Young

STAT E O F T H E A RT R E V I E W
The role of the microbiome in human
BMJ: first published as 10.1136/bmj.j831 on 15 March 2017. Downloaded from http://www.bmj.com/ on 23 June 2021 by guest. Protected by copyright.
health and disease: an introduction for
clinicians
Vincent B Young
Department of Internal Medicine/
Infectious Diseases Division, A B S T RAC T
University of Michigan Medical
School, Ann Arbor, MI 48109- Research into the microbiome—the indigenous microbial communities (microbiota)
5666, USA and the host environment that they inhabit—has changed clinicians’ ideas about
Correspondence to: V B Young
[email protected] microbes in human health and disease. Perhaps the most radical change is the
Cite this as: BMJ 2017;356:j831 realization that most of the microbes that inhabit our body supply crucial ecosystem
doi: 10.1136/bmj.j831
services that benefit the entire host-microbe system. These services include the
production of important resources, bioconversion of nutrients, and protection
against pathogenic microbes. Thus disease can result from a loss of beneficial
functions or the introduction of maladaptive functions by invading microbes.
This review will show how an understanding of the dynamics and function of the
indigenous microbiota has altered our view of microbes in maintaining homeostasis
and causing disease. It will discuss how disruption of the beneficial functions of
the microbiota can lead to disease. Methods for studying the microbiota will be
introduced as part of a conceptual framework for using these methods to delineate
novel roles for microbes in health. Key associations between specific changes in the
microbiome and disease will be discussed. This will lead to an explanation of how
the intentional manipulation of the microbiota, either by restoring missing functions
or eliminating harmful functions, may lead to novel methods to prevent or treat a
variety of diseases. With the explosion of studies relating the microbiome to health
and disease, this review aims to provide a foundation for clinicians to follow this
developing area of biomedical research.
Introduction Sources and selection criteria

The recent announcement of the United States’ National The references used in this review were identified by Pub-
Microbiome Initiative reflects the rise of microbiome Med and Medline searches of articles published between
science in the past decade.1 An understanding of how 1965 and 2016 and through my personal library. Given
complex microbial communities can influence the patho- the exponential increase in the use of the term microbi-
genesis of multiple diseases has implications for preven- ome (fig 1), I focused on the past 10 years. Search terms
tion, diagnosis, and treatment. But because this area of included “microbiome”, “microbiota”, “probiotic”,
microbiology has not traditionally been part of the pre- “prebiotic”, and “metabolome” in conjunction with
medical or medical curriculum,2 practicing physicians specific diseases and health states including “obesity”,
and those in training often find it hard to understand the “infectious diseases”, “inflammatory bowel disease”,
increasing attention paid to the microbiome in clinical “diabetes”, “cardiovascular disease”, and “chronic
practice. obstructive pulmonary disease”. Few high quality sys-
This review aims to help doctors understand the basics tematic reviews and randomized controlled trials (RCTs)
of how the microbiome is being studied, and to provide have assessed the role of the microbiome in disease so
an overview of how knowledge of the structure and func- it is difficult to assess the literature using formal qual-
tion of microbial communities may eventually affect the ity criteria. Because of the broad nature of the subject, I
practice of medicine. Because interest in the microbiome prioritized recent high quality reviews and RCTs in which
spans several biomedical disciplines, detailed discus- multiple references would be relevant. Research literature
sion of many topics is not possible. However, high qual- (much of it observational or using animal models) was
ity reviews are cited for readers to discover more about included if it was published in high impact journals by
specific areas of interest. investigators who are generally respected by others in the
For personal use only 1 of 14

and understand microbial communities are applicable
&LWDWLRQV
to humans. Large scale projects such as the National
Institutes of Health (NIH) Human Microbiome Project and

the MetaHIT consortium were initiated to foster this line
of research.7 8 As the study of human associated micro-
bial communities started to flourish, investigators had
to adopt new ways of thinking and discussing concepts

of microbiology. Part of the difficulty that clinicians and
medical researchers face when they try to understand the
literature is the unfamiliar terminology. For this reason

