nutrients

Review
Efficacy of Dietary Supplements in Inflammatory
Bowel Disease and Related Autoimmune Diseases
Priyanka Jadhav 1 , Yan Jiang 2 , Karolin Jarr 2 , Cosima Layton 3 , Judith F. Ashouri 4, * and
Sidhartha R. Sinha 2, *
1 Northwestern University, Evanston, IL 60208, USA; [email protected]
2 Division of Gastroenterology & Hepatology, Department of Medicine, Stanford University,
Redwood City, CA 94063, USA; [email protected] (Y.J.); [email protected] (K.J.)
3 University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; [email protected]
4 Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, Division of Rheumatology,
Department of Medicine, University of California, San Francisco, CA 94143, USA
* Correspondence: [email protected] (J.F.A.); [email protected] (S.R.S.);
Tel.: +1-(415)-476-4116 (J.F.A.); +1-(650)-497-6216 (S.R.S.)




Received: 30 June 2020; Accepted: 15 July 2020; Published: 20 July 2020


Abstract: The microbiome is an important contributor to a variety of fundamental aspects of

human health, including host metabolism, infection, and the immune response. Gut dysbiosis has
been identified as a contributor to the errant immune response in a variety of immune-mediated
inflammatory diseases (IMIDs), such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA),
and psoriatic disease (psoriasis and psoriatic arthritis). Given this, probiotics and prebiotics have
been investigated as therapeutic options in these disease states. In our review, we highlight the
current evidence on prebiotics and probiotics as well as other supplements (such as fish oils, vitamin
D, and curcumin) as therapies for IBD. Recommendations, however, regarding the specific use of such
supplements in IBD have been lacking, particularly from professional societies, often due to study
limitations related to small sample sizes and design heterogeneity. Hence, we additionally examine
the literature on the use of prebiotics, probiotics, and other supplements in related IMIDs, namely RA
and psoriasis/psoriatic arthritis, as these diseases share many approved therapeutic options with IBD.
Based on these combined findings, we offer additional evidence that may help guide clinicians in
their treatment of patients with IBD (and other IMIDs) and provide recommendations on potential
next steps in therapeutic research in this area.

Keywords: inflammatory bowel disease; psoriasis; rheumatoid arthritis; prebiotics; probiotics;

inflammation; ulcerative colitis; Crohn’s disease; UC; CD

1. Introduction
The microbiome is a key contributor to various fundamental aspects of human health, including
host metabolism, infection, and the immune response [1,2]. It is composed of 1000–1500 species of
bacteria as well as fungi and viruses, whose diversity is important for the maintenance of the metabolic
system and maturation of intestinal immunity [3]. An imbalance of these gut microbial communities
has been shown to disrupt host immunity and has been linked to intestinal disease [4]. While we are
only beginning to understand the complexity of interactions between the microbiome and the host
immune system, it has been shown that gut dysbiosis is one of the key contributors to errant host
immune responses in a variety of immune-mediated inflammatory diseases (IMIDs) [5–8]. As such,
there is strong rationale to suspect demonstrable therapeutic potential with prebiotic and probiotic
usage in inflammatory bowel disease (IBD), a chronic relapsing intestinal disease without medical cure,

