5), 349-361.

[←271]
Arsenault, B. J., Earnest, C. P., Després, J. P., Blair, S. N., & Church, T. S. (2009). Obesity, coffee
consumption and CRP levels in postmenopausal overweight/obese women: importance of hormone
replacement therapy use. European journal of clinical nutrition, 63(12), 1419-1424.
Kotani, K., Tsuzaki, K., Sano, Y., Maekawa, M., Fujiwara, S., Hamada, T., & Sakane, N. (2008). The
relationship between usual coffee consumption and serum C-reactive protein level in a Japanese
female population. Clinical chemistry and laboratory medicine, 46(10), 1434-1437.
Lopez-Garcia, E., van Dam, R. M., Qi, L., & Hu, F. B. (2006). Coffee consumption and markers of
inflammation and endothelial dysfunction in healthy and diabetic women. The American journal of
clinical nutrition, 84(4), 888-893.
Maki, T., Pham, N. M., Yoshida, D., Yin, G., Ohnaka, K., Takayanagi, R., & Kono, S. (2010). The
relationship of coffee and green tea consumption with high-sensitivity C-reactive protein in
Japanese men and women. Clinical chemistry and laboratory medicine, 48(6), 849-854.
Zampelas, A., Panagiotakos, D. B., Pitsavos, C., Chrysohoou, C., & Stefanadis, C. (2004). Associations
between coffee consumption and inflammatory markers in healthy persons: the ATTICA study. The
American journal of clinical nutrition, 80(4), 862-867

[←272]
Mikuls, T. R., Cerhan, J. R., Criswell, L. A., Merlino, L., Mudano, A. S., Burma, M., ... & Saag, K. G. (2002).
Coffee, tea, and caffeine consumption and risk of rheumatoid arthritis: results from the Iowa
Women's Health Study. Arthritis & Rheumatism, 46(1), 83-91.
Löfvenborg, J. E., Andersson, T., Carlsson, P. O., Dorkhan, M., Groop, L., Martinell, M., ... & Carlsson, S.
(2014). Coffee consumption and the risk of latent autoimmune diabetes in adults—results from a
Swedish case–control study. Diabetic Medicine, 31(7), 799-805.

[←273]
 Mikuls, T. R., Cerhan, J. R., Criswell, L. A., Merlino, L., Mudano, A. S., Burma, M., ... & Saag, K. G. (2002).
Coffee, tea, and caffeine consumption and risk of rheumatoid arthritis: results from the Iowa
Women's Health Study. Arthritis & Rheumatism, 46(1), 83-91.
Rebello, S. A., Chen, C. H., Naidoo, N., Xu, W., Lee, J., Chia, K. S., ... & van Dam, R. M. (2011). Coffee and
tea consumption in relation to inflammation and basal glucose metabolism in a multi-ethnic Asian
population: a cross-sectional study. Nutrition journal, 10(1), 1
Kempf, K., Herder, C., Erlund, I., Kolb, H., Martin, S., Carstensen, M., ... & Jaakko, T. (2010). Effects of
coffee consumption on subclinical inflammation and other risk factors for type 2 diabetes: a clinical
trial. The American journal of clinical nutrition, 91(4), 950-957.
Wu, D., Wang, J., Pae, M., & Meydani, S. N. (2012). Green tea EGCG, T cells, and T cell-mediated
autoimmune diseases. Molecular aspects of medicine, 33(1), 107-118.
Yang, E. J., Lee, J., Lee, S. Y., Kim, E. K., Moon, Y. M., Jung, Y. O., ... & Cho, M. L. (2014). EGCG
attenuates autoimmune arthritis by inhibition of STAT3 and HIF-1α with Th17/Treg control. PLoS
One, 9(2), e86062.
Lee, S. Y., Jung, Y. O., Ryu, J. G., Oh, H. J., Son, H. J., Lee, S. H., ... & Kim, H. Y. (2016). Epigallocatechin-3-
gallate ameliorates autoimmune arthritis by reciprocal regulation of T helper-17 regulatory T cells
and inhibition of osteoclastogenesis by inhibiting STAT3 signaling. Journal of leukocyte biology, jlb-
3A0514.
Alghadir, A. H., Gabr, S. A., & Al-Eisa, E. S. (2016). Green tea and exercise interventions as nondrug
remedies in geriatric patients with rheumatoid arthritis. Journal of physical therapy science, 28(10),
2820-2829.

[←274]

Dumas, J. A., Bunn, J. Y., Nickerson, J., Crain, K. I., Ebenstein, D. B., Tarleton, E. K., ... & Kien, C. L.
(2016). Dietary saturated fat and monounsaturated fat have reversible effects on brain function and
the secretion of pro-inflammatory cytokines in young women. Metabolism, 65(10), 1582-1588.
Gupta, S., Knight, A. G., Gupta, S., Keller, J. N., & Bruce-Keller, A. J. (2012). Saturated long-chain fatty
acids activate inflammatory signaling in astrocytes. Journal of neurochemistry, 120(6), 1060-1071.
Håversen, Liliana, et al. "Induction of proinflammatory cytokines by long-chain saturated fatty acids in
human macrophages." Atherosclerosis 202.2 (2009): 382-393.
Kien, C. L., Bunn, J. Y., Fukagawa, N. K., Anathy, V., Matthews, D. E., Crain, K. I., ... & Poynter, M. E.
(2015). Lipidomic evidence that lowering the typical dietary palmitate to oleate ratio in humans
decreases the leukocyte production of proinflammatory cytokines and muscle expression of redox-
sensitive genes. The Journal of nutritional biochemistry, 26(12), 1599-1606.
Soto-Vaca, A., Losso, J. N., McDonough, K., & Finley, J. W. (2013). Differential effect of 14 free fatty
acids in the expression of inflammation markers on human arterial coronary cells. Journal of
agricultural and food chemistry, 61(42), 10074-10079.
Rocha, D. M., Caldas, A. P., Oliveira, L. L., Bressan, J., & Hermsdorff, H. H. (2016). Saturated fatty acids
trigger TLR4-mediated inflammatory response. Atherosclerosis, 244, 211-215.
Snodgrass, R. G., Huang, S., Choi, I. W., Rutledge, J. C., & Hwang, D. H. (2013). Inflammasome-mediated
secretion of IL-1β in human monocytes through TLR2 activation; modulation by dietary fatty acids.
The Journal of Immunology, 191(8), 4337-4347.
Robblee, M. M., Kim, C. C., Abate, J. P., Valdearcos, M., Sandlund, K. L., Shenoy, M. K., ... & Koliwad, S.
K. (2016). Saturated fatty acids engage an IRE1α-dependent pathway to activate the NLRP3
inflammasome in myeloid cells. Cell reports, 14(11), 2611-2623.
Reynolds, C. M., McGillicuddy, F. C., Harford, K. A., Finucane, O. M., Mills, K. H., & Roche, H. M. (2012).
Dietary saturated fatty acids prime the NLRP3 inflammasome via TLR4 in dendritic cells—
implications for diet-induced insulin resistance. Molecular nutrition & food research, 56(8), 1212-
 1222.
Yang, X., Haghiac, M., Glazebrook, P., Minium, J., Catalano, P. M., & Hauguel-de Mouzon, S. (2015).
Saturated fatty acids enhance TLR4 immune pathways in human trophoblasts. Human
Reproduction, dev173.
Gupta, S., Knight, A. G., Gupta, S., Keller, J. N., & Bruce-Keller, A. J. (2012). Saturated long-chain fatty
acids activate inflammatory signaling in astrocytes. Journal of neurochemistry, 120(6), 1060-1071.

[←275]
Lyte, J. M., Gabler, N. K., & Hollis, J. H. (2016). Postprandial serum endotoxin in healthy humans is
modulated by dietary fat in a randomized, controlled, cross-over study. Lipids in Health and Disease,
15(1), 186.
Mani, V., Hollis, J. H., & Gabler, N. K. (2013). Dietary oil composition differentially modulates intestinal
endotoxin transport and postprandial endotoxemia. Nutrition & metabolism, 10(1), 6.

Chapter 5. The Low-Starch Diet in Practice

[←276]
Tommasini, A., Not, T., Kiren, V., Baldas, V., Santon, D., Trevisiol, C., ... & Lenhardt, A. (2004). Mass
screening for coeliac disease using antihuman transglutaminase antibody assay. Archives of disease
in childhood, 89(6), 512-515.

[←277]
Bhatia, B. K., Millsop, J. W., Debbaneh, M., Koo, J., Linos, E., & Liao, W. (2014). Diet and psoriasis, part
II: celiac disease and role of a gluten-free diet. Journal of the American Academy of Dermatology,
71(2), 350-358.
Wu, J. J., Nguyen, T. U., Poon, K. Y. T., & Herrinton, L. J. (2012). The association of psoriasis with
autoimmune diseases. Journal of the American Academy of Dermatology, 67(5), 924-930.

[←278]
Al-Mayouf, S. M., Al-Mehaidib, A. I., & Alkaff, M. A. (2003). The significance of elevated serologic
markers of celiac disease in children with juvenile rheumatoid arthritis. Saudi Journal of
Gastroenterology, 9(2), 75.

[←279]
Woo WK, McMillan SA, Watson RG, McCluggage WG, Sloan JM, McMillan JC. Coeliac disease-
associated antibodies correlate with psoriasis activity. Br J Dermatol. 2004;151:891–4; 26.
Lindqvist U, Rudsander A, Boström A, Nilsson B, Michaëlsson G. IgA antibodies to gliadin and coeliac
disease in psoriatic arthritis. Rheumatology (Oxford) 2002;41:31–7. [PubMed])

[←280]
Michaëlsson G, Gerdén B, Hagforsen E, Nilsson B, Pihl-Lundin I, Kraaz W, et al. Psoriasis patients with
antibodies to gliadin can be improved by a gluten-free diet. Br J Dermatol. 2000;142:44–51 )

[←281]
 Addolorato, G., Parente, A., de Lorenzi, G., D’angelo Di Paola, M. E., Abenavoli, L., Leggio, L., ... &
Gasbarrini, G. (2003). Rapid regression of psoriasis in a coeliac patient after gluten-free diet.
Digestion, 68(1), 9-12.
Frikha F, Snoussi M, Bahloul Z. Osteomalacia associated with cutaneous psoriasis as the presenting
feature of coeliac disease: a case report. Pan Afr Med J. 2012;11:58.)

[←282]
Hafström, I., Ringertz, B., Spångberg, A., Von Zweigbergk, L., Brannemark, S., Nylander, I., ... &
Klareskog, L. (2001). A vegan diet free of gluten improves the signs and symptoms of rheumatoid
arthritis: the effects on arthritis correlate with a reduction in antibodies to food antigens.
Rheumatology, 40(10), 1175-1179.

[←283]
Hollon, J., Puppa, E. L., Greenwald, B., Goldberg, E., Guerrerio, A., & Fasano, A. (2015). Effect of gliadin
on permeability of intestinal biopsy explants from celiac disease patients and patients with non-
celiac gluten sensitivity. Nutrients, 7(3), 1565-1576.
Drago, S., El Asmar, R., Di Pierro, M., Grazia Clemente, M., Sapone, A. T. A., Thakar, M., ... & Zampini, L.
(2006). Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and
intestinal cell lines. Scandinavian journal of gastroenterology, 41(4), 408-419.
Lammers, K. M., Lu, R., Brownley, J., Lu, B., Gerard, C., Thomas, K., ... & Netzel–Arnett, S. (2008).
Gliadin induces an increase in intestinal permeability and zonulin release by binding to the
chemokine receptor CXCR3. Gastroenterology, 135(1), 194-204.

[←284]
Drago, S., El Asmar, R., Di Pierro, M., Grazia Clemente, M., Sapone, A. T. A., Thakar, M., ... & Zampini, L.
(2006). Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and
intestinal cell lines. Scandinavian journal of gastroenterology, 41(4), 408-419.
De Punder, K., & Pruimboom, L. (2013). The dietary intake of wheat and other cereal grains and their
role in inflammation. Nutrients, 5(3), 771-787.
Lammers, K. M., Lu, R., Brownley, J., Lu, B., Gerard, C., Thomas, K., ... & Netzel–Arnett, S. (2008).
Gliadin induces an increase in intestinal permeability and zonulin release by binding to the
chemokine receptor CXCR3. Gastroenterology, 135(1), 194-204.

[←285]
Fasano, A. (2011). Zonulin and its regulation of intestinal barrier function: the biological door to
inflammation, autoimmunity, and cancer. Physiological reviews, 91(1), 151-175.

[←286]
Uhde, M., Ajamian, M., Caio, G., De Giorgio, R., Indart, A., Green, P. H., ... & Alaedini, A. (2016).
Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat
in the absence of coeliac disease. Gut, 65(12), 1930-1937.

[←287]
Hollon, J. R., Cureton, P. A., Martin, M. L., Puppa, E. L. L., & Fasano, A. (2013). Trace gluten
contamination may play a role in mucosal and clinical recovery in a subgroup of diet-adherent non-
responsive celiac disease patients. BMC gastroenterology, 13(1), 1.
[←288]
Hollon, J. R., Cureton, P. A., Martin, M. L., Puppa, E. L. L., & Fasano, A. (2013). Trace gluten
contamination may play a role in mucosal and clinical recovery in a subgroup of diet-adherent non-
responsive celiac disease patients. BMC gastroenterology, 13(1), 1.

[←289]
Thompson, T., Lee, A. R., & Grace, T. (2010). Gluten contamination of grains, seeds, and flours in the
United States: a pilot study. Journal of the American Dietetic Association, 110(6), 937-940.

[←290]
Lee, H. J., Anderson, Z., & Ryu, D. (2014). Gluten contamination in foods labeled as “gluten free” in the
United States. Journal of Food Protection®, 77(10), 1830-1833.