this review will start by discussing some common topics,

terms, and working definitions (see box).
<HDU
Fig 1 | Increase in publications on the microbiome. When the What is the microbiome?
search term “microbiome” was used to query PubMed from The microbiome is defined in box 1. This term is now
1980 to 2016 an exponential increase in publications was seen commonly used when referring to the complex commu-
in the past decade
nity of microbes that inhabit a specific site on the body9;
for example, in a discussion of the gut microbiome and
field. Important primary literature was cited to provide an its relation to various health and disease states. In this
example of a specific disease association or novel method review, I will use the term microbiota when referring
or approach. purely to the micro-organisms that are present in a spe-
cific site. The term microbiome refers not only to the
Evolving concepts on the role of microbes in health and microbes but also to the environment that they inhabit.10
disease Using the example above, the gut microbiome refers not
Some of the difficulty in understanding how microbial com- only to the microbes but also to elements of the host such
munities affect human health comes from the fact that the as the host epithelium, immune components, and prod-
history of this field is different from that of the standard ucts of both the microbes and host including metabolites.
microbiology and infectious diseases that is taught dur- Furthermore, although much of the work studying the
ing medical training. Our initial understanding of the role indigenous microbiota has focused on bacteria, viruses
of microbes in human health relied on the germ theory of and fungi also inhabit most body sites that are occupied
disease proposed by Louis Pasteur and refined by Robert by microbes. This focus on bacteria partly results from
Koch and others.3 This early work focused on microbes as the fact that the sequencing methods used to examine
agents of disease (pathogens)—Koch’s postulates sought microbial communities were developed to study bacte-
individual microbes as disease causing agents. This led to ria (see below). However, more recent work is beginning
a focus on the attributes of a micro-organism that enabled to focus on the role of viral and fungal members of the
it to disrupt homeostasis of the host. This focus on single indigenous microbiota.
organisms (initially bacteria but then moving on to fungi,
viruses, and prions) and pathogenesis has led to tremen- What are the functions of the indigenous microbiota?
dous advances in medicine.4 The development of methods It might seem that the distinction between microbiome
to control infectious diseases secondary to this understand- and microbiota is simply an exercise in semantics. How-
ing of microbiology resulted in public health and sanitation ever, it is important to understand whether we are dis-
practices as well as the development of antibiotics. cussing just the microbes in a given site or the sum total
Parallel to the development of medical microbiology of the organisms and their environment when considering
and infectious diseases, other scientists began to study the multiple functions that a given microbial community
the role of microbes in the natural environment, such as might carry out (fig 2).
those found in soil and seawater.5 Investigators observed The indigenous microbiota can carry out functions
that microbes in these environments were rarely found related to the effects of their metabolism on the abiotic ele-
in isolation but were most commonly found as members ments of the microbiome or through interactions with their
of complex consortia. These microbiologists developed host.11 Although microbial genomes are much smaller than
closer intellectual ties to researchers in the areas of ecol- that of the host, the microbiota has a potentially greater
ogy and evolutionary biology rather than medicine. metabolic capability in total.12 Additionally, some meta-
When doctors and medical researchers considered bolic activities are carried out jointly, with contributions
complex microbial communities it was usually in the set- from both microbes and the host.13 Similarly, signaling
ting of the alimentary tract, where microbes were consid- between the host and indigenous microbiota can alter the
ered to be commensals (box 1)—organisms that obtain structure and function of both partners in this symbiosis.14
benefit by living in close association with their hosts but The microbiota can carry out multiple metabolic activi-
have no positive or detrimental effects on the host. How- ties ranging from catabolism and bioconversion of com-
ever, it has recently been realized that this relationship plex molecules to synthesis of a wide range of compounds
may not be one sided.6 that can have effects on both the microbiota and the host.
Medical researchers have realized that the concepts In some cases the microbiota can augment pathways
developed by environmental microbiologists to study that are present in the host, but in others the microbiota

acid butyrate is the preferred energy source for colonic

DEFINITIONS
enterocytes and has a variety of effects on host physiol-
Functional metagenomics ogy, ranging from anti-inflammatory effects to antitumor
A method that looks for specific biochemical functions within a metagenome. As first
activity.16
described, the metagenome is cloned into a vector such as a plasmid or bacterial artificial
chromosome This library is then moved into a test microbe (such as Escherichia coli) and Another interesting example of how the metabolic
screened for functions of interest such as antibiotic resistance or the ability to metabolize a activity of the indigenous microbiota can influence host
given substrate health is related to the metabolism of small molecules
Metabolome such as drugs.17 Microbial metabolism can affect the bio-
The total of small metabolites (peptides, oligosaccharides or sugars, lipids and so on) present availability of certain oral drugs, as has been shown for
in a given environment. In terms of a host associated microbiome, the metabolome generally the cardiac glycoside digoxin.18 Because of the narrow
reflects the combined metabolic activity of the host and the microbiota therapeutic range of this drug, alteration of its bioavail-
Metagenome ability can greatly influence the development of toxicity.
The collective genomes of a given community of micro-organisms. It is a measure of the It was recently shown that certain strains of the bacterium
functional potential of a given microbiota. Metagenomics is the study of metagenomes Eggerthella lenta can reduce digoxin owing to the pres-
Microbiome ence of the cardiac glycoside reductase operon.18
A characteristic microbial community that occupies a reasonably well defined habitat and has One example of host-microbe co-metabolism is the
distinct physicochemical properties. The term not only refers to the micro-organisms involved conversion of bile salts and bile acids in the gut.19 These
but also encompasses their theatre of activity. Some people use the term microbiome to compounds, synthesized in the host’s liver and secreted as
refer just to the organisms themselves (however, see “microbiota” below). In addition, some
conjugated bile salts, can undergo microbially mediated
also use the term microbiome to refer to the collective genome of a microbial consortium or
community (however, see “metagenome”above) conversions within the intestine to release unconjugated
bile acids and generate secondary bile acids.19 Although
Microbiota
A community of micro-organisms that occupy a particular site or habitat these compounds have distinct activities from the parent
ones, the host has evolved the ability to recognize and
Operational taxonomic unit (OTU)
A classification unit based on the DNA sequence similarity of a taxonomic marker gene (such respond to these microbially generated compounds in a
as the 16S rRNA encoding gene). One commonly applied threshold for binning organisms on manner similar to the response to bacterially generated
the basis of 16S gene sequencing is to use a similarity of 97% or greater as the definition of an short chain fatty acids. Farnesoid X receptors (FXRs) are
OTU nuclear hormone receptors that respond to bile acids.20
Phylotype Signaling through FXRs and other bile acid receptors can
A classification unit that is based on comparing a query sequence to a given database have a variety of effects on the host. Because bile acids are
and assigning membership to a given bin based on closest similarity to the database. the end products of cholesterol catabolism, changes to bile
Computationally, this method is generally faster than OTU based methods but is very acid metabolism can have effects on cholesterol and lipid
dependent on the comprehensiveness of the database and the accuracy of the underlying metabolism.20 Changes in the gut microbiota are associated
taxonomy
with altered lipid metabolism and various FXR agonists are
Prebiotic being developed as potential treatments for various meta-
Nutrients that favor the growth and predominance of beneficial microbes and their inherent
bolic disorders, ranging from obesity and insulin resist-
functions. Most of these have been carbohydrates that cannot be broken down by the human
digestive machinery but are metabolized by specific members of the microbiota ance to liver fibrosis and non-alcoholic steatohepatitis.21 22
The indigenous microbiota can modify epithelial
Probiotic
Commonly defined as “live micro-organisms which, when administered in adequate amounts,
responses and systemic responses, such as the devel-
confer a health benefit on the host.” In the past, these were often organisms that were first opment and activity of the immune system.23 Germ-free
recognized in fermented food products. Currently, there is interest in identifying potential animals have underdeveloped peripheral lymphoid
probiotics that are members of the microbiota of healthy people organisms and immune responses,24 and colonization
Proteome with a complex microbiota or specific members of the
The comprehensive collection of proteins within a given environment normal microbiota can reverse this immature state.25 26
Symbiosis Similarly, mucosal epithelia modify their expression
Literally means “living together.” When referring to a host-microbe interaction, this is of mucus and nutrient receptors and differentiate in
classically subdivided into “mutualism” where both parties benefit; “parasitism” when response to the presence of the microbiota.27‑29 In turn the
the microbe benefits at the cost of damage to the host; and “commensalism” when the host epithelium and immune system can alter the struc-
microbe benefits but there is neither harm nor benefit to the host. As noted in the text, true ture and function of the microbiota.30 In addition, two
commensalism is probably rare but is a form a mutualism where the benefit to the host is not
reports have shown that the microbiota can alter the anti-
readily apparent
tumor responses to immunotherapies that affect check-
Transcriptome point blockades through targeting cytotoxic T lymphocyte
The collection of transcriptionally active genes of a microbiota under a given condition.
associated protein 4 (CTLA-4) or programmed cell death
Analysis of the transcriptome typically involves harvesting and sequencing the collective RNA
of the microbiota 1 (PD-1).31 32 These altered responses to immunotherapy
were associated with specific members of the microbiota,
encodes for pathways that are unique to the microbial although the precise mechanism has yet to be defined.
component of the microbiome. One important area is the A final global function that has been attributed to
ability of the microbiota of the intestinal tract to ferment the indigenous microbiota is that of colonization resist-
resistant starch (polysaccharides that cannot be digested ance, where the presence of the microbiota protects the
by the host) to produce a variety of compounds, most host from colonization by and disease from potentially
notably short chain fatty acids,15 which can have a variety pathogenic microbes.33 The mechanisms by which this
of effects on the host. For example, the short chain fatty phenomenon is mediated by the microbiota are still being