Nutrients 2020, 12, 2156; doi:10.3390/nu12072156 www.mdpi.com/journal/nutrients

Nutrients 2020, 12, 2156 2 of 14

and other IMIDs. With growing supporting evidence, the interest in probiotics and prebiotics, as well
as additional supplements, to modulate disease has dramatically grown [9,10]. While the importance
of supplements to correct certain aspects of IBD, such as mineral deficiencies [11,12], is well-established,
the role of other dietary supplements in affecting the overall disease course is less clear.
The incidence of IBD—including both Crohn’s disease (CD), which can affect any part of the
gastrointestinal tract, and ulcerative colitis (UC), which is restricted to the colon—is increasing
worldwide [13]. Similar to IBD, there appears to be a dynamic and tightly regulated crosstalk between
dysbiosis-associated microbes and the gut-associated immune response seen prior to the onset of
related autoimmune diseases, such as rheumatoid arthritis (RA), psoriasis, and psoriatic arthritis [14].
In fact, more recent observations implicate a causative role for dysbiosis in the development of
inflammatory arthritides [14–16]. RA, psoriatic disease (psoriasis and psoriatic arthritis), and IBD also
share several treatments [17–19], which highlight some common final pathways in the pathogenesis of
these heterogeneous diseases. In addition, it appears that several common dietary interventions can
result in disease modifications across these IMIDs [14,20].
Recent literature increasingly supports the use of prebiotics, probiotics, and other supplements to
treat gut dysbiosis [14,21]. Despite this, however, there are few clear guidelines advocating for their use
as a treatment for IBD, and results in clinical trials have generally been equivocal. In fact, the American
Gastroenterology Association (AGA) practice guidelines on the role of probiotics in management
of gastrointestinal disorders do not recommend their use outside of a clinical trial as a result of
knowledge gaps caused by low sample sizes as well as study design and treatment heterogeneity [21].
However, there is still much to extract and extrapolate from these IBD studies. Similarly, there are
several well-designed studies investigating supplements in other IMIDs, namely RA and psoriasis,
that offer opportunities to better ascertain their potential in mitigating disease. In this review, we
examine the data surrounding probiotics, prebiotics, and other dietary supplements not only in IBD
but also in RA and psoriatic disease. Through this cross-analysis, we hope to better understand which
forms of supplementation have been most effective, and which provide the most potential for future
therapeutic use.

2. Materials and Methods

We performed a focused literature review using the PubMed database to identify relevant articles
related to IMIDs and dietary supplements. We searched using lexicon commonly used to describe the
IMID (e.g., ulcerative colitis, UC, Crohn’s disease, Crohn’s, rheumatoid arthritis, RA, etc.) combined
with terms to describe the supplement of interest (e.g., prebiotic, probiotic, vitamin D, etc.). We reviewed
a variety of types of research articles, including systematic reviews and meta-analyses, randomized
controlled trials, and observational studies. We generally limited our data to human studies; however, in
areas where clinical research was limited, basic science research pertaining to the proposed mechanism
of action or in vitro effects were also included. Though not a systematic review, studies were excluded
if they were deemed lower quality (very small sample sizes, poor methodology) by a consensus among
our research team, which included gastroenterology and rheumatology physicians.

3. Results

3.1. Probiotics

3.1.1. Use in Inflammatory Bowel Disease

Mounting evidence suggests that the complex interplay between genetics, environmental factors,
immune defenses, and the gut microbiome promotes the development of IBD [22–24]. This has
generated interest in how probiotics may be harnessed to mediate the mucosal inflammation of
IBD [22]. Different strains of probiotics have shown promise in the treatment of both active disease
and the maintenance of disease remission in IBD [25–31].
Nutrients 2020, 12, 2156 3 of 14