[←291]
Zevallos, V. F., Ellis, H. J., Šuligoj, T., Herencia, L. I., & Ciclitira, P. J. (2012). Variable activation of
immune response by quinoa (Chenopodium quinoa Willd.) prolamins in celiac disease. The
American journal of clinical nutrition, 96(2), 337-344.
Ortiz-Sánchez, J. P., Cabrera-Chávez, F., & de la Barca, A. M. C. (2013). Maize prolamins could induce a
gluten-like cellular immune response in some celiac disease patients. Nutrients, 5(10), 4174-4183.
Giménez, M. J., Real, A., García-Molina, M. D., Sousa, C., & Barro, F. (2017). Characterization of celiac
disease related oat proteins: bases for the development of high quality oat varieties suitable for
celiac patients. Scientific reports, 7, 42588.

[←292]
Hollon, J. R., Cureton, P. A., Martin, M. L., Puppa, E. L. L., & Fasano, A. (2013). Trace gluten
contamination may play a role in mucosal and clinical recovery in a subgroup of diet-adherent non-
responsive celiac disease patients. BMC gastroenterology, 13(1), 1.

[←293]
De Punder, K., & Pruimboom, L. (2013). The dietary intake of wheat and other cereal grains and their
role in inflammation. Nutrients, 5(3), 771-787.
Shibasaki, M., Sumazaki, R., Isoyama, S., & Takita, H. (1992). Interaction of lectins with human IgE: IgE-
binding property and histamine-releasing activity of twelve plant lectins. International archives of
allergy and immunology, 98(1), 18-25.
Nachbar, M. S., & Oppenheim, J. D. (1980). Lectins in the United States diet: a survey of lectins in
commonly consumed foods and a review of the literature. The American journal of clinical nutrition,
33(11), 2338-2345;
Matucci, A., Veneri, G., Dalla Pellegrina, C., Zoccatelli, G., Vincenzi, S., Chignola, R., ... & Rizzi, C. (2004).
Temperature-dependent decay of wheat germ agglutinin activity and its implications for food
processing and analysis. Food Control, 15(5), 391-395.
Rizzi, C., Galeoto, L., Zoccatelli, G., Vincenzi, S., Chignola, R., & Peruffo, A. D. (2003). Active soybean
lectin in foods: quantitative determination by ELISA using immobilised asialofetuin. Food research
international, 36(8), 815-821.
Pramod, S. N., Venkatesh, Y. P., & Mahesh, P. A. (2007). Potato lectin activates basophils and mast cells
of atopic subjects by its interaction with core chitobiose of cell-bound non-specific immunoglobulin
E. Clinical & Experimental Immunology, 148(3), 391-401
[←294]
Pan, L., Qin, G., Zhao, Y., Wang, J., Liu, F., & Che, D. (2013). Effects of soybean agglutinin on mechanical
barrier function and tight junction protein expression in intestinal epithelial cells from piglets.
International journal of molecular sciences, 14(11), 21689-21704.
Nachbar, M. S., & Oppenheim, J. D. (1980). Lectins in the United States diet: a survey of lectins in
commonly consumed foods and a review of the literature. The American journal of clinical nutrition,
33(11), 2338-2345;
Pusztai, A., & Bardocz, S. (1996). Biological effects of plant lectins on the gastrointestinal tract:
metabolic consequences and applications. Trends in glycoscience and glycotechnology, 8, 149-166.
Dalla Pellegrina, C., Perbellini, O., Scupoli, M. T., Tomelleri, C., Zanetti, C., Zoccatelli, G., ... & Chignola,
R. (2009). Effects of wheat germ agglutinin on human gastrointestinal epithelium: insights from an
experimental model of immune/epithelial cell interaction. Toxicology and applied pharmacology,
237(2), 146-153
Pan, L., Qin, G., Zhao, Y., Wang, J., Liu, F., & Che, D. (2013). Effects of soybean agglutinin on mechanical
barrier function and tight junction protein expression in intestinal epithelial cells from piglets.
International journal of molecular sciences, 14(11), 21689-21704.

[←295]
Patel, B., Schutte, R., Sporns, P., Doyle, J., Jewel, L., & Fedorak, R. N. (2002). Potato glycoalkaloids
adversely affect intestinal permeability and aggravate inflammatory bowel disease. Inflammatory
bowel diseases, 8(5), 340-346.

[←296]
Kamo, S., Suzuki, S., & Sato, T. (2014). The content of soyasaponin and soyasapogenol in soy foods and
their estimated intake in the Japanese. Food science & nutrition, 2(3), 289-297.
Francis, G., Kerem, Z., Makkar, H. P., & Becker, K. (2002). The biological action of saponins in animal
systems: a review. British journal of Nutrition, 88(06), 587-605.
Nickel, J., Spanier, L. P., Botelho, F. T., Gularte, M. A., & Helbig, E. (2016). Effect of different types of
processing on the total phenolic compound content, antioxidant capacity, and saponin content of
Chenopodium quinoa Willd grains. Food chemistry, 209, 139-143.

[←297]
Gee, J. M., Price, K. R., Ridout, C. L., Wortley, G. M., Hurrell, R. F., & Johnson, I. T. (1993). Saponins of
quinoa (Chenopodium quinoa): effects of processing on their abundance in quinoa products and
their biological effects on intestinal mucosal tissue. Journal of the Science of Food and Agriculture,
63(2), 201-209.
Knudsen, D., Jutfelt, F., Sundh, H., Sundell, K., Koppe, W., & Frøkiær, H. (2008). Dietary soya saponins
increase gut permeability and play a key role in the onset of soyabean-induced enteritis in Atlantic
salmon (Salmo salar L.). British Journal of Nutrition, 100(01), 120-129.

[←298]
Reddy, N. R., & Pierson, M. D. (1994). Reduction in antinutritional and toxic components in plant foods
by fermentationa. Food Research International, 27(3), 281-290.

[←299]
Messina, V. (2014). Nutritional and health benefits of dried beans. The American journal of clinical
 nutrition, 100(Supplement 1), 437S-442S.

[←300]
Carlini, C. R., & Udedibie, A. B. (1997). Comparative effects of processing methods on hemagglutinating
and antitryptic activities of Canavalia ensiformis and Canavalia braziliensis seeds. Journal of
Agricultural and Food Chemistry, 45(11), 4372-4377.

[←301]
Thomson, L. U., Rea, R. L., & Jenkins, D. J. (1983). Effect of heat processing on hemagglutinin activity in
red kidney beans. Journal of Food Science, 48(1), 235-236.
Carlini, C. R., & Udedibie, A. B. (1997). Comparative effects of processing methods on hemagglutinating
and antitryptic activities of Canavalia ensiformis and Canavalia braziliensis seeds. Journal of
Agricultural and Food Chemistry, 45(11), 4372-4377.

[←302]
Atkinson, F. S., Foster-Powell, K., & Brand-Miller, J. C. (2008). International tables of glycemic index and
glycemic load values: 2008. Diabetes care, 31(12), 2281-2283.

[←303]
Katschinski, B., Logan, R. F., Edmond, M., & Langman, M. J. (1988). Smoking and sugar intake are
separate but interactive risk factors in Crohn's disease. Gut, 29(9), 1202-1206.

[←304]
Hu, Y., Costenbader, K. H., Gao, X., Al-Daabil, M., Sparks, J. A., Solomon, D. H., ... & Lu, B. (2014). Sugar-
sweetened soda consumption and risk of developing rheumatoid arthritis in women. The American
journal of clinical nutrition, 100(3), 959-967.

[←305]
Gibson, P. R., Newnham, E., Barrett, J. S., Shepherd, S. J., & Muir, J. G. (2007). Review article: fructose
malabsorption and the bigger picture. Alimentary pharmacology & therapeutics, 25(4), 349-363.

[←306]
Payne, A. N., Chassard, C., & Lacroix, C. (2012). Gut microbial adaptation to dietary consumption of
fructose, artificial sweeteners and sugar alcohols: implications for host–microbe interactions
contributing to obesity. Obesity reviews, 13(9), 799-809.

[←307]
Bian, X., Chi, L., Gao, B., Tu, P., Ru, H., & Lu, K. (2017). The artificial sweetener acesulfame potassium
affects the gut microbiome and body weight gain in CD-1 mice. PloS one, 12(6), e0178426.
Rodriguez-Palacios, A., Harding, A., Menghini, P., Himmelman, C., Retuerto, M., Nickerson, K. P., ... &
Pizarro, T. T. (2018). The artificial sweetener Splenda promotes gut proteobacteria, dysbiosis, and
myeloperoxidase reactivity in Crohn’s disease–like ileitis. Inflammatory bowel diseases, 24(5), 1005-
1020.
[←308]
Hvatum, M., Kanerud, L., Hällgren, R., & Brandtzaeg, P. (2006). The gut–joint axis: cross reactive food
antibodies in rheumatoid arthritis. Gut, 55(9), 1240-1247.
Cabrera-Chávez, F., & de la Barca, A. M. C. (2009). Bovine milk intolerance in celiac disease is related to
IgA reactivity to α-and β-caseins. Nutrition, 25(6), 715-716.

[←309]
Nickerson, K. P., & McDonald, C. (2012). Crohn's disease-associated adherent-invasive Escherichia coli
adhesion is enhanced by exposure to the ubiquitous dietary polysaccharide maltodextrin. PLoS
One, 7(12), e52132.
Munyaka, P. M., Sepehri, S., Ghia, J. E., & Khafipour, E. (2016). Carrageenan gum and adherent invasive
Escherichia coli in a piglet model of inflammatory bowel disease: impact on intestinal mucosa-
associated microbiota. Frontiers in microbiology, 7, 462.
Shang, Q., Sun, W., Shan, X., Jiang, H., Cai, C., Hao, J., ... & Yu, G. (2017). Carrageenan-induced colitis is
associated with decreased population of anti-inflammatory bacterium, akkermansia muciniphila, in
the gut microbiota of c57bl/6j mice. Toxicology letters, 279, 87-95.
Necas, J., & Bartosikova, L. (2013). Carrageenan: a review. Veterinarni Medicina, 58(4).

[←310]
De Filippo, Carlotta et al. “Impact of Diet in Shaping Gut Microbiota Revealed by a Comparative Study
in Children from Europe and Rural Africa.” Proceedings of the National Academy of Sciences of the
United States of America 107.33 (2010): 14691–14696.

[←311]
Roberts, C. L., Keita, Å. V., Duncan, S. H., O'kennedy, N., Söderholm, J. D., Rhodes, J. M., & Campbell, B.
J. (2010). Translocation of Crohn's disease Escherichia coli across M-cells: contrasting effects of
soluble plant fibres and emulsifiers. Gut, 59(10), 1331-1339.

[←312]
Castaldo, G., Galdo, G., Aufiero, F. R., & Cereda, E. (2016). Very low-calorie ketogenic diet may allow
restoring response to systemic therapy in relapsing plaque psoriasis. Obesity research & clinical
practice, 10(3), 348-352.

[←313]
O'Hearn, L. A. (2017). Ketogenic Diets, Caloric Restriction, and Hormones. Journal of Evolution and
Health, 2(3), 13.

[←314]
Jensen, P., Egeberg, A., Thyssen, J. P., Gislason, G., & Skov, L. (2017). Psoriatic Arthritis, but not
Psoriasis, is Associated with Primary Adrenal Insufficiency. Acta dermato-venereologica, 97(4), 519-
521.
Kebapcilar, L., Bilgir, O., Alacacioglu, A., Yildiz, Y., Taylan, A., Gunaydin, R., ... & Sari, I. (2010). Impaired
hypothalamo-pituitary-adrenal axis in patients with ankylosing spondylitis. Journal of
endocrinological investigation, 33(1), 42-47.
[←315]
Kossoff, E. H., Cervenka, M. C., Henry, B. J., Haney, C. A., & Turner, Z. (2013). A decade of the modified
Atkins diet (2003–2013): results, insights, and future directions. Epilepsy & Behavior, 29(3), 437-442.

[←316]
Kossoff, E. H., Cervenka, M. C., Henry, B. J., Haney, C. A., & Turner, Z. (2013). A decade of the modified
Atkins diet (2003–2013): results, insights, and future directions. Epilepsy & Behavior, 29(3), 437-442.

[←317]
Pendyala, S., Walker, J. M., & Holt, P. R. (2012). A high-fat diet is associated with endotoxemia that
originates from the gut. Gastroenterology, 142(5), 1100-1101.
Lyte, J. M., Gabler, N. K., & Hollis, J. H. (2016). Postprandial serum endotoxin in healthy humans is
modulated by dietary fat in a randomized, controlled, cross-over study. Lipids in health and
disease, 15(1), 186.
Cani, P. D., Amar, J., Iglesias, M. A., Poggi, M., Knauf, C., Bastelica, D., ... & Waget, A. (2007). Metabolic
endotoxemia initiates obesity and insulin resistance. Diabetes, 56(7), 1761-1772.
Cani, P. D., Bibiloni, R., Knauf, C., Waget, A., Neyrinck, A. M., Delzenne, N. M., & Burcelin, R. (2008).
Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet–
induced obesity and diabetes in mice. Diabetes, 57(6), 1470-1481.
Lam, Y. Y., Ha, C. W., Hoffmann, J., Oscarsson, J., Dinudom, A., Mather, T. J., ... & Storlien, L. H. (2015).
Effects of dietary fat profile on gut permeability and microbiota and their relationships with
metabolic changes in mice. Obesity, 23(7), 1429-1439.
Erridge, C., Attina, T., Spickett, C. M., & Webb, D. J. (2007). A high-fat meal induces low-grade
endotoxemia: evidence of a novel mechanism of postprandial inflammation–. The American journal
of clinical nutrition, 86(5), 1286-1292.
Moreira, A. P. B., Texeira, T. F. S., Ferreira, A. B., Peluzio, M. D. C. G., & Alfenas, R. D. C. G. (2012).
Influence of a high-fat diet on gut microbiota, intestinal permeability and metabolic
endotoxaemia. British Journal of Nutrition, 108(5), 801-809.
Serino, M., Luche, E., Gres, S., Baylac, A., Bergé, M., Cenac, C., ... & Mariette, J. (2012). Metabolic
adaptation to a high-fat diet is associated with a change in the gut microbiota. Gut, 61(4), 543-553.
Lyte, J. M., Gabler, N. K., & Hollis, J. H. (2016). Postprandial serum endotoxin in healthy humans is
modulated by dietary fat in a randomized, controlled, cross-over study. Lipids in health and
disease, 15(1), 186.