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Fig 2 | Potential functions of the indigenous microbiota. The microbiota can have effects through the microbes’ synthetic or catabolic metabolic activity or through
direct host-microbe interactions. Catabolism and bioconversion of dietary or host derived compounds can make nutrients more available to the host or alter the
bioavailability of drugs. Some members of the microbiota can synthesize important cofactors or bioactive signaling molecules such as amines. Signaling between
the microbiota and the host can trigger alterations in host function, such as altered expression of mucus or alteration of the immune response
delineated, but it probably involves a combination of met- How is the microbiome studied?
abolic activities such as short chain fatty acid production, Structure versus function
direct competition for nutrients, and immunologic effects Several techniques are used to examine various aspects
on the host.34 of the indigenous microbiota (fig 3), and many reviews of
Thus, a precise and intricate symbiosis exists between these techniques are available.35 36 These techniques can
mammalian hosts and their microbial partners, and any be divided into those that assess the structure (analogous
disturbance of this symbiosis can have detrimental effects to anatomy) and those that assess the function (analo-
on both partners. For the host, alteration of this symbiosis gous to physiology) of the microbiota. Whereas anatomy
can lead to a variety of disease states, as will be discussed provides information about the structure of an organism
below. or a part of an organism, physiology provides insight into

techniques used to study the microbiome and how they

,QVLWXIXQFWLRQ
ţZKDWDUHWKH\GRLQJ"Ť are used to investigate the structure and function of our
indigenous microbiota.
Microbial structure
Several techniques can be used to delineate the struc-
ture of microbial communities (fig 3)—that is, cataloging
0HWDERORPLFV which microbes are present in a given community and
determining the relative abundance of each type. One of
3URWHRPLFV
the most common techniques for performing a census of
microbes involves the retrieval of sequence data of the
7UDQVFULSWRPLF gene that encodes the RNA component of the small ribo-
VHTXHQFLQJ somal subunit (16S rRNA).41‑43 This sequence dependent
method does not depend on microbial cultivation.44 DNA
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is extracted from a sample of the microbial community of
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interest and polymerase chain reaction (PCR) primers tar-
geting broadly conserved regions of the 16S gene are used
to amplify most of the microbial species present. These
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PCR amplicons are then subjected to high throughput
PLFURDUUD\V PHWDJHQRPLFV VHTXHQFLQJ DNA sequence analysis. Although a detailed discussion
of this analysis is beyond the scope of this review (several
6U51$JHQH 6LQJOHFHOO
excellent reviews are available45‑47) the analysis can be
VHTXHQFLQJ JHQRPH discussed in broad principles.
7D[RQWDUJHWHGT3&5 VHTXHQFLQJ Analysis of 16S data ultimately involves grouping the
6WUXFWXUH )XQFWLRQDOSRWHQWLDO sequences obtained into discrete bins that give rise to a
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taxonomy. Two different methods are used to accomplish
Fig 3 | Methods for studying the structure and function of the microbiota. The methods used to this. In one, all of the DNA sequences in a given analysis
discern the structure (“anatomy”) and function (“physiology”) of the indigenous microbiota can are compared with each other and grouped into opera-
be divided according to which aspect of the microbiota they can interrogate and are positioned tional taxonomic units (OTUs; see box 1) generally on the
accordingly. At the most basic level, methods can simply describe the community structure basis of a given predefined degree of sequence similarity.
of the microbiota—that is, which taxa are present and in what relative amounts. Methods that Each OTU can be classified to known bacteria, although
investigate functional potential generally catalog the coding potential of individual members OTUs themselves serve as a surrogate for a given microbe
of the microbiota or the entire community (the metagenome). To measure function directly a in the community, whether or not a formal name can be
catalog of the expressed microbial genes (the metatranscriptome) or the proteins or metabolites
assigned. The other commonly used method considers
present in the microbiome environment must be generated. qPCR=quantitative polymerase
chain reaction each sequence of 16S amplicons individually and com-
pares it to a set database of sequences and thus classifies
the function. While function can sometimes be predicted each sequence in the experiment to a previously defined
from structure, as anatomy may provide clues about phys- bin. There are advantages and disadvantages to each
iology, true assessment of physiology requires the direct of these approaches,46 but in general the two different
measurement of function. approaches yield concordant observations regarding
Many of the techniques have leveraged the advances community structure. Perhaps the most important con-
in high throughput nucleic acid sequencing that arose clusion is that robust biological effects can be observed
from the Human Genome Project. Given the involvement through 16S analysis and these insights are not depend-
of the genome centers sponsored by the NIH, it is no ent on the specific data analysis technique used.
coincidence that the Human Microbiome Project echoes With regard to human health, investigators use 16S
the previous effort to study and characterize the human analysis to compare people with and without a given
genome. Sequence based techniques (which can obvi- disease in a cross sectional manner.44 In addition, longi-
ate the need to isolate and grow microbes) have been tudinal analysis can be conducted to monitor the effect
invaluable for understanding the role of indigenous of treatments or the development of disease on the struc-
microbes in health and disease.37 However, full assess- ture of the microbiota.48 However, although this type of
ment of microbial function and the ability to test spe- analysis is powerful and provides important observations
cific hypotheses requires other techniques. In particular, about the potential role of microbes in health, it does not
microbial cultivation is still an essential part of studying directly assess the function of the microbotia.
microbes.38‑40 Future treatments that target the micro- Methods have been developed to infer potential function
biota (see below) may use specific microbes to replace on the basis of a specific microbial community structure,49
missing microbes and this can be accomplished only but as with all inferences this tends to be more hypothesis