In active IBD, there are additional efficacy differences found in UC and CD. Though there
have been numerous studies investigating probiotic usage and outcomes in UC, the diversity of
probiotic usage and variance in study design have limited the conclusions that can be drawn from
meta-analyses [31,32]. This being said, there have been studies showing the therapeutic benefit of
probiotics either alone or in conjunction with standard-of-care therapy in UC [26,27]. Specifically, there
are several trials that support the use of VSL#3—a multi-strain probiotic mixture—to induce remission
in patients with mild-to-moderate UC [27]. A double-blind randomized study investigating standard
pharmaceutical treatment plus VSL#3 supplementation versus placebo for 8 weeks found a significant
reduction in the ulcerative colitis disease activity index (UCDAI, which assesses stool frequency, rectal
bleeding, endoscopic mucosal appearance, and physician’s rating of disease activity) (p = 0.01) and
rectal bleeding (p = 0.014) [33]. Improvements in stool frequency, physician’s rate of disease activity,
and endoscopic scores were also seen, but these did not reach statistical significance. These findings
support VSL#3 as a potential add-on to conventional pharmacologic therapy [33]. In contrast to VSL#3,
the probiotic bacterium Escherichia coli Nissle 1917 (EcN) does not seem to improve disease and may, in
fact, worsen clinical outcomes in active IBD. EcN has been tested in a double-blind randomized study
for 8 weeks as an adjunctive therapy to ciprofloxacin in mild-to-moderate UC. Though there were no
significant differences found in the ciprofloxacin/placebo versus ciprofloxacin/EcN groups, patients in
the EcN/placebo group had poorer outcomes. In fact, fewer patients reached remission (p < 0.05) in
the EcN/placebo treatment group compared to placebo/placebo, and experienced greater withdrawals
(p < 0.05) compared to other groups combined [34].
Published literature on probiotic use as therapy for active CD is more limited. The available
study results are difficult to generalize due to their non-randomized trial methodology or small patient
populations [35]. Further investigation is required to make generalizable prognostic statements about
probiotic use in the induction of disease remission for IBD, but the evidence supporting their use in UC
is more promising than in CD. Perhaps ongoing studies evaluating the efficacy of probiotic adjunctive
therapies in UC—including one investigating the effects of Lactobacillus rhamnosus GG [36] and another
one investigating SER-287 (microbiome therapy containing a consortium of live bacterial spores) [37]
on mild-to-moderate UC—will further elucidate the effects of probiotics on clinical disease outcomes.
Similar to treatment of active disease in IBD, the evidence of probiotic usage for the maintenance
of remission in both UC and CD has also been limited and mixed. Despite EcN not showing
efficacy in active UC, there is evidence supporting its use in maintaining remission. In a 12-month
double-blind study, there was no clinically significant difference in maintenance of remission between
patients who took the probiotic monotherapy twice a day versus mesalamine, a standard therapy for
mild-to-moderate UC, three times a day (p < 0.01 for equivalence) [28]. This suggests that probiotics
may provide an alternative to conventional therapies to maintain disease remission. Furthermore, a
meta-analysis conducted by Sang et al. analyzed 13 studies and found that probiotic treatment was
more effective than placebo for maintaining remission in UC [29]. However, prior to initiating all UC
patients on probiotics, clear guidance should be provided as there appear to be species and strain
efficacy differences. In a recent Japanese study, for example, investigating Bifidobacterium + Lactobacillus
treatment versus placebo in quiescent UC, the study was terminated early after the 48-week follow-up
due to a lack of efficacy as no significant difference was found between the two arms in relapse-free
survival (p = 0.64) [38]. These mixed results may also reflect differences in genetics and environmental
exposures, in addition to highlighting differences based on probiotic composition. Thus, though
studies show promise for probiotic use in disease as maintenance therapy, additional well-controlled
trials are necessary to understand the impact of various probiotics on clinical disease outcomes.
In CD, there are more data investigating probiotic use as a maintenance therapy (compared
to its use in active CD). Though some studies have suggested that probiotics may have efficacy in
maintaining CD remission [39], this has not been consistently reflected in improved clinical markers of
disease activity [40–42]. In a study of VSL#3 in preventing the relapse of CD after surgery, inflammatory
cytokines were found to be significantly reduced between the VSL#3 versus placebo groups (p < 0.05).
Nutrients 2020, 12, 2156 4 of 14

A trend for improvement in the number of endoscopic lesions and severe recurrence with early VSL#3
treatment (p = 0.09) was also observed. However, no differences in clinical and disease activity
index scores were found between the two groups [30]. An additional study investigating the effect
of Saccharomyces boulardii on time to relapse in patients with CD showed no significant differences
between the probiotic and placebo groups (p = 0.78) [42].