[←318]

 Chapter 6. Anti-inflammatory Fats and Oils

Estruch, R., Ros, E., Salas-Salvadó, J., Covas, M. I., Corella, D., Arós, F., ... & Lamuela-Raventos, R. M.
(2013). Primary prevention of cardiovascular disease with a Mediterranean diet. New England
Journal of Medicine, 368(14), 1279-1290.
Sofi, F., Abbate, R., Gensini, G. F., & Casini, A. (2010). Accruing evidence on benefits of adherence to
the Mediterranean diet on health: an updated systematic review and meta-analysis. The American
journal of clinical nutrition, 92(5), 1189-1196.
Schwingshackl, L., & Hoffmann, G. (2014). Adherence to Mediterranean diet and risk of cancer: A
systematic review and meta-analysis of observational studies. International journal of cancer,
135(8), 1884-1897.
Tresserra-Rimbau, A., Rimm, E. B., Medina-Remón, A., Martínez-González, M. A., López-Sabater, M. C.,
Covas, M. I., ... & Arós, F. (2014). Polyphenol intake and mortality risk: a re-analysis of the
PREDIMED trial. BMC medicine, 12(1), 77.
Martínez-González, M. Á., De la Fuente-Arrillaga, C., Nuñez-Cordoba, J. M., Basterra-Gortari, F. J.,
Beunza, J. J., Vazquez, Z., ... & Bes-Rastrollo, M. (2008). Adherence to Mediterranean diet and risk of
developing diabetes: prospective cohort study. Bmj, 336(7657), 1348-1351.

[←319]
Chrysohoou, C., Panagiotakos, D. B., Pitsavos, C., Das, U. N., & Stefanadis, C. (2004). Adherence to the
Mediterranean diet attenuates inflammation and coagulation process in healthy adults: The ATTICA
Study. Journal of the American College of Cardiology, 44(1), 152-158.
Richard, C., Couture, P., Desroches, S., & Lamarche, B. (2013). Effect of the Mediterranean diet with
and without weight loss on markers of inflammation in men with metabolic syndrome. Obesity,
21(1), 51-57.
Sköldstam, L., Hagfors, L., & Johansson, G. (2003). An experimental study of a Mediterranean diet
intervention for patients with rheumatoid arthritis. Annals of the rheumatic diseases, 62(3), 208-
214.

[←320]
Skoldstam, L., Hagfors, L., & Johansson, G. (2003). An experimental study of a Mediterranean diet
intervention for patients with rheumatoid arthritis. Annals of the Rheumatic Diseases, 62(3), 208–
214;
Abendroth, A., Michalsen, A., Luedtke, R., Rueffer, A., Musial, F., Dobos, G. J., & Langhorst, J. (2010).
Changes of intestinal microflora in patients with rheumatoid arthritis during fasting or a
Mediterranean diet. Forschende Komplementärmedizin/Research in Complementary Medicine,
17(6), 307-313;
McKellar, G., Morrison, E., McEntegart, A., Hampson, R., Tierney, A., Mackle, G., ... & Capell, H. A.
(2007). A pilot study of a Mediterranean-type diet intervention in female patients with rheumatoid
arthritis living in areas of social deprivation in Glasgow. Annals of the rheumatic diseases, 66(9),
1239-1243.
Preedy, V. R., & Watson, R. R. (Eds.). (2014). The Mediterranean Diet: An Evidence-Based Approach.
Academic press.
Barrea, L., Balato, N., Di Somma, C., Macchia, P. E., Napolitano, M., Savanelli, M. C., ... & Savastano, S.
(2015). Nutrition and psoriasis: is there any association between the severity of the disease and
adherence to the Mediterranean diet?. Journal of translational medicine, 13(1), 18.
[←321]
Barrea L., Balato N., Di Somma C., Macchia P.E., Napolitano M., Savanelli M.C., Esposito K., Colao A.,
Savastano S. Nutrition and psoriasis: Is there any association between the severity of the disease
and adherence to the Mediterranean diet? J. Transl. Med. 2015;13:18. doi: 10.1186/s12967-014-
0372-1.)
Hayashi, H., Satoi, K., Sato-Mito, N., Kaburagi, T., Yoshino, H., Higaki, M., ... & Sato, K. (2012).
Nutritional status in relation to adipokines and oxidative stress is associated with disease activity in
patients with rheumatoid arthritis. Nutrition, 28(11), 1109-1114.
Skoldstam, L., Hagfors, L., & Johansson, G. (2003). An experimental study of a Mediterranean diet
intervention for patients with rheumatoid arthritis. Annals of the Rheumatic Diseases, 62(3), 208–
214. http://doi.org/10.1136/ard.62.3.208
Guida, B., Napoleone, A., Trio, R., Nastasi, A., Balato, N., Laccetti, R., & Cataldi, M. (2014). Energy-
restricted, n-3 polyunsaturated fatty acids-rich diet improves the clinical response to immuno-
modulating drugs in obese patients with plaque-type psoriasis: a randomized control clinical trial.
Clinical Nutrition, 33(3), 399-405.
Hansen, G. V. O., Nielsen, L., Kluger, E., Thysen, M., Emmertsen, H., Stengaard-Pedersen, K., ... &
Andersen, P. W. (1996). Nutritional status of Danish rheumatoid arthritis patients and effects of a
diet adjusted in energy intake, fish-meal, and antioxidants. Scandinavian journal of rheumatology,
25(5), 325-333.

[←322]
Skoldstam, L., Hagfors, L., & Johansson, G. (2003). An experimental study of a Mediterranean diet
intervention for patients with rheumatoid arthritis. Annals of the Rheumatic Diseases, 62(3), 208–
214.

[←323]
Hagfors, L., Nilsson, I., Sköldstam, L., & Johansson, G. (2005). Fat intake and composition of fatty acids
in serum phospholipids in a randomized, controlled, Mediterranean dietary intervention study on
patients with rheumatoid arthritis. Nutrition & metabolism, 2(1), 26.

[←324]
Guida, B., Napoleone, A., Trio, R., Nastasi, A., Balato, N., Laccetti, R., & Cataldi, M. (2014). Energy-
restricted, n-3 polyunsaturated fatty acids-rich diet improves the clinical response to immuno-
modulating drugs in obese patients with plaque-type psoriasis: a randomized control clinical trial.
Clinical Nutrition, 33(3), 399-405.

[←325]
Barrea, L., Balato, N., Di Somma, C., Macchia, P. E., Napolitano, M., Savanelli, M. C., ... & Savastano, S.
(2015). Nutrition and psoriasis: is there any association between the severity of the disease and
adherence to the Mediterranean diet?. Journal of translational medicine, 13(1), 18.

[←326]
Miles, E. A., & Calder, P. C. (2012). Influence of marine n-3 polyunsaturated fatty acids on immune
function and a systematic review of their effects on clinical outcomes in rheumatoid arthritis. British
Journal of Nutrition, 107(S2), S171-S184.
van den Elsen, L. W., Nusse, Y., Balvers, M., Redegeld, F. A., Knol, E. F., Garssen, J., & Willemsen, L. E.
 (2013). n-3 Long-chain PUFA reduce allergy-related mediator release by human mast cells in vitro
via inhibition of reactive oxygen species. British Journal of Nutrition, 109(10), 1821-1831;
Murata, M., Kaneniwa, M., Saito, H., Shinohara, K., Maeda-Yamamoto, M., ... & Ooizumi, T. (1998).
Effect of tetracosahexaenoic acid on the content and release of histamine, and eicosanoid
production in MC/9 mouse mast cell. Lipids, 33(11), 1107-1114
Liu, Y., Chen, F., Odle, J., Lin, X., Jacobi, S. K., Zhu, H., ... & Hou, Y. (2012). Fish oil enhances intestinal
integrity and inhibits TLR4 and NOD2 signaling pathways in weaned pigs after LPS challenge. The
Journal of nutrition, 142(11), 2017-2024.

[←327]
Berbert, A. A., Kondo, C. R. M., Almendra, C. L., Matsuo, T., & Dichi, I. (2005). Supplementation of fish
oil and olive oil in patients with rheumatoid arthritis. Nutrition, 21(2), 131-136.
Beauchamp, G. K., Keast, R. S., Morel, D., Lin, J., Pika, J., Han, Q., ... & Breslin, P. A. (2005).
Phytochemistry: ibuprofen-like activity in extra-virgin olive oil. Nature, 437(7055), 45-46.

[←328]
Bogani, P., Galli, C., Villa, M., & Visioli, F. (2007). Postprandial anti-inflammatory and antioxidant effects
of extra virgin olive oil. Atherosclerosis, 190(1), 181-186.

[←329]
Kremer, J. M., Lawrence, D. A., Jubiz, W., Digiacomo, R., Rynes, R., Bartholomew, L. E., & Sherman, M.
(1990). Dietary fish oil and olive oil supplementation in patients with Rheumatoid Arthritis clinical
and immunologic effects. Arthritis & Rheumatology, 33(6), 810-820.

[←330]
Kremer, J. M., Lawrence, D. A., Jubiz, W., Digiacomo, R., Rynes, R., Bartholomew, L. E., & Sherman, M.
(1990). Dietary fish oil and olive oil supplementation in patients with Rheumatoid Arthritis clinical
and immunologic effects. Arthritis & Rheumatology, 33(6), 810-820.

[←331]
Berbert, A. A., Kondo, C. R. M., Almendra, C. L., Matsuo, T., & Dichi, I. (2005). Supplementation of fish
oil and olive oil in patients with rheumatoid arthritis. Nutrition, 21(2), 131-136.

[←332]
Adam, O., Beringer, C., Kless, T., Lemmen, C., Adam, A., Wiseman, M., ... & Forth, W. (2003). Anti-
inflammatory effects of a low arachidonic acid diet and fish oil in patients with rheumatoid arthritis.
Rheumatology international, 23(1), 27-36.

[←333]
Gerster, H. (1998). Can adults adequately convert a-linolenic acid (18: 3n-3) to eicosapentaenoic acid
(20: 5n-3) and docosahexaenoic acid (22: 6n-3)?. International Journal for Vitamin and Nutrition
Research, 68(3), 159-173.
Lane, K., Derbyshire, E., Li, W., & Brennan, C. (2014). Bioavailability and potential uses of vegetarian
sources of omega-3 fatty acids: a review of the literature. Critical reviews in food science and
nutrition, 54(5), 572-579.
[←334]
Karimi, R., Fitzgerald, T. P., & Fisher, N. S. (2012). A quantitative synthesis of mercury in commercial
seafood and implications for exposure in the United States. Environmental health perspectives,
120(11), 1512. Supplemental Material. Available at
http://www.stonybrook.edu/commcms/gelfond/docs/Seafood%20Mercury%20Database.pdf
USDA data, available at
https://health.gov/dietaryguidelines/dga2005/report/html/table_g2_adda2.htm

[←335]
Blanchet, C., Lucas, M., Julien, P., Morin, R., Gingras, S., & Dewailly, É. (2005). Fatty acid composition of
wild and farmed Atlantic salmon (Salmo salar) and rainbow trout (Oncorhynchus mykiss). Lipids,
40(5), 529-531.

[←336]
Ponnampalam, E. N., Mann, N. J., & Sinclair, A. J. (2006). Effect of feeding systems on omega-3 fatty
acids, conjugated linoleic acid and trans fatty acids in Australian beef cuts: potential impact on
human health. Asia Pacific Journal of Clinical Nutrition, 15(1), 21.
Daley, C. A., Abbott, A., Doyle, P. S., Nader, G. A., & Larson, S. (2010). A review of fatty acid profiles and
antioxidant content in grass-fed and grain-fed beef. Nutrition journal, 9(1), 10.

[←337]
Senftleber, N. K., Nielsen, S. M., Andersen, J. R., Bliddal, H., Tarp, S., Lauritzen, L., ... & Christensen, R.
(2017). Marine Oil Supplements for Arthritis Pain: A Systematic Review and Meta-Analysis of
Randomized Trials. Nutrients, 9(1), 42.

[←338]
Millsop, J. W., Bhatia, B. K., Debbaneh, M., Koo, J., & Liao, W. (2014). Diet and psoriasis, part III: role of
nutritional supplements. Journal of the American Academy of Dermatology, 71(3), 561-569.

[←339]
Miles, E. A., & Calder, P. C. (2012). Influence of marine n-3 polyunsaturated fatty acids on immune
function and a systematic review of their effects on clinical outcomes in rheumatoid arthritis. British
Journal of Nutrition, 107(S2), S171-S184.

[←340]
Sundström, B., Stålnacke, K., Hagfors, L., & Johansson, G. (2006). Supplementation of omega-3 fatty
acids in patients with ankylosing spondylitis. Scandinavian journal of rheumatology, 35(5), 359-362.

[←341]
Belluzzi, A., Brignola, C., Campieri, M., Pera, A., Boschi, S., & Miglioli, M. (1996). Effect of an enteric-
coated fish-oil preparation on relapses in Crohn's disease. New England Journal of Medicine,
334(24), 1557-1560.

[←342]
 Gheita, T., Kamel, S., Helmy, N., El-Laithy, N., & Monir, A. (2012). Omega-3 fatty acids in juvenile
idiopathic arthritis: effect on cytokines (IL-1 and TNF-α), disease activity and response criteria.
Clinical rheumatology, 31(2), 363-366.

[←343]
Paoli, A., Moro, T., Bosco, G., Bianco, A., Grimaldi, K. A., Camporesi, E., & Mangar, D. (2015). Effects of
n-3 polyunsaturated fatty acids (ω-3) supplementation on some cardiovascular risk factors with a
ketogenic Mediterranean diet. Marine drugs, 13(2), 996-1009.