through isolation and propagation of microbes. There- generating rather than specifically determining function.
fore, to understand the role that microbes play in health Any inferences need to be considered with appropriate
we need to know which microbes are present and what caveats. For example, if a 16S analysis shows the pres-
activities they can carry out in their specific environ- ence of an OTU corresponding to Escherichia coli, this
ment. The next section will discuss some of the common result needs to take into account that this could represent

everything from a probiotic, to a benign indigenous E coli, These initial efforts saw large variations in the micro-
to pathogenic E coli O157:H7. The 16S gene gives insight biota found in people without apparent clinical disease.57
into the phylogenetic characterization of a given bacterium This may partly be a product of the methods that were
in a community, but it does not provide information on the used for these initial studies. The bulk of the work used
functions encoded by the rest of the genome. nucleic acid sequencing, with an emphasis on 16S gene
sequence analysis, and limited metagenomic analysis.
Assaying potential microbial function The variation encountered in these studies reflects what
As indicated above, obtaining the full genome sequence we have come to understand about the relation between
of a given bacterial species can provide insight into the the structure and function of a microbial community. It
potential function of a given bacterium. In a similar man- has become clear that multiple communities as defined by
ner metagenomic sequence analysis has been developed 16S analysis can have similar functions.58 Furthermore,
to assess the functional potential of an entire microbial even when functional capacity is examined by looking
community.50 51 Starting with community DNA, as with at metagenomic sequences, the functional redundancy
16S gene analysis, instead of using PCR to amplify this that lies across large taxonomic distances can again yield
particular phylogenetic marker, the DNA sequence of similarly normal function.
the entire community is sequenced directly using high Along with defining the normal status of the micro-
throughput techniques.47 This provides a catalog of all of biota, other studies looked for associations between the
the genomes present in the microbial community. Analy- structure and function of the microbiome and disease
sis of either the metagenome or genomes of specific mem- states. The initial efforts, which continue to this day,
bers of a microbial community provides insight into the sought associations between the microbiota and health
potential function of the community. The relative abun- and disease. Once again, most of the studies analyzed the
dance of specific metabolic pathways that are exhibited structure of the microbial community through 16S based
by the community can help predict the functional capac- analysis. Importantly, much of this work looks at associa-
ity of that community.12 However, this is only a catalog tion rather than causation. As will be discussed in more
of potential; the next section will review methods that detail below, investigation of the role of the gut micro-
allow direct determination of the actual function of a biota in the pathogenesis of inflammatory bowel diseases
given microbiome. (IBD) is illustrative. Early studies performed cross sec-
tional comparisons between patients with and without
Measuring in situ microbial function disease.59 Differences were seen between the microbiota
The final group of analytic techniques used to study the of affected patients and controls without IBD, but it was
microbiome directly measure functional output. Using unclear whether they were causative or secondary to the
sequence based techniques, metatranscriptomic analysis presence of the disease. Subsequent studies tried to estab-
assays the proportion of a microbial metagenome that is lish associations at first recognition of the disease but
being expressed at a specific point in time under certain these studies still could not investigate directly.60
conditions.37 This technique assays the RNA transcripts More recently, studies have attempted to characterize
present in a microbiome by performing sequence analysis microbiota before the development of overt disease.61 62
of all of the expressed genes through reverse transcriptase Two studies recruited people at high risk of a specific dis-
mediated RNA sequencing. When these data are consid- ease (IBD and type I diabetes) and followed their micro-
ered in conjunction with a corresponding metagenome, biota longitudinally, comparing those who subsequently
the metatranscriptome provides a snapshot of the func- developed disease with those who did not. Other studies
tionally active genes at a given point in time. Two other looked at the effects of specific treatments for specific ill-
techniques are often used to determine directly the effect nesses on the microbiota, again in an attempt to define
of transcriptional activity on the metabolic environment a role for the microbiota in the pathogenesis of the dis-
of the microbiome. These final two techniques, proteomic ease.63
and metabolomic analysis, use advanced mass spectros- Finally, for diseases where adequate animal models
copy to measure the relative abundance of proteins and exist, tests of potential causation have been attempted.
metabolites (including peptides, oligosaccharides, and Examples of each of these strategies for studying the asso-
lipids) in a given microbiome.12‑53 This generally includes ciation between the microbiome and health and disease
metabolite species that arise from the host with potential will be briefly presented here. These examples are not
co-metabolism on the part of the microbiota and is thus meant to be comprehensive but to provide a conceptual
a true measure of the metabolic environment of a given framework for readers to understand and evaluate studies
microbiome. that they encounter in the future.
Conceptual framework for the study of the microbiome Disease associations with the microbiome
The initial activities of the Human Microbiome Project Infectious diseases
and other efforts that began about a decade ago focused Because the study of the microbiome is tied to the field
on establishing the boundaries of what would be consid- of microbiology, it is appropriate to start with a discus-
ered “normal” in terms of the microbial communities in sion of infectious diseases. Since the publication of the
and on the human body.8‑56 It was hoped that by defining fulfillment of Koch’s postulates for the toxin producing
what is normal, associations between deviations from bacterium Clostridium difficile nearly 40 years ago,64C
this normal state and disease could be discerned. difficile infection has been taught in medical school as