3.1.2. Use in RA and Psoriasis

While the majority of probiotic research in IMIDs has been conducted in IBD, there are several
studies investigating their efficacy in patients with RA and psoriasis (Table 1). Evaluating the efficacy of
probiotics in patients with RA and psoriasis, in addition to IBD, may provide a generalized framework
to understand its utility in the treatment of autoimmune inflammatory diseases, and provide further
insights into its role in the treatment of IBD.

Table 1. Highlighted studies on dietary supplements in immune-mediated inflammatory diseases.

Probiotics: Outcomes related to the use of probiotics in patients with certain IMIDs provide additional guidance for its
potential use in patients with IBD.
Study Disease Design N Results
Those who received 8-week supplementation with L casei had decreased
Alipour [43] RA RCT 46
inflammatory markers and disease activity scores.
8-week probiotic containing 3 different strains decreased disease activity
Zamani [44] RA RCT 60
scores and CRP.
2-month supplementation with bacillus strain probiotic improved pain
Mandel [45] RA RCT 45
assessment scores.
Navarro-Lopez Higher prevalence of reduced psoriasis area and severity index of up to
Ps * RCT 90
[46] 75% in those who took 3 months of probiotics.
8-week treatment course of VSL#3 decreased disease activity scores and
Tursi [33] UC RCT 144
clinical symptoms.
Adjunctive therapy with EcN may worsen clinical outcomes compared
Petersen [34] UC RCT 100
to placebo.
Prebiotics: Limited data exist in both IBD and other IMID populations. There have been a few studies demonstrating
proposed mechanism of microbiome and prebiotic interactions, which could be the foundation for additional research.
Study Disease Design N Results
Prospective High-fiber supplementation for 1 month increased circulating T regulatory
Häger [47] RA 36
cohort cells and decreased markers of bone erosion.
Pilot
15g/day of inulin-type fructans increased production of colonic butyrate, an
Valcheva [48] UC intervention25
anti-inflammatory short-chain fatty acid.
study
Supplements: Omega-3 supplementation seems promising for potential IBD-related arthropathies. Curcumin also
appears to have a potential role based on positive studies in the IMID population. Further studies on vitamin D and
targetable levels are needed.
Study Disease Design N Results
Proudman Those who received fish oil supplementation had higher rates of remission
RA RCT 122
[49] and reduced DMARD failure rates.
Kristensen The n-3-supplemented group showed improved outcomes in measures for
PsA * RCT 145
[50] disease activity and a reduction in use of NSAIDs and paracetamol.
In those on methotrexate, there was a non-significant difference in efficacy
Salesi [51] RA RCT 117
outcomes after 12 weeks of vitamin D compared to placebo.
Improved disease activity scores in those who received both low and high
Amalraj [52] RA RCT 36
doses of curcumin for 90 days.
Not all studies mentioned in text are included in Table 1. * Ps—psoriasis; PsA—psoriatic arthritis; RCT—randomized,
controlled trial; N—number of study participants.

Trials investigating the effects of probiotic use in patients with RA have also shown clinical and
symptomatic improvement. In two randomized double-blind clinical trials, there was a significant
reduction in serum proinflammatory cytokine levels found in patients receiving Lactobacillus casei [43,44].
Two trials also found a significant reduction in C-reactive protein (CRP) and Disease Activity Score
Nutrients 2020, 12, 2156 5 of 14