[←344]
Endres, S., Ghorbani, R., Kelley, V. E., Georgilis, K., Lonnemann, G., van der Meer, J. W., ... & Schaefer,
E. J. (1989). The effect of dietary supplementation with n—3 polyunsaturated fatty acids on the
synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. New England Journal of
Medicine, 320(5), 265-271.

[←345]
Albert, B. B., Cameron-Smith, D., Hofman, P. L., & Cutfield, W. S. (2013). Oxidation of marine omega-3
supplements and human health. BioMed research international, 2013.

[←346]
Albert, B. B., Cameron-Smith, D., Hofman, P. L., & Cutfield, W. S. (2013). Oxidation of marine omega-3
supplements and human health. BioMed research international, 2013;
Albert, B. B., Derraik, J. G., Cameron-Smith, D., Hofman, P. L., Tumanov, S., Villas-Boas, S. G., ... &
Cutfield, W. S. (2015). Fish oil supplements in New Zealand are highly oxidised and do not meet
label content of n-3 PUFA. Scientific reports, 5, 7928.

[←347]
Albert, B. B., Cameron-Smith, D., Hofman, P. L., & Cutfield, W. S. (2013). Oxidation of marine omega-3
supplements and human health. BioMed research international, 2013;
Albert, B. B., Derraik, J. G., Cameron-Smith, D., Hofman, P. L., Tumanov, S., Villas-Boas, S. G., ... &
Cutfield, W. S. (2015). Fish oil supplements in New Zealand are highly oxidised and do not meet
label content of n-3 PUFA. Scientific reports, 5, 7928.

[←348]
Senftleber, N. K., Nielsen, S. M., Andersen, J. R., Bliddal, H., Tarp, S., Lauritzen, L., ... & Christensen, R.
(2017). Marine Oil Supplements for Arthritis Pain: A Systematic Review and Meta-Analysis of
Randomized Trials. Nutrients, 9(1), 42.
Millsop, J. W., Bhatia, B. K., Debbaneh, M., Koo, J., & Liao, W. (2014). Diet and psoriasis, part III: role of
nutritional supplements. Journal of the American Academy of Dermatology, 71(3), 561-569

[←349]
Halvorsen, B. L., & Blomhoff, R. (2011). Determination of lipid oxidation products in vegetable oils and
marine omega-3 supplements. Food & nutrition research, 55.

[←350]
 Kragballe, K., & Fogh, K. (1988). A low-fat diet supplemented with dietary fish oil (Max-EPA) results in
improvement of psoriasis and in formation of leukotriene B5. Acta dermato-venereologica, 69(1),
23-28.

[←351]
Proudman, S. M., James, M. J., Spargo, L. D., Metcalf, R. G., Sullivan, T. R., Rischmueller, M., ... &
Cleland, L. G. (2013). Fish oil in recent onset rheumatoid arthritis: a randomised, double-blind
controlled trial within algorithm-based drug use. Annals of the rheumatic diseases, annrheumdis-
2013.

[←352]
Cleland, L. G., James, M. J., & Proudman, S. M. (2005). Fish oil: what the prescriber needs to know.
Arthritis research & therapy, 8(1), 202.

[←353]
Gheita, T., Kamel, S., Helmy, N., El-Laithy, N., & Monir, A. (2012). Omega-3 fatty acids in juvenile
idiopathic arthritis: effect on cytokines (IL-1 and TNF-α), disease activity and response criteria.
Clinical rheumatology, 31(2), 363-366.

[←354]
Halvorsen, B. L., & Blomhoff, R. (2011). Determination of lipid oxidation products in vegetable oils and
marine omega-3 supplements. Food & nutrition research, 55.

[←355]
Jackowski, S. A., Alvi, A. Z., Mirajkar, A., Imani, Z., Gamalevych, Y., Shaikh, N. A., & Jackowski, G. (2015).
Oxidation levels of North American over-the-counter n-3 (omega-3) supplements and the influence
of supplement formulation and delivery form on evaluating oxidative safety. Journal of nutritional
science, 4, e30.

[←356]
Jackowski, S. A., Alvi, A. Z., Mirajkar, A., Imani, Z., Gamalevych, Y., Shaikh, N. A., & Jackowski, G. (2015).
Oxidation levels of North American over-the-counter n-3 (omega-3) supplements and the influence
of supplement formulation and delivery form on evaluating oxidative safety. Journal of nutritional
science, 4, e30.

[←357]
Dyerberg, J., Madsen, P., Møller, J. M., Aardestrup, I., & Schmidt, E. B. (2010). Bioavailability of marine
n-3 fatty acid formulations. Prostaglandins, Leukotrienes and Essential Fatty Acids, 83(3), 137-141.

[←358]
Eritsland, J. (2000). Safety considerations of polyunsaturated fatty acids. The American journal of
clinical nutrition, 71(1), 197S-201S.

[←359]
 http://olivecenter.ucdavis.edu/research/files/oliveoilfinal071410updated.pdf

[←360]
Silva, L., Pinto, J., Carrola, J., & Paiva-Martins, F. (2010). Oxidative stability of olive oil after food
processing and comparison with other vegetable oils. Food Chemistry, 121(4), 1177-1187;
Casal, S., Malheiro, R., Sendas, A., Oliveira, B. P., & Pereira, J. A. (2010). Olive oil stability under deep-
frying conditions. Food and chemical toxicology, 48(10), 2972-2979.

[←361]
Berasategi, I., Barriuso, B., Ansorena, D., & Astiasarán, I. (2012). Stability of avocado oil during heating:
Comparative study to olive oil. Food Chemistry, 132(1), 439-446.
Werman, M. J., & Neeman, I. (1986). Oxidative stability of avocado oil. Journal of the American Oil
Chemists’ Society, 63(3), 355-360.

[←362]
Frankel EN, Smith LM, Hamblin CL, Creveling RK, Clifford AJ. Occurrence of cyclic fatty acid monomers
in frying oils used for fast foods. J Am Oil Chem Soc. 1984;61:87-90.
Koski, A., Psomiadou, E., Tsimidou, M., Hopia, A., Kefalas, P., Wähälä, K., & Heinonen, M. (2002).
Oxidative stability and minor constituents of virgin olive oil and cold-pressed rapeseed oil. European
Food Research and Technology, 214(4), 294-298.
Halvorsen, B. L., & Blomhoff, R. (2011). Determination of lipid oxidation products in vegetable oils and
marine omega-3 supplements. Food & nutrition research, 55.

[←363]
Halvorsen, B. L., & Blomhoff, R. (2011). Determination of lipid oxidation products in vegetable oils and
marine omega-3 supplements. Food & nutrition research, 55.

[←364]
Chen, C., & Khismatullin, D. B. (2015). Oxidized low-density lipoprotein contributes to atherogenesis via
co-activation of macrophages and mast cells. PloS one, 10(3), e0123088;
Meng, Z., Yan, C., Deng, Q., Dong, X., Duan, Z. M., Gao, D. F., & Niu, X. L. (2013). Oxidized low-density
lipoprotein induces inflammatory responses in cultured human mast cells via Toll-like receptor 4.
Cellular Physiology and Biochemistry, 31(6), 842-853;
Shaik-Dasthagirisaheb, Y. B., Varvara, G., Murmura, G., Saggini, A., Caraffa, A., Antinolfi, P., ... &
Toniato, E. (2012). Role of vitamins D, E and C in immunity and inflammation. Journal of biological
regulators and homeostatic agents, 27(2), 291-295.
Kanner, J. (2007). Dietary advanced lipid oxidation endproducts are risk factors to human health.
Molecular nutrition & food research, 51(9), 1094-1101.
Staprans I, Rapp JH, Pan XM, Kim KY, Feingold KR. Oxidized lipids in the diet are a source of oxidized
lipid in chylomicrons of human serum. Arterioscler Thromb. 1994;14:1900-1905.

[←365]
Halvorsen, B. L., & Blomhoff, R. (2011). Determination of lipid oxidation products in vegetable oils and
marine omega-3 supplements. Food & nutrition research, 55.
[←366]
Frankel EN, Smith LM, Hamblin CL, Creveling RK, Clifford AJ. Occurrence of cyclic fatty acid monomers
in frying oils used for fast foods. J Am Oil Chem Soc. 1984;61:87-90.
Koski, A., Psomiadou, E., Tsimidou, M., Hopia, A., Kefalas, P., Wähälä, K., & Heinonen, M. (2002).
Oxidative stability and minor constituents of virgin olive oil and cold-pressed rapeseed oil. European
Food Research and Technology, 214(4), 294-298.
Halvorsen, B. L., & Blomhoff, R. (2011). Determination of lipid oxidation products in vegetable oils and
marine omega-3 supplements. Food & nutrition research, 55.

[←367]
Mozaffarian, D., Aro, A., & Willett, W. C. (2009). Health effects of trans-fatty acids: experimental and
observational evidence. European journal of clinical nutrition, 63, S5-S21.
Kanner, J. (2007). Dietary advanced lipid oxidation endproducts are risk factors to human health.
Molecular nutrition & food research, 51(9), 1094-1101.

[←368]
Kochhar, S. P., & Henry, C. J. K. (2009). Oxidative stability and shelf-life evaluation of selected culinary
oils. International journal of food sciences and nutrition, 60(sup7), 289-296.

[←369]
Ramsden, C. E., Zamora, D., Majchrzak-Hong, S., Faurot, K. R., Broste, S. K., Frantz, R. P., ... & Hibbeln, J.
R. (2016). Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from
Minnesota Coronary Experiment (1968-73). bmj, 353, i1246;
Siri-Tarino, P. W., Sun, Q., Hu, F. B., & Krauss, R. M. (2010). Meta-analysis of prospective cohort studies
evaluating the association of saturated fat with cardiovascular disease. The American journal of
clinical nutrition, ajcn-27725.

[←370]
Dumas, J. A., Bunn, J. Y., Nickerson, J., Crain, K. I., Ebenstein, D. B., Tarleton, E. K., ... & Kien, C. L.
(2016). Dietary saturated fat and monounsaturated fat have reversible effects on brain function and
the secretion of pro-inflammatory cytokines in young women. Metabolism, 65(10), 1582-1588.

[←371]
Kien, C. L., Bunn, J. Y., Fukagawa, N. K., Anathy, V., Matthews, D. E., Crain, K. I., ... & Poynter, M. E.
(2015). Lipidomic evidence that lowering the typical dietary palmitate to oleate ratio in humans
decreases the leukocyte production of proinflammatory cytokines and muscle expression of redox-
sensitive genes. The Journal of nutritional biochemistry, 26(12), 1599-1606.

[←372]
Rocha, D. M., Caldas, A. P., Oliveira, L. L., Bressan, J., & Hermsdorff, H. H. (2016). Saturated fatty acids
trigger TLR4-mediated inflammatory response. Atherosclerosis, 244, 211-215.
Snodgrass, R. G., Huang, S., Choi, I. W., Rutledge, J. C., & Hwang, D. H. (2013). Inflammasome-mediated
secretion of IL-1β in human monocytes through TLR2 activation; modulation by dietary fatty acids.
The Journal of Immunology, 191(8), 4337-4347.
Robblee, M. M., Kim, C. C., Abate, J. P., Valdearcos, M., Sandlund, K. L., Shenoy, M. K., ... & Koliwad, S.
 K. (2016). Saturated fatty acids engage an IRE1α-dependent pathway to activate the NLRP3
inflammasome in myeloid cells. Cell reports, 14(11), 2611-2623.

[←373]
Reynolds, C. M., McGillicuddy, F. C., Harford, K. A., Finucane, O. M., Mills, K. H., & Roche, H. M. (2012).
Dietary saturated fatty acids prime the NLRP3 inflammasome via TLR4 in dendritic cells—
implications for diet-induced insulin resistance. Molecular nutrition & food research, 56(8), 1212-
1222.

[←374]
Kien, C. L., Bunn, J. Y., Fukagawa, N. K., Anathy, V., Matthews, D. E., Crain, K. I., ... & Poynter, M. E.
(2015). Lipidomic evidence that lowering the typical dietary palmitate to oleate ratio in humans
decreases the leukocyte production of proinflammatory cytokines and muscle expression of redox-
sensitive genes. The Journal of nutritional biochemistry, 26(12), 1599-1606.

[←375]
Soto-Vaca, A., Losso, J. N., McDonough, K., & Finley, J. W. (2013). Differential effect of 14 free fatty
acids in the expression of inflammation markers on human arterial coronary cells. Journal of
agricultural and food chemistry, 61(42), 10074-10079.

[←376]
Yang, X., Haghiac, M., Glazebrook, P., Minium, J., Catalano, P. M., & Hauguel-de Mouzon, S. (2015).
Saturated fatty acids enhance TLR4 immune pathways in human trophoblasts. Human
Reproduction, dev173.

[←377]
Gupta, S., Knight, A. G., Gupta, S., Keller, J. N., & Bruce-Keller, A. J. (2012). Saturated long-chain fatty
acids activate inflammatory signaling in astrocytes. Journal of neurochemistry, 120(6), 1060-1071.

[←378]
Gupta, S., Knight, A. G., Gupta, S., Keller, J. N., & Bruce-Keller, A. J. (2012). Saturated long-chain fatty
acids activate inflammatory signaling in astrocytes. Journal of neurochemistry, 120(6), 1060-1071.
Håversen, Liliana, et al. "Induction of proinflammatory cytokines by long-chain saturated fatty acids in
human macrophages." Atherosclerosis 202.2 (2009): 382-393.
Soto-Vaca, A., Losso, J. N., McDonough, K., & Finley, J. W. (2013). Differential effect of 14 free fatty
acids in the expression of inflammation markers on human arterial coronary cells. Journal of
agricultural and food chemistry, 61(42), 10074-10079.