an example of a disease where disruption of the normal initial presentation of disease.60 Others have studied
microbiota plays a key role in the pathogenesis. Although subtypes of IBD such as the development of pouchitis in
the association between antibiotic administration and the patients who have undergone total colectomy with ileal
development of C difficile infection has long been appreci- pouch anal anastomosis to examine the microbiota in
ated,65 more recent work has started to define the mecha- patients before the onset of overt disease.62 80 The avail-
nisms underlying this association. In particular, much ability of numerous mouse models of IBD has led to mul-
work has been done on the microbial functions encoded tiple studies that have tried to discern the underlying
by the indigenous microbiota that serve to mediate colo- mechanisms by which the microbiota can contribute to
nization resistance against C difficile. the pathogenesis of IBD.81‑83
One area is the role that the intestinal microbiota play Studies of the genetic susceptibility to the development
in bile salt and bile acid metabolism.66 67 When conju- of IBD highlight the importance of host immunity and the
gated bile salts are secreted by the liver into the gastroin- pathogenesis of this disease. Of particular relevance is
testinal tract microbes that can perform de-conjugation the fact that genetic variations in the host machinery that
and conversion (for example, dehydroxylation) reactions interact with microbes are associated with an increased
convert these compounds into unconjugated primary and risk of developing IBD.84 85 Thus, IBD truly is a microbi-
secondary bile acids.19 Some of these molecular species ome related disease because both the host and microbe,
promote the germination of C difficile spores whereas oth- and thus the environment created through their interac-
ers inhibit the growth of the vegetative form of the organ- tion, are altered in this condition.
ism.67‑69 This understanding of molecular mechanism has
led to the exploration of novel treatments. For example, Obesity and metabolic disease
because the pathogenesis of C difficile infection, and in The complex metabolic interplay between the indigenous
particular recurrent infection, is associated with a loss microbiota of the intestinal tract and the host has led to
of normal microbial diversity and function, microbiota an examination of the potential role of the microbiome in
replacement therapy including fecal microbiota trans- metabolic conditions such as obesity and diabetes. Nearly
plantation is an active area of interest.70 a decade ago, landmark studies showed that there was
The intestinal microbiota can also influence several an association between obesity and the intestinal micro-
other infections and inflammatory conditions. In patients biota in both humans and mouse models of disease.86 87
undergoing allogeneic stem cell transplantation, the The close association between host factors and microbial
status of the microbiota is associated with the risk of factors in the complex pathogenesis of conditions such
developing bacteremia.71‑73 The lungs of patients with as obesity is highlighted through the use of leptin defi-
sepsis and the acute respiratory distress syndrome have cient animals in a study that examined the role of the
enrichment of gastrointestinal microbes and this seems microbiota and obesity.88 Despite these studies a compre-
to drive the pulmonary inflammatory response.74 Finally, hensive understanding of the precise mechanisms under-
the composition of the gut microbiota may play a key role lying this association remains elusive.88‑90 Furthermore, a
in influencing the healing of surgical intestinal anastomo- recent meta-analysis of multiple studies suggests that the
ses.75 These observations have implications for treatment strength of the direct association between the microbiota
and potentially for diagnosis and prognosis. and obesity may be weaker than previously suggested.91
Whatever the size of the effect, it is clear that the micro-
Inflammatory bowel diseases biota can influence the handling of nutrients by the intes-
Unlike microbe-microbe interactions in the setting of tinal tract. Microbially produced products such as short
infectious diseases whereby the microbiota can interfere chain fatty acids and bile acids can influence the expres-
with a classic microbial pathogen, in the IBDs Crohn’s sion of important metabolic regulatory peptides such as
disease and ulcerative colitis no classic pathogen has glucagon-like peptide 1 and peptide YY.92 Recent work
been definitively identified.76 In this case, the intesti- has begun to elicit some of the mechanisms by which the
nal microbiota itself is thought to be pathogenic and in microbiota can influence host energy metabolism.93 94
predisposed hosts contributes to the development of the Other studies have shown that manipulation of the host
dysregulated inflammatory response that characterizes diet has effects on the intestinal microbiota, setting up a
these diseases. Multiple studies show that the intestinal complex system whereby intrinsic and extrinsic associa-
microbiota of patients with IBD is distinct from that of tions in the microbiome can alter host metabolism.95 An
people without IBD.59‑78 interesting line of research that has received much atten-
Studies of IBD were some of the first studies of disease tion is how unintentional alteration of the microbiota—for
that extensively used culture independent characteriza- example, through antibiotic administration—can disrupt
tion of the intestinal microbiota to show an association the normal balance and skew towards development of the
between disease and an altered microbial community. metabolic syndrome and obesity.96 97
Early studies used both 16S based sequencing methods Recent work has looked at the effects of microbial metab-
and fluorescent in situ hybridization to show that the olism on other organ systems. A key example studied the
community structure found in patients with disease was role of the metabolism of trimethylamine N-oxide (TMAO),
distinct from that of controls.79 Although the associations a metabolite that is used to predict the risk of develop-
were strong, the studies were cross sectional, making it ing cardiovascular disease. Dietary choline was shown
difficult to ascribe causation. More recent studies have to be metabolized by the intestinal microbiota to gener-
tried to address causation by examining patients at the ate TMAO and modulation of the microbiota to increase