(DAS-28, consisting of tender and swollen joint count, CRP, and visual analog scale of global health)
after treatment with Lactobacillus casei [44,53]. A randomized double-blind trial investigating the
effect of probiotic Bacillus coagulans GBI-30 also demonstrated improvements in patient pain global
assessment (Patient Pain Assessment p = 0.05, Pain Scale p < 0.05) and with improvement, albeit limited,
in self-diagnosed disability (ability to walk p = 0.07, ability to reach p = 0.11) [45]. The promising
efficacy of these probiotics in RA suggests they may be altering, and potentially addressing, the
contribution of dysbiosis to disease activity. If so, this could provide an additional framework for its
use in patients with IBD, or at least for those suffering from IBD-associated arthropathy.
Similar to RA, some studies exist assessing probiotic use and clinical outcomes in patients with
psoriasis. From these limited studies, it appears that probiotic mixtures including strains of Lactobacillus
and Bifidobacterium have some efficacy on disease activity. One randomized double-blind study
investigating a combination probiotic mixture of Bifidobacterium longum, B. lactis, and Lactobacillus
rhamnosus showed a reduction of the Psoriasis Area and Severity Index (PASI) up to 75% (p < 0.05),
and an improvement in the Physician Global Assessment Index (48.9% in the probiotic group received
0 or 1, representative of remission, compared to 30.2% in the placebo group) [46]. Additionally, a study
done on only the effect of Lactobacillus pentosus in a mouse model of psoriasis demonstrated a significant
reduction in scaling lesions and the gene expression of proinflammatory cytokines [54], providing
additional evidence for the beneficial use of Lactobacillus species in the treatment of psoriasis. Though
both Lactobacillus and Bifidobacterium strains have indicated potential in treating psoriasis and IBD,
there is evidence that the inflammatory pathways targeted by these probiotics varies by disease. One
study investigating Bifidobacterium infantis 35624 across IBD, psoriasis, and chronic fatigue syndrome
(CFS) showed that it induced a reduction in CRP across all three conditions. The effects, however, on
different proinflammatory markers between IBD versus CFS and psoriasis differed. Tumor necrosis
factor alpha (TNF-α) was reduced in psoriasis (p = 0.04) and CFS (p = 0.02), while interleukin (IL)-6,
for example, was reduced in CFS (p = 0.05) and UC (p = 0.06) [55]. The differing cytokine responses
could, at least in part, also be explained by the different background therapies the patients with CFS,
psoriasis or IBD were on. Overall, the efficacy of a variety of Lactobacillus strains in both RA as well
as psoriasis, in addition to some therapeutic benefit seen in IBD, indicate that these strains are likely
reasonable candidates to consider for therapeutic use.

3.2. Prebiotics
Diet has a known impact on maintaining intestinal microbial homeostasis. Prebiotics are food
products that promote the growth of microorganisms thought to benefit the host [9,48,56]. We commonly
think of prebiotics as non-digestible fibers and nutrients that promote a healthier gut microbiome
through the stimulation of growth of healthy bacteria. Types of prebiotics, including fructans (polymers
of fructose molecules) and galacto-oligosaccharides (a type of oligosaccharide that is not hydrolyzed
by humans but rather fermented by gut bacteria), can be found naturally in foods, such as asparagus,
beets, garlic, and lentils to name a few [56]. Compared to probiotic usage, trials investigating the
clinical efficacy of prebiotics are substantially more limited. Even so, studies in IBD reveal beneficial
clinical effects of prebiotics, specifically fiber and oligosaccharides.
Variations of inulin, common soluble fibers such as those found in chicory root, have shown
promise. One study investigating the effects of inulin on clinical symptoms of patients with UC
(Mayo score 3–8) found a significant reduction in the high-treatment group (p = 0.04) associated
with a significant increase in colonic butyrate production (p = 0.04), a short-chain fatty acid with
anti-inflammatory effects [48]. This offers a proposed mechanism of effect, as butyrate production
inversely correlates with clinical symptoms [57]. Other studies found that oligofructose-enriched
inulin significantly decreased the Rachmilewitz score [58], an index used to assess endoscopic disease
activity (p < 0.05), as well as the fecal inflammatory marker calprotectin (p < 0.05) in patients with
mild-to-moderate UC after 14 days [59]. Additionally, germinated barley foodstuff was found to
significantly reduce CRP levels (p = 0.02), as well as abdominal pain and cramping (p = 0.02) compared
Nutrients 2020, 12, 2156 6 of 14