[←379]
Soto-Vaca, A., Losso, J. N., McDonough, K., & Finley, J. W. (2013). Differential effect of 14 free fatty
acids in the expression of inflammation markers on human arterial coronary cells. Journal of
agricultural and food chemistry, 61(42), 10074-10079;
Huang, S., Rutkowsky, J. M., Snodgrass, R. G., Ono-Moore, K. D., Schneider, D. A., Newman, J. W., ... &
Hwang, D. H. (2012). Saturated fatty acids activate TLR-mediated proinflammatory signaling
pathways. Journal of lipid research, 53(9), 2002-2013.
[←380]
Lyte, J. M., Gabler, N. K., & Hollis, J. H. (2016). Postprandial serum endotoxin in healthy humans is
modulated by dietary fat in a randomized, controlled, cross-over study. Lipids in Health and Disease,
15(1), 186.

[←381]
Lyte, J. M., Gabler, N. K., & Hollis, J. H. (2016). Postprandial serum endotoxin in healthy humans is
modulated by dietary fat in a randomized, controlled, cross-over study. Lipids in Health and Disease,
15(1), 186.

[←382]
Mani, V., Hollis, J. H., & Gabler, N. K. (2013). Dietary oil composition differentially modulates intestinal
endotoxin transport and postprandial endotoxemia. Nutrition & metabolism, 10(1), 6.

[←383]
Mani, V., Hollis, J. H., & Gabler, N. K. (2013). Dietary oil composition differentially modulates intestinal
endotoxin transport and postprandial endotoxemia. Nutrition & metabolism, 10(1), 6.

[←384]
Johnson, G. H., & Fritsche, K. (2012). Effect of dietary linoleic acid on markers of inflammation in
healthy persons: a systematic review of randomized controlled trials. Journal of the Academy of
Nutrition and Dietetics, 112(7), 1029-1041;
Pischon, T., Hankinson, S. E., Hotamisligil, G. S., Rifai, N., Willett, W. C., & Rimm, E. B. (2003). Habitual
dietary intake of n-3 and n-6 fatty acids in relation to inflammatory markers among US men and
women. Circulation, 108(2), 155-160

[←385]
Liou, Y. A., & Innis, S. M. (2009). Dietary linoleic acid has no effect on arachidonic acid, but increases n-
6 eicosadienoic acid, and lowers dihomo-γ-linolenic and eicosapentaenoic acid in plasma of adult
men. Prostaglandins, Leukotrienes and Essential Fatty Acids, 80(4), 201-206.
Liou, Y. A., King, D. J., Zibrik, D., & Innis, S. M. (2007). Decreasing linoleic acid with constant α-linolenic
acid in dietary fats increases (n-3) eicosapentaenoic acid in plasma phospholipids in healthy men.
The Journal of nutrition, 137(4), 945-952.

[←386]
Millsop, J. W., Bhatia, B. K., Debbaneh, M., Koo, J., & Liao, W. (2014). Diet and psoriasis, part III: role of
nutritional supplements. Journal of the American Academy of Dermatology, 71(3), 561-569.

[←387]
Sköldstam, L., Larsson, L., & Lindström, F. D. (1979). Effects of fasting and lactovegetarian diet on
rheumatoid arthritis. Scandinavian journal of rheumatology, 8(4), 249-255.
Hafstrom I, Ringertz B, Spangberg A, von Zweigbergk L, Brannemark S, Nylander I, et al. A vegan diet
free of gluten improves the signs and symptoms of rheumatoid arthritis: the effects on arthritis
correlate with a reduction in antibodies to food antigens. Rheumatology 2001; 40:1175-9.
[←388]
Hafstorm.

[←389]
Adam, O., Beringer, C., Kless, T., Lemmen, C., Adam, A., Wiseman, M., ... & Forth, W. (2003). Anti-
inflammatory effects of a low arachidonic acid diet and fish oil in patients with rheumatoid arthritis.
Rheumatology international, 23(1), 27-36.

[←390]
Adam, O., Beringer, C., Kless, T., Lemmen, C., Adam, A., Wiseman, M., ... & Forth, W. (2003). Anti-
inflammatory effects of a low arachidonic acid diet and fish oil in patients with rheumatoid arthritis.
Rheumatology international, 23(1), 27-36.

[←391]

Chapter 7. Troubleshooting and Customizing the Keystone
Diet

Williams, R. (1981). Rheumatoid arthritis and food: a case study. British medical journal (Clinical
research ed.), 283(6290), 563.

[←392]
Beri, D., Malaviya, A. N., Shandilya, R., & Singh, R. R. (1988). Effect of dietary restrictions on disease
activity in rheumatoid arthritis. Annals of the Rheumatic Diseases, 47(1), 69–72.
Williams, R. (1981). Rheumatoid arthritis and food: a case study. British medical journal (Clinical
research ed.), 283(6290), 563.
Pacor, M. L., Lunardi, C., Di Lorenzo, G., Biasi, D., & Corrocher, R. (2001). Food allergy and seronegative
arthritis: report of two cases. Clinical rheumatology, 20(4), 279-281.
Parke, A. L., & Hughes, G. R. V. (1981). Rheumatoid arthritis and food: a case study. Br Med J (Clin Res
Ed), 282(6281), 2027-2029.
Hvatum, M., Kanerud, L., Hällgren, R., & Brandtzaeg, P. (2006). The gut–joint axis: cross reactive food
antibodies in rheumatoid arthritis. Gut, 55(9), 1240-1247.

[←393]
Ratner, D., Vigder, K., & Eshel, E. (1985). Juvenile rheumatoid arthritis and milk allergy. Journal of the
Royal Society of Medicine, 78(5), 410-413.
Schrander, J. J., Marcelis, C., De Vries, M. P., & van Santen-Hoeufft, H. M. (1997). Does food intolerance
play a role in juvenile chronic arthritis?. Rheumatology, 36(8), 905-908.

[←394]
Appelboom, T., & Durez, P. (1994). Effect of milk product deprivation on spondyloarthropathy. Annals
of the Rheumatic Diseases, 53(7), 481–482.

[←395]
 Van de Laar, M. A., Aalbers, M., Bruins, F. G., van Dinther-Janssen, A. C., Van Der Korst, J. K., & Meijer,
C. J. (1992). Food intolerance in rheumatoid arthritis. II. Clinical and histological aspects. Annals of
the rheumatic diseases, 51(3), 303-306

[←396]
Hvatum, M., Kanerud, L., Hällgren, R., & Brandtzaeg, P. (2006). The gut–joint axis: cross reactive food
antibodies in rheumatoid arthritis. Gut, 55(9), 1240-1247.

[←397]
Panush, R. S., Stroud, R. M., & Webster, E. M. (1986). Food-induced (allergic) arthritis. Inflammatory
arthritis exacerbated by milk. Arthritis & Rheumatism, 29(2), 220-226.

[←398]
Titchenal, C. A., & Dobbs, J. (2007). A system to assess the quality of food sources of calcium. Journal of
Food Composition and Analysis, 20(8), 717-724;
Wien, E. M., & Schwartz, R. (1983). Comparison of in vitro and in vivo measurements of dietary Ca
exchangeability and bioavailability. The Journal of nutrition, 113(2), 388-393.

[←399]
Rodríguez del Río, P., Sánchez-García, S., Escudero, C., Pastor-Vargas, C., Sánchez Hernández, J. J.,
Pérez-Rangel, I., & Ibáñez, M. D. (2012). Allergy to goat’s and sheep’s milk in a population of cow’s
milk–allergic children treated with oral immunotherapy. Pediatric Allergy and Immunology, 23(2),
128-132.

[←400]

Hodge, L., Swain, A., & Faulkner-Hogg, K. (2009). Food allergy and intolerance. Australian family
physician, 38(9), 705.

[←401]
Malakar, S., Gibson, P. R., Barrett, J. S., & Muir, J. G. (2017). Naturally occurring dietary salicylates: A
closer look at common Australian foods. Journal of Food Composition and Analysis, 57, 31-39.

[←402]
Swain, A. R., Soutter, V. L., & Loblay, R. H. (2011). RPAH elimination diet handbook: with food &
shopping guide. Allergy Unit, Royal Prince Alfred Hospital.

[←403]
Swain, A. R., Dutton, S. P., & Truswell, A. S. (1985). Salicylates in foods. J Am Diet Assoc, 85(8), 950-60.
Hodge, L., Swain, A., & Faulkner-Hogg, K. (2009). Food allergy and intolerance. Australian family
physician, 38(9), 705.

[←404]
Skypala, I. J., Williams, M., Reeves, L., Meyer, R., & Venter, C. (2015). Sensitivity to food additives, vaso-
 active amines and salicylates: a review of the evidence. Clinical and translational allergy, 5(1), 34.

[←405]
Swain, A. R., Soutter, V. L., & Loblay, R. H. (2011). RPAH elimination diet handbook: with food &
shopping guide. Allergy Unit, Royal Prince Alfred Hospital.

[←406]
http://www.fedup.com.au/images/stories/SCarthritis.pdf

[←407]
Panush, R. S., Carter, R. L., Katz, P., Kowsari, B., Longley, S., & Finnie, S. (1983). Diet therapy for
rheumatoid arthritis. Arthritis & Rheumatology, 26(4), 462-471.

[←408]
Jemima, E. A., Prema, A., & Thangam, E. B. (2014). Functional characterization of histamine H4 receptor
on human mast cells. Molecular immunology, 62(1), 19-28.
Steinke, J. W., Negri, J., Liu, L., Payne, S. C., & Borish, L. (2014). Aspirin activation of eosinophils and
mast cells: implications in the pathogenesis of aspirin-exacerbated respiratory disease. The Journal
of Immunology, 193(1), 41-47.
Mita, H., Endoh, S., Kudoh, M., Kawagishi, Y., Kobayashi, M., Taniguchi, M., & Akiyama, K. (2001).
Possible involvement of mast-cell activation in aspirin provocation of aspirin-induced asthma.
Allergy, 56(11), 1061-1067.
O’Sullivan, S., Dahlén, B., Dahlén, S. E., & Kumlin, M. (1996). Increased urinary excretion of the
prostaglandin D 2 metabolite 9α, 11β-prostaglandin F 2 after aspirin challenge supports mast cell
activation in aspirin-induced airway obstruction. Journal of Allergy and Clinical Immunology, 98(2),
421-432.
Togo, K., Suzuki, Y., Yoshimaru, T., Inoue, T., Terui, T., Ochiai, T., & Ra, C. (2009). Aspirin and salicylates
modulate IgE-mediated leukotriene secretion in mast cells through a dihydropyridine receptor-
mediated Ca 2+ influx. Clinical Immunology, 131(1), 145-156.

[←409]
Noordenbos, T., Yeremenko, N., Gofita, I., van de Sande, M., Tak, P. P., Caňete, J. D., & Baeten, D.
(2012). Interleukin-17–positive mast cells contribute to synovial inflammation in spondylarthritis.
Arthritis & Rheumatism, 64(1), 99-109.
Keijsers, R. R., Joosten, I., Erp, P. E., Koenen, H. J., & Kerkhof, P. (2014). Cellular sources of IL-17 in
psoriasis: a paradigm shift?. Experimental dermatology, 23(11), 799-803.
Lin, A. M., Rubin, C. J., Khandpur, R., Wang, J. Y., Riblett, M., Yalavarthi, S., ... & Bruce, A. T. (2011).
Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis. The
Journal of Immunology, 187(1), 490-500.
Hueber, A. J., Asquith, D. L., Miller, A. M., Reilly, J., Kerr, S., Leipe, J., ... & McInnes, I. B. (2010). Cutting
edge: mast cells express IL-17A in rheumatoid arthritis synovium. The Journal of Immunology,
184(7), 3336-3340.
Shin, K., Nigrovic, P. A., Crish, J., Boilard, E., McNeil, H. P., Larabee, K. S., ... & Lee, D. M. (2009). Mast
cells contribute to autoimmune inflammatory arthritis via their tryptase/heparin complexes. The
Journal of Immunology, 182(1), 647-656.
Henderson, W. R. (1994). The role of leukotrienes in inflammation. Annals of internal medicine, 121(9),
 684-697.

[←410]
Barcik, W., Pugin, B., Westermann, P., Perez, N. R., Ferstl, R., Wawrzyniak, M., ... & Akdis, C. A. (2016).
Histamine-secreting microbes are increased in the gut of adult asthma patients. Journal of Allergy
and Clinical Immunology, 138(5), 1491-1494.
Özoğul, F. (2004). Production of biogenic amines by Morganella morganii, Klebsiella pneumoniae and
Hafnia alvei using a rapid HPLC method. European Food Research and Technology, 219(5), 465-469.
Pugin, B., Barcik, W., Westermann, P., Heider, A., Wawrzyniak, M., Hellings, P., ... & O’Mahony, L.
(2017). A wide diversity of bacteria from the human gut produces and degrades biogenic
amines. Microbial ecology in health and disease, 28(1), 1353881.

[←411]
Johnston, C. S., Retrum, K. R., & Srilakshmi, J. C. (1992). Antihistamine effects and complications of
supplemental vitamin C. Journal of the American Dietetic Association (USA).
Bucca, C., Rolla, G., Oliva, A., & Farina, J. C. (1990). Effect of vitamin C on histamine bronchial
responsiveness of patients with allergic rhinitis. Annals of allergy, 65(4), 311-314.

[←412]
Healy, E., Newell, L., Howarth, P., & Friedmann, P. S. (2008). Control of salicylate intolerance with fish
oils. British Journal of Dermatology, 159(6), 1368-1369.

[←413]
http://www.noarthritis.com/nightshades.htm

[←414]
Afifi, L., Danesh, M. J., Lee, K. M., Beroukhim, K., Farahnik, B., Ahn, R. S., ... & Liao, W. (2017). Dietary
behaviors in psoriasis: patient-reported outcomes from a US National Survey. Dermatology and
therapy, 7(2), 227-242.

[←415]
Cantwell, M. (1996). A review of important facts about potato glycoalkaloids. Perishables Handling
Newsletter, 87, 26-27.