dietary choline blocked enhanced atherosclerosis.98 This Other bacteria have been shown to alter local immune
work provides a potential mechanism by which the indig- responses in the sinuses that are associated with a shift in
enous microbiota can explain the well established link the resident microbiota.114 In a manner analogous to the
between certain dietary habits and the development of a interaction between pathogens and the microbiota in the
given health condition, such as cardiovascular disease. intestinal tract, the status of the upper respiratory tract
microbiota may be associated with susceptibility to both
Lung disease viral and bacterial upper respiratory tract infections.115
Recent interest in the study of microbial communities has Additionally, acute upper respiratory tract infection
led to a re-examination of sites that were formerly consid- with rhinovirus can alter the microbiota, and it has been
ered to be free of microbes, such as the upper and lower suggested that this can lead to increased susceptibility
respiratory tract. Although the lungs were formerly con- to infections elsewhere in the respiratory tract, such as
sidered to be a sterile site, the use of culture independent otitis media and pneumonia.116
methods suggests that the lungs are inhabited by a low
biomass of relatively diverse microbes.99 100 Early studies Emerging treatments: the microbiome as a therapeutic
cast doubt on the importance of this small population of target
microbes in the healthy lung,101 but more recent stud- The microbiome may play a role in a variety of diseases,
ies indicate that the composition of the lung microbiota potentially when a microbial community is deficient
can determine basal inflammatory tone even in healthy in a beneficial function or because of the presence of a
people.102 detrimental microbial activity. It is therefore tempting to
Furthermore, it is clear that microbial communities think that restoration of a beneficial microbial structure
are present and biologically important in specific disease or function would represent a novel treatment for certain
states involving the respiratory tract. It has long been diseases. Several potential strategies have been proposed
known that many patients with cystic fibrosis become to accomplish this. Although success to date has been
chronically colonized with pathogenic organisms, but restricted to a few conditions and therapies, the promise
more recently the lungs of these patients have been found for this novel approach to disease treatment and preven-
to contain a much more diverse community than had previ- tion warrants a discussion of what the future may hold.
ously been recognized.103 The importance of this finding Figure 4 lists potential strategies for therapeutic micro-
for the pathogenesis of lung disease and cystic fibrosis biome manipulation. The rationale for each strategy and
is still be explored, but it is reasonable to assume that relevant studies that have examined their efficacy are
microbe-microbe interactions in this environment might discussed.
be as important as such interactions within the gastrointes-
tinal tract.104 105 For example, bacteria found in the lungs of Antibiotics
these patients may be adapted to degrade the excess mucin Although collateral damage from therapeutic antibiotics
seen in cystic fibrosis and this may support the growth of on the indigenous gut microbiota plays a key role in the
the typical pathogens seen in this environment.106 pathogenesis of C difficile infection, antibiotic mediated
Important work is being done on the role of microbial alteration of the microbiota may serve to alter a disease
communities in the pathogenesis of lung diseases such associated microbial community to restore a healthy
as asthma and chronic obstructive pulmonary disease state. This strategy was used long before the current
(COPD).107‑110 Many of the early studies show association interest in the microbiome developed. For example, thera-
rather than causation, but more recent work is examin- peutic trials of antibiotics have been used for conditions
ing how the lung microbiota may drive the inflammatory such as hepatic encephalopathy,117 irritable bowel syn-
responses central to the pathogenesis of COPD.111 Further drome,118 and pouchitis in patients who have undergone
study is likely to provide a clearer indication of the causal colectomy for ulcerative colitis.119 In these early therapeu-
role of altered microbial communities in these lung dis- tic trials, it was assumed that an occult typical bacterial
eases. pathogen was not present. Conditions such as bacterial
In the upper respiratory tract, polymicrobial interac- overgrowth or microbial imbalance were posited and the
tions in acute and chronic rhinosinusitis have been inves- antibiotic was given in the hope of altering this abnormal
tigated.112 As with the lower respiratory tract, the role of state. One obvious disadvantage of this approach is that it
pathogens and other microbes has been investigated in is generally empiric in nature. As yet, we cannot predict
terms of their ability to modify host physiology. Specific exactly how a particular course of antibiotics will affect a
microbes have been found to be enriched in sinusitis. given microbial community. In addition, our elementary
In one study humans with sinusitis had an increase in understanding of the structure-function relations of the
the abundance of Corynebacterium tuberculostearicum, microbiota adds to the current lack of precision with this
which had not been previously recognized as a potential approach.
pathogen.113 Installation of this organism into a mouse A variant of this approach is proposed for the preven-
model of sinusitis demonstrated its pathogenic poten- tion of recurrent C difficile infection. Some of the more
tial.113 Further examination of the indigenous microbiota recent antibiotics developed for the treatment of C difficile
of the upper respiratory tract in patients with and without infection are designed to be more narrowly restricted to
sinus disease suggested that other members of the indig- the pathogen in the hope of limiting collateral damage
enous sinus community mediate resistance to coloniza- to the indigenous microbiota, which is associated with
tion by this organism.113 recurrent disease. The use of fidaxomicin, which has less