to placebo in mild-to-moderate patients with UC [60]. It also appeared to improve other clinical signs
of IBD (e.g., episodes of diarrhea, visible blood in stool) compared to baseline, though these did not
meet statistical significance [60].
Interestingly, prebiotic use in CD not only reduces disease activity [61,62] but may also alter
susceptibility to disease. The latter was highlighted in a prospective study, which analyzed data
from over 170,000 women, followed over 26 years, who participated in the Nurses’ Health Study
to investigate the effects of long-term dietary fiber intake on the risk of developing IBD. Dietary
information was obtained via a validated semiquantitative food questionnaire that was administered
every 4 years during the follow-up period. Intake of a high-fiber diet, particularly of fruit, was
associated with a 40% reduction in CD development (multivariate HR for CD, 0.59; 95% confidence
interval (CI), 0.39–0.90) [63]. Prebiotics have also been shown to reduce disease activity in CD. Analysis
of prebiotic complex carbohydrates, such as fructans (also known as fructooligosaccharides (FOS)),
have shown some promise for patients with CD. A small study (n = 10) demonstrated FOS induced
remission, as defined by a reduction in a commonly used clinical disease activity measure, the Harvey
Bradshaw Index (HBI), from 9.8 to 6.9 (p < 0.01) [61]. A larger study (n = 103) in patients with moderate
and severe CD (as defined by the Crohn’s disease activity index, CDAI, ≥220) showed an improvement
in CDAI scores compared to placebo, though this did not meet statistical significance (p = 0.07) [62].
While there are a paucity of data available on prebiotic use and their clinical effects on the
inflammatory arthropathies, there are some data indicating dietary fiber’s ability to restore microbial
diversity in patients with RA, likely driven by an increase in the observed circulatory T regulatory cells
and a favorable shift in the T helper immune response (Table 1) [47]. Based on these results, and what
we know about the positive effects of prebiotics on maintaining intestinal microbial homeostasis [9,48],
prebiotics have potential to modulate IBD disease activity. In the future, it will be important to offer
additional personalization of prebiotic regimens, perhaps starting with which types are most effective
for specific IMIDs.

3.3. Other Dietary Supplementation

Non-probiotic/-prebiotic dietary supplements are also commonly used in the treatment of
IMIDs [64]. As further described below, several supplements have shown promise in modulating the
clinical symptoms associated with IMIDs [65–68]. Hence, even potentially more than with prebiotics
and probiotics, IBD providers, by discerning data from their use in other IMIDs, may be able to identify
potential therapeutic supplements for patients with IBD.

3.3.1. Omega-3 Supplementation

Omega-3 (or n-3) fatty acids from sources, such as fish oils, have been used to treat chronic
inflammatory disorders, such as IBD [68]. A meta-analysis looking at a total of 1039 patients across
6 studies found that n-3 supplementation may lead to improvement in the maintenance of remission
in CD (RR 0.77, 95% CI 0.61 to 0.98) [69]. However, when using evidence from two of the six large
high-quality studies, which appeared to be free of bias, the authors concluded that n-3 supplements
are probably ineffective for the maintenance of remission in CD [69]. In UC, the effectiveness of n-3
fatty acid oral supplementation was examined alongside other supplements, including FOS, vitamin
E, vitamin C, and selenium, in patients with mild-to-moderate disease activity. This combination
therapy appeared to reduce the prednisone dose required to alleviate clinical symptoms (p < 0.001) [70].
However, attributing the effect to a specific supplement is not possible.
When examining the published literature on the effect of n-3 supplements in other IMIDs, such as
RA, psoriasis, and psoriatic arthritis, the results are generally positive. For example, in RA, it is thought
that fish oil and omega-3 supplementation may directly inhibit the production of proinflammatory
cytokines [71]. In another study of newly diagnosed patients with RA investigating the adjunctive
effects of high- versus low-dose fish oil in conjunction with disease-modifying antirheumatic drugs
(DMARDs), higher doses were found to have lower DMARD failure (p < 0.01) and higher rates of
Nutrients 2020, 12, 2156 7 of 14