[←416]
Patel, B., Schutte, R., Sporns, P., Doyle, J., Jewel, L., & Fedorak, R. N. (2002). Potato glycoalkaloids
adversely affect intestinal permeability and aggravate inflammatory bowel disease. Inflammatory
bowel diseases, 8(5), 340-346.
Hashimoto, K., Kawagishi, H., Nakayama, T., & Shimizu, M. (1997). Effect of capsianoside, a diterpene
glycoside, on tight-junctional permeability. Biochimica et Biophysica Acta (BBA)-Biomembranes,
1323(2), 281-290.

[←417]
Patel, B., Schutte, R., Sporns, P., Doyle, J., Jewel, L., & Fedorak, R. N. (2002). Potato glycoalkaloids
adversely affect intestinal permeability and aggravate inflammatory bowel disease. Inflammatory
 bowel diseases, 8(5), 340-346.

[←418]
Hashimoto, K., Kawagishi, H., Nakayama, T., & Shimizu, M. (1997). Effect of capsianoside, a diterpene
glycoside, on tight-junctional permeability. Biochimica et Biophysica Acta (BBA)-Biomembranes,
1323(2), 281-290.

[←419]
Jensen-Jarolim, E., Gajdzik, L., Haberl, I., Kraft, D., Scheiner, O., & Graf, J. (1998). Hot spices influence
permeability of human intestinal epithelial monolayers. The Journal of nutrition, 128(3), 577-581.
Isoda, H., Han, J., Tominaga, M., & Maekawa, T. (2001). Effects of capsaicin on human intestinal cell
line Caco-2. Cytotechnology, 36(1-3), 155-161;
Tsukura, Y., Mori, M., Hirotani, Y., Ikeda, K., Amano, F., Kato, R., ... & Tanaka, K. (2007). Effects of
capsaicin on cellular damage and monolayer permeability in human intestinal Caco-2 cells.
Biological and Pharmaceutical Bulletin, 30(10), 1982-1986.

[←420]
Nachbar, M. S., & Oppenheim, J. D. (1980). Lectins in the United States diet: a survey of lectins in
commonly consumed foods and a review of the literature. The American journal of clinical nutrition,
33(11), 2338-2345;
Pramod, S. N., Venkatesh, Y. P., & Mahesh, P. A. (2007). Potato lectin activates basophils and mast cells
of atopic subjects by its interaction with core chitobiose of cell-bound non-specific immunoglobulin
E. Clinical & Experimental Immunology, 148(3), 391-401.

[←421]
Pramod, S. N., Venkatesh, Y. P., & Mahesh, P. A. (2007). Potato lectin activates basophils and mast cells
of atopic subjects by its interaction with core chitobiose of cell-bound non-specific immunoglobulin
E. Clinical & Experimental Immunology, 148(3), 391-401.

[←422]
Pramod, S. N., Venkatesh, Y. P., & Mahesh, P. A. (2007). Potato lectin activates basophils and mast cells
of atopic subjects by its interaction with core chitobiose of cell-bound non-specific immunoglobulin
E. Clinical & Experimental Immunology, 148(3), 391-401.

[←423]
Kaushal, N., Jain, S., Kondaiah, P., & Tiwary, A. K. (2009). Influence of piperine on transcutaneous
permeation of repaglinide in rats and on tight junction proteins in HaCaT cells: unveiling the
mechanisms for enhanced permeation. Sci Pharm, 77, 877-897.

[←424]
Feng, X., Liu, Y., Wang, X., & Di, X. (2014). Effects of piperine on the intestinal permeability and
pharmacokinetics of linarin in rats. Molecules, 19(5), 5624-5633.
Jin, M. J., & Han, H. K. (2010). Effect of piperine, a major component of black pepper, on the intestinal
absorption of fexofenadine and its implication on food–drug interaction. Journal of food science,
75(3), H93-H96.

Chapter 8. Anti-inflammatory Supplements

[←425]

Milliken, S. V., Wassall, H., Lewis, B. J., Logie, J., Barker, R. N., Macdonald, H., ... & Ormerod, A. D.
(2012). Effects of ultraviolet light on human serum 25-hydroxyvitamin D and systemic immune
function. Journal of Allergy and Clinical Immunology, 129(6), 1554-1561.
Bryson, K. J., Nash, A. A., & Norval, M. (2014). Does vitamin D protect against respiratory viral
infections?. Epidemiology and infection, 142(09), 1789-1801.

[←426]

Webb, A. R., Kline, L., & Holick, M. F. (1988). Influence of season and latitude on the cutaneous
synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote
vitamin D3 synthesis in human skin. The journal of clinical endocrinology & metabolism, 67(2), 373-
378.

[←427]
Grazio, S., Grubišić, F., Kavanagh, H. S., Naglić, Đ. B., Anić, B., Bakula, M., ... & Cvijetić, S. (2015).
Vitamin D serum level, disease activity and functional ability in different rheumatic patients. The
American journal of the medical sciences, 349(1), 46-49.
Holick, M. F. (2006, March). High prevalence of vitamin D inadequacy and implications for health. In
Mayo Clinic Proceedings (Vol. 81, No. 3, pp. 353-373).
Rossini, M., Bongi, S. M., La Montagna, G., Minisola, G., Malavolta, N., Bernini, L., ... & Adami, S. (2010).
Vitamin D deficiency in rheumatoid arthritis: prevalence, determinants and associations with
disease activity and disability. Arthritis research & therapy, 12(6), R216.

[←428]
Ricceri F, Pescitelli L, Tripo L, Prignano F. Deficiency of serum concentration of 25-hydroxyvitamin D
correlates with severity of disease in chronic plaque psoriasis. J Am Acad Dermatol. 2013;68:511–2
Grazio, S., Grubišić, F., Kavanagh, H. S., Naglić, Đ. B., Anić, B., Bakula, M., ... & Cvijetić, S. (2015).
Vitamin D serum level, disease activity and functional ability in different rheumatic patients. The
American journal of the medical sciences, 349(1), 46-49.
Lin, J., Liu, J., Davies, M. L., & Chen, W. (2016). Serum vitamin D level and rheumatoid arthritis disease
activity: review and meta-analysis. PloS one, 11(1), e0146351.
Cutolo, M., Otsa, K., Laas, K., Yprus, M., Lehtme, R., Secchi, M. E., ... & Seriolo, B. (2006). Circannual
vitamin D serum levels and disease activity in rheumatoid arthritis: Northern versus Southern
Europe. Clin Exp Rheumatol, 24(6), 702-4.
Oelzner, P., Müller, A., Deschner, F., Hüller, M., Abendroth, K., Hein, G., & Stein, G. (1998). Relationship
between disease activity and serum levels of vitamin D metabolites and PTH in rheumatoid arthritis.
Calcified tissue international, 62(3), 193-198.
Patel, S., Farragher, T., Berry, J., Bunn, D., Silman, A., & Symmons, D. (2007). Association between
serum vitamin D metabolite levels and disease activity in patients with early inflammatory
polyarthritis. Arthritis & Rheumatism, 56(7), 2143-2149.
Lange, U., Jung, O., Teichmann, J., & Neeck, G. (2001). Relationship between disease activity and serum
 levels of vitamin D metabolites and parathyroid hormone in ankylosing spondylitis. Osteoporosis
International, 12(12), 1031-1035.

[←429]
Finamor, D. C., Sinigaglia-Coimbra, R., Neves, L. C., Gutierrez, M., Silva, J. J., Torres, L. D., ... & Lopes, A.
C. (2013). A pilot study assessing the effect of prolonged administration of high daily doses of
vitamin D on the clinical course of vitiligo and psoriasis. Dermato-endocrinology, 5(1), 222-234.
Morimoto, S., Yoshikawa, K., Kozuka, T., Kitano, Y., Imanaka, S., Fukuo, K., ... & Kumahara, Y. (1986).
Treatment of psoriasis vulgaris by oral administration of 1α-hydroxyvitamin D 3—Open-design
study. Calcified tissue international, 39(3), 209-212.
Smith, E. L., Pincus, S. H., Donovan, L., & Holick, M. F. (1988). A novel approach for the evaluation and
treatment of psoriasis: oral or topical use of 1, 25-dihydroxyvitamin D3 can be a safe and effective
therapy for psoriasis. Journal of the American Academy of Dermatology, 19(3), 516-528.
Takamoto, S., Onishi, T., Morimoto, S., Imanaka, S., Yukawa, S., Kozuka, T., ... & Kumahara, Y. (1986).
Effect of 1α-hydroxycholecalciferol on psoriasis vulgaris: a pilot study. Calcified tissue international,
39(6), 360-364.
Perez, A., Raab, R., Chen, T. C., Turner, A., & HOLLCK, M. (1996). Safety and efficacy of oral calcitriol (1,
25-dihydroxyvitamin D3) for the treatment of psoriasis. British journal of dermatology, 134(6),
1070-1078.

[←430]
Finamor, D. C., Sinigaglia-Coimbra, R., Neves, L. C., Gutierrez, M., Silva, J. J., Torres, L. D., ... & Lopes, A.
C. (2013). A pilot study assessing the effect of prolonged administration of high daily doses of
vitamin D on the clinical course of vitiligo and psoriasis. Dermato-endocrinology, 5(1), 222-234.
Morimoto, S., Yoshikawa, K., Kozuka, T., Kitano, Y., Imanaka, S., Fukuo, K., ... & Kumahara, Y. (1986).
Treatment of psoriasis vulgaris by oral administration of 1α-hydroxyvitamin D 3—Open-design
study. Calcified tissue international, 39(3), 209-212.
Smith, E. L., Pincus, S. H., Donovan, L., & Holick, M. F. (1988). A novel approach for the evaluation and
treatment of psoriasis: oral or topical use of 1, 25-dihydroxyvitamin D3 can be a safe and effective
therapy for psoriasis. Journal of the American Academy of Dermatology, 19(3), 516-528.
Takamoto, S., Onishi, T., Morimoto, S., Imanaka, S., Yukawa, S., Kozuka, T., ... & Kumahara, Y. (1986).
Effect of 1α-hydroxycholecalciferol on psoriasis vulgaris: a pilot study. Calcified tissue international,
39(6), 360-364.
Perez, A., Raab, R., Chen, T. C., Turner, A., & HOLLCK, M. (1996). Safety and efficacy of oral calcitriol (1,
25-dihydroxyvitamin D3) for the treatment of psoriasis. British journal of dermatology, 134(6),
1070-1078.

[←431]
Holick, M. F. (2006, March). High prevalence of vitamin D inadequacy and implications for health. In
Mayo Clinic Proceedings (Vol. 81, No. 3, pp. 353-373). Elsevier.

[←432]
Andjelkovic, Z., Vojinovic, J., Pejnovic, N., Popovic, M., Dujic, A., Mitrovic, D., ... & Stefanovic, D. (1999).
Disease modifying and immunomodulatory effects of high dose 1 (OH) D3 in rheumatoid arthritis
patients. Clinical and experimental rheumatology, 17, 453-456.
GaáL, J., Lakos, G., Szodoray, P., Kiss, J., HORVáTH, I., Horkay, E., ... & SzEGEDI, A. (2009).
Immunological and clinical effects of alphacalcidol in patients with psoriatic arthropathy: results of
 an open, follow-up pilot study. Acta dermato-venereologica, 89(2), 140-144
Huckins, D., Felson, D. T., & Holick, M. (1990). Treatment of psoriatic arthritis with oral 1, 25-
dihydroxyvitamin D3: a pilot study. Arthritis & Rheumatology, 33(11), 1723-1727

[←433]
Holick, M. F. (2006, March). High prevalence of vitamin D inadequacy and implications for health. In
Mayo Clinic Proceedings (Vol. 81, No. 3, pp. 353-373). Elsevier.

[←434]
Lange, U., Jung, O., Teichmann, J., & Neeck, G. (2001). Relationship between disease activity and serum
levels of vitamin D metabolites and parathyroid hormone in ankylosing spondylitis. Osteoporosis
International, 12(12), 1031-1035.
Bianchi, M. L., Bardare, M., Caraceni, M. P., Cohen, E., Falvella, S., Borzani, M., & DeGaspari, M. G.
(1990). Bone metabolism in juvenile rheumatoid arthritis. Bone and mineral, 9(2), 153-162.
Grossman, J. M., Gordon, R., Ranganath, V. K., Deal, C., Caplan, L., Chen, W., ... & Volkmann, E. (2010).
American College of Rheumatology 2010 recommendations for the prevention and treatment of
glucocorticoid-induced osteoporosis. Arthritis care & research, 62(11), 1515-1526.

[←435]
Grossman, J. M., Gordon, R., Ranganath, V. K., Deal, C., Caplan, L., Chen, W., ... & Volkmann, E. (2010).
American College of Rheumatology 2010 recommendations for the prevention and treatment of
glucocorticoid-induced osteoporosis. Arthritis care & research, 62(11), 1515-1526.

[←436]
Souberbielle, J. C., Body, J. J., Lappe, J. M., Plebani, M., Shoenfeld, Y., Wang, T. J., ... & Gandini, S.
(2010). Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer:
recommendations for clinical practice. Autoimmunity reviews, 9(11), 709-715

[←437]
Holick, M. F. (2006, March). High prevalence of vitamin D inadequacy and implications for health. In
Mayo Clinic Proceedings (Vol. 81, No. 3, pp. 353-373). Elsevier.

[←438]
Rossini, M., Bongi, S. M., La Montagna, G., Minisola, G., Malavolta, N., Bernini, L., ... & Adami, S. (2010).
Vitamin D deficiency in rheumatoid arthritis: prevalence, determinants and associations with
disease activity and disability. Arthritis research & therapy, 12(6), R216.

[←439]
Souberbielle, J. C., Body, J. J., Lappe, J. M., Plebani, M., Shoenfeld, Y., Wang, T. J., ... & Gandini, S.
(2010). Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer:
recommendations for clinical practice. Autoimmunity reviews, 9(11), 709-715

[←440]
Urashima, M., Segawa, T., Okazaki, M., Kurihara, M., Wada, Y., & Ida, H. (2010). Randomized trial of
vitamin D supplementation to prevent seasonal influenza A in schoolchildren. The American journal
 of clinical nutrition, 91(5), 1255-1260.
Hyppönen, E., Läärä, E., Reunanen, A., Järvelin, M. R., & Virtanen, S. M. (2001). Intake of vitamin D and
risk of type 1 diabetes: a birth-cohort study. The Lancet, 358(9292), 1500-1503.