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Fig 4 | Potential strategies for therapeutic microbiome manipulation
microbiota disrupting potential, is also associated with have not been developed or validated to fulfill this defini-
lower rates of recurrent disease while maintaining good tion. Even when studies have been conducted to show
efficacy against the pathogen.120 This strategy is restricted potential health benefits, a mechanistic basis is often not
to treating C difficile infection, but the use of broad spec- investigated. This has led to the accusation by some that
trum antibiotics should be limited when treating a known there is a “non-scientific” aspect to the probiotic field.
bacterial pathogen to spare the microbiota when treat- Furthermore, regulatory agencies such as the US Food
ing any infection.121 Therefore, appropriate antibiotic and Drug Administration have allowed many probiotics to
stewardship helps limit the development or selection of fall under the dietary supplement rule provided they are
antibiotic resistant organisms and can prevent excessive not “intended to diagnose, cure, mitigate, treat or prevent
damage to the indigenous microbiota.122 a human disease.” This has prompted the proposal of new
Another approach for treating infections that is thought terms for live biotherapeutics that are meant to be used as
to have minimal effects on the microbiota is the use of drugs. However, if the formal WHO definition for probiotic
bacteriophage therapies. Bacteriophages are bacteriot- is adhered to, the formal testing and validation needed for
ropic viruses that generally have a restricted host range. a novel drug would be required and thus a new definition
Bacteriophage therapies have been developed that target might not be needed.126
specific bacterial pathogens, and by their very nature they Nonetheless, many studies have used probiotics in
are unlikely to have off-target effects on other members therapeutic trials for several conditions. In many cases
of the microbiota.123 Although bacteriophages are known the organisms used in these trials have been studied for
to select for bacterial variants that are resistant, these a long time, long before the current interest in the micro-
resistant bacteria often have altered surface structures biome. Indeed, Élie Metchnikoff, who received the Nobel
that while leading to phage resistance also attenuate prize in 1908 for studies on phagocytosis, proposed that
virulence within the host.124 Much more work is needed microbes could have beneficial as well as harmful effects
before bacteriophages can be developed into therapeutic on their host.127 He suggested that ingestion of fermented
agents,125 but there is much interest in exploring novel milk products could have a beneficial health effect, and
therapies designed to minimize microbiome disruption. this led to the development of members of the bacterial
genera Lactobacillus and Bifidobacterium as potential
Probiotics and other live microbial biotherapies probitoics.128 These organisms are often administered in
Because many microbiota related conditions are thought the form of therapeutic foods, generally fermented milk
to arise from a deficit in beneficial organisms, replace- products such as yogurt and kefir. Studies suggest that
ment of “missing” elements of the microbiota is a strat- these agents can help prevent and treat acute gastroen-
egy that also predates recent attention to the microbiome. teritis in children. Effects include limiting the develop-
Probiotics are defined by the World Health Organization ment of antibiotic associated diarrhea and preventing
as “live micro-organisms which, when administered C difficile infection.129 130 Previous results of small trials
in adequate amounts, confer a health benefit on the using typical probiotic agents have been mixed, prompt-
host.”126 Despite this definition, many putative probiotics ing most published guidelines to recommend against