[←441]
Pavelká, K., Gatterová, J., Olejarová, M., Machacek, S., Giacovelli, G., & Rovati, L. C. (2002).
Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized,
placebo-controlled, double-blind study. Archives of Internal Medicine, 162(18), 2113-2123.
Reginster, J. Y., Deroisy, R., Rovati, L. C., Lee, R. L., Lejeune, E., Bruyere, O., ... & Gossett, C. (2001).
Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-
controlled clinical trial. The Lancet, 357(9252), 251-256.

[←442]
Reginster, J. Y., Deroisy, R., Rovati, L. C., Lee, R. L., Lejeune, E., Bruyere, O., ... & Gossett, C. (2001).
Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-
controlled clinical trial. The Lancet, 357(9252), 251-256.

[←443]
Sawitzke, A. D., Shi, H., Finco, M. F., Dunlop, D. D., Bingham, C. O., Harris, C. L., ... & Lane, N. E. (2008).
The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a
report from the glucosamine/chondroitin arthritis intervention trial. Arthritis & Rheumatology,
58(10), 3183-3191.

[←444]
Cunnane, G., FitzGerald, O., Beeton, C., Cawston, T. E., & Bresnihan, B. (2001). Early joint erosions and
serum levels of matrix metalloproteinase 1, matrix metalloproteinase 3, and tissue inhibitor of
metalloproteinases 1 in rheumatoid arthritis. Arthritis & Rheumatism, 44(10), 2263-2274.
Chen, J. J., Huang, J. F., Du, W. X., & Tong, P. J. (2014). Expression and significance of MMP3 in
synovium of knee joint at different stage in osteoarthritis patients. Asian Pacific journal of tropical
medicine, 7(4), 297-300.

[←445]
Nakamura, H., Masuko, K., Yudoh, K., Kato, T., Kamada, T., & Kawahara, T. (2007). Effects of
glucosamine administration on patients with rheumatoid arthritis. Rheumatology international,
27(3), 213-218.

[←446]
Cunnane, G., FitzGerald, O., Beeton, C., Cawston, T. E., & Bresnihan, B. (2001). Early joint erosions and
serum levels of matrix metalloproteinase 1, matrix metalloproteinase 3, and tissue inhibitor of
metalloproteinases 1 in rheumatoid arthritis. Arthritis & Rheumatism, 44(10), 2263-2274.
Chen, J. J., Huang, J. F., Du, W. X., & Tong, P. J. (2014). Expression and significance of MMP3 in
synovium of knee joint at different stage in osteoarthritis patients. Asian Pacific journal of tropical
medicine, 7(4), 297-300.

[←447]
 Viswanath, V., Myles, A., Dayal, R., & Aggarwal, A. (2011). Levels of serum matrix metalloproteinase-3
correlate with disease activity in the enthesitis-related arthritis category of juvenile idiopathic
arthritis. The Journal of rheumatology, 38(11), 2482-2487.
van Kuijk, A. W., Reinders-Blankert, P., Smeets, T. J., Dijkmans, B. A., & Tak, P. P. (2006). Detailed
analysis of the cell infiltrate and the expression of mediators of synovial inflammation and joint
destruction in the synovium of patients with psoriatic arthritis: implications for treatment. Annals of
the rheumatic diseases, 65(12), 1551-1557.
Sarma, P. K., Misra, R., & Aggarwal, A. (2008). Elevated serum receptor activator of NFκB ligand
(RANKL), osteoprotegerin (OPG), matrix metalloproteinase (MMP) 3, and ProMMP1 in patients with
juvenile idiopathic arthritis. Clinical rheumatology, 27(3), 289-294.

[←448]
Chan, P. S., Caron, J. P., & Orth, M. W. (2007). Effects of glucosamine and chondroitin sulfate on bovine
cartilage explants under long-term culture conditions. American journal of veterinary research,
68(7), 709-715.
Dodge, G. R., & Jimenez, S. A. (2003). Glucosamine sulfate modulates the levels of aggrecan and matrix
metalloproteinase-3 synthesized by cultured human osteoarthritis articular chondrocytes.
Osteoarthritis and Cartilage, 11(6), 424-432.
Byron, C. R., Orth, M. W., Venta, P. J., Lloyd, J. W., & Caron, J. P. (2003). Influence of glucosamine on
matrix metalloproteinase expression and activity in lipopolysaccharide-stimulated equine
chondrocytes. American journal of veterinary research, 64(6), 666-671.
Nakamura, H., Shibakawa, A., Tanaka, M., Kato, T., & Nishioka, K. (2003). Effects of glucosamine
hydrochloride on the production of prostaglandin E2, nitric oxide and metalloproteases by
chondrocytes and synoviocytes in osteoarthritis. Clinical and experimental rheumatology, 22(3),
293-299.

[←449]
Kim, L. S., Axelrod, L. J., Howard, P., Buratovich, N., & Waters, R. F. (2006). Efficacy of
methylsulfonylmethane (MSM) in osteoarthritis pain of the knee: a pilot clinical trial. Osteoarthritis
and Cartilage, 14(3), 286-294.
Debbi, E. M., Agar, G., Fichman, G., Ziv, Y. B., Kardosh, R., Halperin, N., ... & Debi, R. (2011). Efficacy of
methylsulfonylmethane supplementation on osteoarthritis of the knee: a randomized controlled
study. BMC complementary and alternative medicine, 11(1), 50.

[←450]
Ziboh, V. A., & Fletcher, M. P. (1992). Dose-response effects of dietary gamma-linolenic acid-enriched
oils on human polymorphonuclear-neutrophil biosynthesis of leukotriene B4. The American journal
of clinical nutrition, 55(1), 39-45.
Surette, M. E., Swan, D. D., Fonteh, A. N., Johnson, M. M., & Chilton, F. H. (1996). Metabolism of
gammalinolenic acid in human neutrophils. The Journal of Immunology, 156(8), 2941-2947.

[←451]
Davidson, E. M., Rae, S. A., & Smith, M. J. (1983). Leukotriene B4, a mediator of inflammation present
in synovial fluid in rheumatoid arthritis. Annals of the rheumatic diseases, 42(6), 677-679.

[←452]
 Iversen, L., Kragballe, K., & Ziboh, V. A. (1997). Significance of leukotriene-A4 hydrolase in the
pathogenesis of psoriasis. Skin Pharmacology and Physiology, 10(4), 169-177.

[←453]
Belch, J. J., & Hill, A. (2000). Evening primrose oil and borage oil in rheumatologic conditions. The
American journal of clinical nutrition, 71(1), 352s-356s.

[←454]
Leventhal, L. J., Boyce, E. G., & Zurier, R. B. (1993). Treatment of rheumatoid arthritis with
gammalinolenic acid. Annals of Internal Medicine, 119(9), 867-873.
Zurier, R. B., Rossetti, R. G., Jacobson, E. W., Demarco, D. M., Liu, N. Y., Temming, J. E., ... & Laposata,
M. (1996). Gamma-linolenic acid treatment of rheumatoid arthritis. A randomized, placebo-
controlled trial. Arthritis & Rheumatism, 39(11), 1808-1817.

[←455]
Ziboh, V. A., & Fletcher, M. P. (1992). Dose-response effects of dietary gamma-linolenic acid-enriched
oils on human polymorphonuclear-neutrophil biosynthesis of leukotriene B4. The American journal
of clinical nutrition, 55(1), 39-45.

[←456]
Jäntti, J., Nikkari, T., Solakivi, T., Vapaatalo, H., & Isomäki, H. (1989). Evening primrose oil in rheumatoid
arthritis: changes in serum lipids and fatty acids. Annals of the rheumatic diseases, 48(2), 124-127.

[←457]
Barham, J. B., Edens, M. B., Fonteh, A. N., Johnson, M. M., Easter, L., & Chilton, F. H. (2000). Addition of
eicosapentaenoic acid to γ-linolenic acid–supplemented diets prevents serum arachidonic acid
accumulation in humans. The Journal of nutrition, 130(8), 1925-1931.

[←458]
Ziboh, V. A., & Fletcher, M. P. (1992). Dose-response effects of dietary gamma-linolenic acid-enriched
oils on human polymorphonuclear-neutrophil biosynthesis of leukotriene B4. The American journal
of clinical nutrition, 55(1), 39-45.

[←459]
Jiang, Q. (2014). Natural forms of vitamin E: metabolism, antioxidant, and anti-inflammatory activities
and their role in disease prevention and therapy. Free Radical Biology and Medicine, 72, 76-90.

[←460]
Edmonds, S. E., Winyard, P. G., Guo, R., Kidd, B., Merry, P., Langrish-Smith, A., ... & Blake, D. R. (1997).
Putative analgesic activity of repeated oral doses of vitamin E in the treatment of rheumatoid
arthritis. Results of a prospective placebo controlled double blind trial. Annals of the rheumatic
diseases, 56(11), 649-655.
Helmy, M., Shohayeb, M., Helmy, M. H., & El-Bassiouni, E. A. (2001). Antioxidants as adjuvant therapy
in rheumatoid disease. Arzneimittelforschung, 51(04), 293-298.
Wittenborg, A., Petersen, G., Lorkowski, G., & Brabant, T. (1998). Effectiveness of vitamin E in
 comparison with diclofenac sodium in treatment of patients with chronic polyarthritis. Zeitschrift
fur Rheumatologie, 57(4), 215-221.
Kolarz, G., Scherak, O., El Shohoumi, M., & Blankenhorn, G. (1990). Hochdosiertes Vitamin E bei
chronischer Polyarthritis. Aktuelle Rheumatologie, 15(06), 233-237.
Kharaeva, Z., Gostova, E., De Luca, C., Raskovic, D., & Korkina, L. (2009). Clinical and biochemical effects
of coenzyme Q 10, vitamin E, and selenium supplementation to psoriasis patients. Nutrition, 25(3),
295-302.

[←461]
Kharaeva, Z., Gostova, E., De Luca, C., Raskovic, D., & Korkina, L. (2009). Clinical and biochemical effects
of coenzyme Q 10, vitamin E, and selenium supplementation to psoriasis patients. Nutrition, 25(3),
295-302.

[←462]
Hagfors, L., Leanderson, P., Sköldstam, L., Andersson, J., & Johansson, G. (2003). Antioxidant intake,
plasma antioxidants and oxidative stress in a randomized, controlled, parallel, Mediterranean
dietary intervention study on patients with rheumatoid arthritis. Nutrition journal, 2(1), 5.

[←463]
Reiter, E., Jiang, Q., & Christen, S. (2007). Anti-inflammatory properties of α-and γ-tocopherol.
Molecular aspects of medicine, 28(5), 668-691.

[←464]
Kurd, S. K., Smith, N., VanVoorhees, A., Troxel, A. B., Badmaev, V., Seykora, J. T., & Gelfand, J. M.
(2008). Oral curcumin in the treatment of moderate to severe psoriasis vulgaris: A prospective
clinical trial. Journal of the American Academy of Dermatology, 58(4), 625-631.

[←465]
Dcodhar, S. D., Sethi, R., & Srimal, R. C. (2013). Preliminary study on antirheumatic activity of curcumin
(diferuloyl methane). Indian journal of medical research, 138(1).
Kurd, S. K., Smith, N., VanVoorhees, A., Troxel, A. B., Badmaev, V., Seykora, J. T., & Gelfand, J. M.
(2008). Oral curcumin in the treatment of moderate to severe psoriasis vulgaris: A prospective
clinical trial. Journal of the American Academy of Dermatology, 58(4), 625-631

[←466]
Stohs, S. J., Ji, J., Bucci, L. R., & Preuss, H. G. (2018). A Comparative Pharmacokinetic Assessment of a
Novel Highly Bioavailable Curcumin Formulation with 95% Curcumin: A Randomized, Double-Blind,
Crossover Study. Journal of the American College of Nutrition, 37(1), 51-59.

[←467]
Belcaro, G., Cesarone, M. R., Dugall, M., Pellegrini, L., Ledda, A., Grossi, M. G., ... & Appendino, G.
(2010). Efficacy and safety of Meriva (R), a curcumin-phosphatidylcholine complex, during extended
administration in osteoarthritis patients. Altern Med Rev, 15(4), 337-44.

[←468]
 Haroyan, A., Mukuchyan, V., Mkrtchyan, N., Minasyan, N., Gasparyan, S., Sargsyan, A., ... &
Hovhannisyan, A. (2018). Efficacy and safety of curcumin and its combination with boswellic acid in
osteoarthritis: a comparative, randomized, double-blind, placebo-controlled study. BMC
complementary and alternative medicine, 18(1), 7.

[←469]
Di Pierro Francesco, R. G., Eleonora, A. D. M., Giovanni, A., Federico, F., & Stefano, T. (2013).
Comparative evaluation of the pain-relieving properties of a lecithinized formulation of curcumin
(Meriva®), nimesulide, and acetaminophen. Journal of pain research, 6, 201.

[←470]
Allegri, P., Mastromarino, A., & Neri, P. (2010). Management of chronic anterior uveitis relapses:
efficacy of oral phospholipidic curcumin treatment. Long-term follow-up. Clinical Ophthalmology
(Auckland, NZ), 4, 1201.

[←471]
Kumar, S., Ahuja, V., Sankar, M. J., Kumar, A., & Moss, A. C. (2010). Curcumin for maintenance of
remission in ulcerative colitis. Cochrane Database of Systematic Reviews, 10.

[←472]
Antiga, E., Bonciolini, V., Volpi, W., Del Bianco, E., & Caproni, M. (2015). Oral curcumin (Meriva) is
effective as an adjuvant treatment and is able to reduce IL-22 serum levels in patients with psoriasis
vulgaris. BioMed research international, 2015.