their use.131 More recently, a large randomized, double that go against what previous data suggest would be ben-
blind, placebo controlled multicenter trial in older people eficial, underscoring how little we know about therapeu-
failed to show efficacy of a probiotic mixture of lactoba- tic manipulation of the microbiota.
cilli and bifidobacteria in preventing antibiotic associated
diarrhea or C difficile infection.132 This provides further Microbial restoration
support for not recommending the routine use of probiot- The replacement or restoration of a dysfunctional com-
ics to prevent these conditions. munity is a logical extension of the probiotic strategy.
As noted, many of the traditional organisms being pro- However, there are some differences. In particular, there
posed as probiotics were isolated from fermented food has been much interest in the strategy of transplanting
products. As such, they were chosen for reasons other an intact microbial community from a healthy person to
than theoretic or experimentally proved mechanisms of one with a microbiota associated disease, often referred
action. Recent studies of the microbiome, in particular to as microbiota transplantation.139‑141 Such treatments
those that include examination of microbial function, date to antiquity, particularly transplantation of intact
have led to the development and preclinical testing of feces or material derived from feces.142 Recent interest in
organisms that could be used therapeutically for specific fecal microbiota transplantation (FMT) for the treatment
indications. of recurrent C difficile infection has led to several studies
Returning to C difficile infection, recognition of the of this specific form of microbiome therapy.143 The first
importance of bile acid metabolism in the pathogenesis report of FMT for the treatment of antibiotic associated
of disease has prompted trials of bile acids, bile acid pseudomembranous colitis, presumably due to C diffi-
analogs, and organisms that could potentially alter bile cile infection, was published in 1958.144 More recently
acid metabolism within the gastrointestinal tract.66‑133 clinical trials of FMT for recurrent C difficile infection have
Although this treatment is still in a developmental stage, used different preparations of feces145‑147 and compared
the paradigm of developing live biotherapeutics on the different delivery modalities.148 In one placebo controlled
basis of rationally chosen mechanisms of action will trial the patient’s own stool was returned to subjects in
hopefully become an important strategy for the future the placebo arm.149
development of probiotics. In general, the remarkable success rate of all forms
of FMT for recurrent C difficile infection has generated
Prebiotics and diet therapy excitement that microbiome replacement might be used
Another strategy for beneficially modifying the indig- in other diseases. However, to date this success has not
enous microbiota is to alter environmental conditions of been replicated in other conditions such as obesity and
the microbiome to supply nutrients that favor the growth IBD. Contradictory results have been seen in small (some-
and predominance of beneficial microbes and their func- times uncontrolled) trials.150 151 It has been suggested that
tions.15 134 This strategy has largely been applied to modu- this treatment might not be directly translatable to other
lating the diet to modify the gastrointestinal microbiota. conditions.152 It seems that the beneficial effect of FMT in
At the most basic level this approach would entail supply- recurrent C difficile lies within the spore forming fraction
ing a single food source that is meant to foster beneficial of the intestinal microbiota.145 The use of FMT as prepared
microbes or microbial functions. for C difficile, which generally favors administration of
Prebiotics are generally non-digestible carbohydrates spore forming organisms, may not necessarily be success-
that are meant to be metabolized by specific microbes ful in other conditions.
to foster their growth.135 Given the beneficial effects of
microbial fermentation products such as butyrate, many The therapeutic future: precision microbiome therapy?
strategies are designed to increase the production of In the future therapeutic approaches are likely to become
this metabolic product and other short chain fatty acids. embedded in precision medicine.153 Precision medicine
Because such treatments presume that the appropriate has largely focused on host variables that can influence
microbes are present, a variation is to administer a "syn- health and the response to treatment, such as host genet-
biotic" containing both the relevant probiotic organism ics, but because the indigenous microbiota can play a key
and prebiotic carbohydrate.136 role, the precision medicine paradigm can be expanded
While focusing on a single nutrient has been use- to include these microbial variables. This approach
ful, broader changes in diet that depend at least in part would be predicated on a better understanding of the
on altering the indigenous microbiota have also been precise causative roles of the microbiota in a given dis-
used. Children with IBD, particularly Crohn’s disease, ease as well as knowledge of precise, functional mecha-
have been successfully treated with exclusive enteral nisms that underlie this causation. Given this, diagnostic
nutritional (EEN) therapy.137 This consists of a precisely and prognostic analysis could be performed to delineate
defined liquid diet that is used exclusively for all nutri- the absence of specific beneficial microbial functions in
tion. It has a remarkable success rate for inducing remis- the presence of deleterious ones and integrated with an
sion in these children but it is difficult to maintain long assessment of patient variables (fig 5). Once this had
term adherence to this diet. Recent studies of the effect been defined for a given patient, a customized strategy
of EEN on the intestinal microbiota indicate that it has a that might involve several of the potential therapeutic
statistically significant effect on the structure and func- modalities discussed here could be formulated to pro-
tion of the bacterial community.137 138 These changes are vide a precision treatment. Although this would be an
associated with functional alterations of the microbiome ideal situation in the future, for this to become reality

QUESTIONS FOR FUTURE RESEARCH

• For health conditions that have been proved to be
associated with changes in the microbiota, are the changes
observed in microbiota structure or function causative?
• How can we move from detecting altered community
structure to elucidating altered community function?
• What principles govern the assembly of the microbiota? Is it
possible to alter community assembly, either during initial
ţ0LFURELRWDFHQWHUHGŤSUHFLVLRQ ţ+RVWFHQWHUHGŤSUHFLVLRQPHGLFLQH establishment of the microbiota in infancy or once it has
PHGLFLQH '1$51$ been established?
0LFURELRWDFRPSRVLWLRQ 0HWDEROLWHV • To date, much of the focus has been on bacterial
0LFURELRWDIXQFWLRQ ,PPXQHIXQFWLRQ inhabitants of the microbiome. What roles do viruses
(host and microbiota-tropic), fungi, and other eukaryotic
microbes (such as helminths) play in human health and
disease? What new technologies need to be developed to
accomplish this?
• Can the assessment and alteration of the microbiota be
incorporated into the developing precision medicine
paradigm?
can maintain health and trigger disease. With this greater

0LFURELRWD +RVW understanding it is hoped that we will be in a position to
DVVHVVPHQW DVVHVVPHQW develop new ways to prevent and treat a wide range of
diseases and to foster health by tending to our microbial
symbionts.
Competing interests: I have read and understood BMJ policy on declaration
'DWDDQDO\VLV of interests and declare that I have received money for consultancy work
from Merck, Sharp & Dohme, Vedanta Biosciences, and MedImmune and
,GHQWLI\GHOHWHULRXVRUJDQLVPV *HQRPLFVXVFHSWLELOLW\ have received a research grant from MedImmune.
,GHQWLI\GHƟFLHQWPLFURELRWD 3UHGLFWGUXJUHVSRQVH Provenance and peer review: Commissioned; externally peer reviewed.
IXQFWLRQV 3UHGLFWDGYHUVHUHDFWLRQV Patient involvement was not sought.
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