[←473]
Kurd, S. K., Smith, N., VanVoorhees, A., Troxel, A. B., Badmaev, V., Seykora, J. T., & Gelfand, J. M.
(2008). Oral curcumin in the treatment of moderate to severe psoriasis vulgaris: A prospective
clinical trial. Journal of the American Academy of Dermatology, 58(4), 625-631.

[←474]
Cuomo, J., Appendino, G., Dern, A. S., Schneider, E., McKinnon, T. P., Brown, M. J., ... & Dixon, B. M.
(2011). Comparative absorption of a standardized curcuminoid mixture and its lecithin
formulation. Journal of natural products, 74(4), 664-669.

[←475]
Ohno, M., Nishida, A., Sugitani, Y., Nishino, K., Inatomi, O., Sugimoto, M., ... & Andoh, A. (2017).
Nanoparticle curcumin ameliorates experimental colitis via modulation of gut microbiota and
induction of regulatory T cells. PloS one, 12(10), e0185999.
Feng, W., Wang, H., Zhang, P., Gao, C., Tao, J., Ge, Z., ... & Bi, Y. (2017). Modulation of gut microbiota
contributes to curcumin-mediated attenuation of hepatic steatosis in rats. Biochimica et Biophysica
Acta (BBA)-General Subjects, 1861(7), 1801-1812.
McFadden, R. M. T., Larmonier, C. B., Shehab, K. W., Midura-Kiela, M., Ramalingam, R., Harrison, C. A.,
... & Ghishan, F. K. (2015). The role of curcumin in modulating colonic microbiota during colitis and
colon cancer prevention. Inflammatory bowel diseases, 21(11), 2483-2494.
Shen, L., Liu, L., & Ji, H. F. (2017). Regulative effects of curcumin spice administration on gut microbiota
 and its pharmacological implications. Food & nutrition research, 61(1), 1361780.

[←476]
Wang, J., Ghosh, S. S., & Ghosh, S. (2017). Curcumin improves intestinal barrier function: modulation of
intracellular signaling, and organization of tight junctions. American Journal of Physiology-Cell
Physiology, 312(4), C438-C445.

[←477]
Khajuria, A., Zutshi, U., & Bedi, K. L. (1998). Permeability characteristics of piperine on oral absorption-
An active alkaloid from peppers and a bioavailability enhancer. Indian journal of experimental
biology, 36, 46-50.
Kaushal, N., Jain, S., Kondaiah, P., & Tiwary, A. K. (2009). Influence of piperine on transcutaneous
permeation of repaglinide in rats and on tight junction proteins in HaCaT cells: unveiling the
mechanisms for enhanced permeation. Sci Pharm, 77, 877-897.
Feng, X., Liu, Y., Wang, X., & Di, X. (2014). Effects of piperine on the intestinal permeability and
pharmacokinetics of linarin in rats. Molecules, 19(5), 5624-5633.
Jin, M. J., & Han, H. K. (2010). Effect of piperine, a major component of black pepper, on the intestinal
absorption of fexofenadine and its implication on food–drug interaction. Journal of food science,
75(3), H93-H96.

[←478]
Interlandi, J. (2016) Supplements Can Make You Sick. Dietary supplements are not regulated the same
way as medications. This lack of oversight puts consumers' health at risk.
July 27, 2016. http://www.consumerreports.org/vitamins-supplements/supplements-can-make-you-
sick/

[←479]
Suskind, D. (2016). Nutrition in Immune Balance (NIMBAL) Therapy: Using Diet to Treat Inflammatory
Bowel Disease. Seattle, Washington. Nimbal Publishing.

Chapter 9. The Science of Low-Dose Naltrexone

[←480]
Gironi, M., Martinelli-Boneschi, F., Sacerdote, P., Solaro, C., Zaffaroni, M., Cavarretta, R., ... &
Rodegher, M. E. (2008). A pilot trial of low-dose naltrexone in primary progressive multiple
sclerosis. Multiple Sclerosis Journal, 14(8), 1076-1083.

[←481]

Gironi, M., Martinelli-Boneschi, F., Sacerdote, P., Solaro, C., Zaffaroni, M., Cavarretta, R., ... &
Rodegher, M. E. (2008). A pilot trial of low-dose naltrexone in primary progressive multiple
sclerosis. Multiple Sclerosis Journal, 14(8), 1076-1083.

[←482]
 Cree, B. A., Kornyeyeva, E., & Goodin, D. S. (2010). Pilot trial of low-dose naltrexone and quality of life
in multiple sclerosis. Annals of neurology, 68(2), 145-150.

[←483]
Younger, J., Noor, N., McCue, R., & Mackey, S. (2013). Low-dose naltrexone for the treatment of
fibromyalgia: Findings of a small, randomized, double-blind, placebo-controlled, counterbalanced,
crossover trial assessing daily pain levels. Arthritis & Rheumatism, 65(2), 529-538.

[←484]
Younger, J., Noor, N., McCue, R., & Mackey, S. (2013). Low-dose naltrexone for the treatment of
fibromyalgia: Findings of a small, randomized, double-blind, placebo-controlled, counterbalanced,
crossover trial assessing daily pain levels. Arthritis & Rheumatism, 65(2), 529-538.

[←485]
Smith, J. P., Bingaman, S. I., Ruggiero, F., Mauger, D. T., Mukherjee, A., McGovern, C. O., & Zagon, I. S.
(2011). Therapy with the opioid antagonist naltrexone promotes mucosal healing in active Crohn’s
disease: a randomized placebo-controlled trial. Digestive diseases and sciences, 56(7), 2088-2097.
Smith, J. P., Stock, H., Bingaman, S., Mauger, D., Rogosnitzky, M., & Zagon, I. S. (2007). Low-dose
naltrexone therapy improves active Crohn's disease. The American journal of gastroenterology,
102(4), 820-828.
Smith, J. P., Field, D., Bingaman, S., Evans, R., & Mauger, D. (2013). Safety and tolerability of low dose
naltrexone therapy in children with moderate to severe crohn’s disease: a pilot study. Journal of
clinical gastroenterology, 47(4), 339.

[←486]
Smith, J. P., Bingaman, S. I., Ruggiero, F., Mauger, D. T., Mukherjee, A., McGovern, C. O., & Zagon, I. S.
(2011). Therapy with the opioid antagonist naltrexone promotes mucosal healing in active Crohn’s
disease: a randomized placebo-controlled trial. Digestive diseases and sciences, 56(7), 2088-2097.

[←487]
Jackson, B. D., Lewis, D. J., Beswick, L., Van Langenberg, D., Sparrow, M., & Gibson, P. R. (2013).
Apparent efficacy and safety of low dose naltrexone in australian patients with active Crohn's
disease. Journal of Gastroenterology and Hepatology, 28, 99.
Shannon, A., Alkhouri, N., Mayacy, S., Kaplan, B., & Mahajan, L. (2010). Low-dose naltrexone for
treatment of duodenal Crohn's disease in a pediatric patient. Inflammatory bowel diseases, 16(9),
1457.

[←488]
Shannon, A., Alkhouri, N., Mayacy, S., Kaplan, B., & Mahajan, L. (2010). Low-dose naltrexone for
treatment of duodenal Crohn's disease in a pediatric patient. Inflammatory bowel diseases, 16(9),
1457.

[←489]
Lie, M. R., Giessen, J., Fuhler, G. M., Lima, A., Peppelenbosch, M. P., Ent, C., & Woude, C. J. (2018). Low
dose Naltrexone for induction of remission in inflammatory bowel disease patients. Journal of
 translational medicine, 16(1), 55.

[←490]
Jackson, B. D., Lewis, D. J., Beswick, L., Van Langenberg, D., Sparrow, M., & Gibson, P. R. (2013).
Apparent efficacy and safety of low dose naltrexone in australian patients with active Crohn's
disease. Journal of Gastroenterology and Hepatology, 28, 99.

[←491]
Younger, J., Parkitny, L., & McLain, D. (2014). The use of low-dose naltrexone (LDN) as a novel anti-
inflammatory treatment for chronic pain. Clinical rheumatology, 33(4), 451-459.

[←492]
Wang, X., Zhang, Y., Peng, Y., Hutchinson, M. R., Rice, K. C., Yin, H., & Watkins, L. R. (2016).
Pharmacological characterization of the opioid inactive isomers (+)-naltrexone and (+)-naloxone as
antagonists of toll-like receptor 4. British journal of pharmacology, 173(5), 856-869.
Stevens, C. W., Aravind, S., Das, S., & Davis, R. L. (2013). Pharmacological characterization of LPS and
opioid interactions at the toll-like receptor 4. British journal of pharmacology, 168(6), 1421-1429.

[←493]
Hutchinson, M. R., Zhang, Y., Brown, K., Coats, B. D., Shridhar, M., Sholar, P. W., ... & Rice, K. C. (2008).
Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-
like receptor 4 (TLR4). European Journal of Neuroscience, 28(1), 20-29.

[←494]
Smith, R. L., Hébert, H. L., Massey, J., Bowes, J., Marzo-Ortega, H., Ho, P., ... & Warren, R. B. (2016).
Association of Toll-like receptor 4 (TLR4) with chronic plaque type psoriasis and psoriatic arthritis.
Archives of dermatological research, 308(3), 201-205.
Assassi, S., Reveille, J. D., Arnett, F. C., Weisman, M. H., Ward, M. M., Agarwal, S. K., ... & Mayes, M. D.
(2011). Whole-blood gene expression profiling in ankylosing spondylitis shows upregulation of toll-
like receptor 4 and 5. The Journal of rheumatology, 38(1), 87-98.

[←495]
Xu, D., Yan, S., Wang, H., Gu, B., Sun, K., Yang, X., ... & Wang, X. (2015). IL-29 enhances LPS/TLR4-
mediated inflammation in rheumatoid arthritis. Cellular Physiology and Biochemistry, 37(1), 27-34.
Yang, Z. X., Liang, Y., Zhu, Y., Li, C., Zhang, L. Z., Zeng, X. M., & Zhong, R. Q. (2007). Increased expression
of Toll-like receptor 4 in peripheral blood leucocytes and serum levels of some cytokines in patients
with ankylosing spondylitis. Clinical & Experimental Immunology, 149(1), 48-55.
Garcia–Rodriguez, S., Arias–Santiago, S., Perandrés–López, R., Castellote, L., Zumaquero, E., Navarro,
P., ... & Zubiaur, M. (2013). Increased gene expression of Toll-like receptor 4 on peripheral blood
mononuclear cells in patients with psoriasis. Journal of the European Academy of Dermatology and
Venereology, 27(2), 242-250.
De Rycke, L., Vandooren, B., Kruithof, E., De Keyser, F., Veys, E. M., & Baeten, D. (2005). Tumor necrosis
factor α blockade treatment down-modulates the increased systemic and local expression of toll-
like receptor 2 and toll-like receptor 4 in spondylarthropathy. Arthritis & Rheumatology, 52(7),
2146-2158.
[←496]
Hu, F., Li, Y., Zheng, L., Shi, L., Liu, H., Zhang, X., ... & Yang, Y. (2014). Toll-like receptors expressed by
synovial fibroblasts perpetuate Th1 and th17 cell responses in rheumatoid arthritis. PLoS One, 9(6),
e100266.
Begon, É., Michel, L., Flageul, B., Beaudoin, I., Jean-Louis, F., Bachelez, H., ... & Musette, P. (2007).
Expression, subcellular localization and cytokinic modulation of Toll-like receptors (TLRs) in normal
human keratinocytes: TLR2 up-regulation in psoriatic skin. European Journal of Dermatology, 17(6),
497-506.

[←497]
Younger, J., Parkitny, L., & McLain, D. (2014). The use of low-dose naltrexone (LDN) as a novel anti-
inflammatory treatment for chronic pain. Clinical rheumatology, 33(4), 451-459.

[←498]
Younger, J., Noor, N., McCue, R., & Mackey, S. (2013). Low-dose naltrexone for the treatment of
fibromyalgia: Findings of a small, randomized, double-blind, placebo-controlled, counterbalanced,
crossover trial assessing daily pain levels. Arthritis & Rheumatism, 65(2), 529-538.
Gironi, M., Martinelli-Boneschi, F., Sacerdote, P., Solaro, C., Zaffaroni, M., Cavarretta, R., ... &
Rodegher, M. E. (2008). A pilot trial of low-dose naltrexone in primary progressive multiple
sclerosis. Multiple Sclerosis Journal, 14(8), 1076-1083.

[←499]
Younger, J., Noor, N., McCue, R., & Mackey, S. (2013). Low-dose naltrexone for the treatment of
fibromyalgia: Findings of a small, randomized, double-blind, placebo-controlled, counterbalanced,
crossover trial assessing daily pain levels. Arthritis & Rheumatism, 65(2), 529-538.

Chapter 10: Putting It All Together

[←500]
Ebringer, A., & Wilson, C. (1996). The use of a low starch diet in the treatment of patients suffering
from ankylosing spondylitis. Clinical rheumatology, 15(1), 62-66.

[←501]
Chapter 12. The Recipes

Hernandez, A. L., Kitz, A., Wu, C., Lowther, D. E., Rodriguez, D. M., Vudattu, N., ... & Hafler, D. A. (2015).
Sodium chloride inhibits the suppressive function of FOXP3+ regulatory T cells. The Journal of
clinical investigation, 125(11), 4212-4222.
Binger, K. J., Gebhardt, M., Heinig, M., Rintisch, C., Schroeder, A., Neuhofer, W., ... & Voelkl, J. (2015).
High salt reduces the activation of IL-4–and IL-13–stimulated macrophages. The Journal of clinical
investigation, 125(11), 4223-4238.
Salgado, E., Bes-Rastrollo, M., de Irala, J., Carmona, L., & Gomez-Reino, J. J. (2015). High sodium intake
is associated with self-reported rheumatoid arthritis: a cross sectional and case control analysis
 within the SUN cohort. Medicine, 94(37), e0924.