remission (p = 0.04) [49]. In psoriasis, the results are more conflicted [72]. In a recent meta-analysis of
randomized controlled trials, fish oil did not demonstrate a significant reduction in the severity of
psoriasis, and individual trials reviewed over the last decade also yielded mixed results [73]. However,
in one of the larger and more well-controlled trials investigating the efficacy of n-3 supplementation
versus olive oil in psoriatic arthritis, an improvement was shown in the disease activity score, 68 tender
joint count, and PASI scores [50]. There was a significant reduction in the amount of non-steroidal
medication necessary to alleviate clinical symptoms in patients receiving n-3 supplementation (p = 0.04).
Given the favorable outcomes observed in patients with RA and psoriatic arthritis, it is possible that the
effects of supplementation may be more evident in patients with inflammatory arthritides. Therefore,
it may be worthwhile to explore the use of n-3 supplementation in patients with IBD-associated
inflammatory arthritis [74,75]

3.3.2. Vitamin D Supplementation

There has been considerable evidence associating low vitamin D levels and inflammation [76]. Thus,
vitamin D supplementation has been studied for possible therapeutic benefit in chronic inflammatory
conditions. In a retrospective longitudinal study investigating the relationship between serum vitamin
D levels, inflammatory markers, and clinical disease activity in patients with IBD, it was shown that
low vitamin D levels correlated with higher fecal calprotectin in UC and CD (p < 0.001) and higher
CRP levels in UC (p = 0.01) [77]. Furthermore, a deficiency in vitamin D3 correlated with an increase in
disease flares, hospitalizations, and steroid treatment (p < 0.01). When examining the literature on other
related IMIDs, limited data exist. In a short-term study looking at patients with RA, it appeared that
high weekly doses of vitamin D3 on a background of methotrexate therapy resulted in a non-significant
improvement in clinical disease activity by DAS-28 [51]. Although topical vitamin D is an established
treatment in psoriasis [78], its role as an oral therapeutic is less clear. A randomized double-blind trial
found that oral vitamin D3 supplementation resulted in only a slight improvement in PASI (45% vs.
38%) [79]. Given the known role of vitamin D in maintaining mucosal barriers and the function of T
cells [80], further exploration is required to better understand the possible therapeutic potential of
vitamin D in patients with inflammatory diseases. Though there are data linking vitamin D deficiency
to worse clinical outcomes in patients with IBD, an increased therapeutic vitamin D target level is yet
to be determined, which may better guide vitamin D replacement strategies.

3.3.3. Curcumin Supplementation

Curcumin—a strong antioxidant and predominant polyphenol in the turmeric root—has been
used in many cultures for millennia for its antioxidative and anti-inflammatory properties [81]. Due to
its potential in modulating inflammation, curcumin is commercially offered as an over-the-counter
treatment [82]. Though controlled trials directly examining curcumin’s anti-inflammatory effects are
limited in IBD, there are some favorable data for its use as an adjunctive anti-inflammatory therapy.
In fact, high-dose curcumin (3 g/day) significantly improved disease activity and induced clinical
and endoscopic remission in patients with mild-to-moderate UC disease activity on a background
of mesalamine therapy [83]. A larger trial with 300 patients with mild-to-moderate UC did not find
a significant clinical benefit when using much lower doses of curcumin (450 mg/day) [84]. Larger,
randomized controlled trials in RA using moderate doses of curcumin (from 120 mg to 1.2 g a day)
demonstrated an improvement in clinical disease activity scores, tender joint count, and swollen joint
count [52,85,86]. Though clinical trials of curcumin use in psoriatic disease are limited, in vitro studies
suggest a potential benefit [87]. Additionally, topical curcumin treatment demonstrated inhibition of
the inflammatory IL-23/IL-17 axis (pathogenic drivers of psoriatic disease) and other inflammatory
cytokines (p < 0.05) in a mouse model of psoriasis [88]. It appears that curcumin’s anti-inflammatory
properties may in fact provide benefit as an adjunctive therapy in inflammatory diseases, though
studies suggest perhaps high doses are required to see clinical benefit.
Nutrients 2020, 12, 2156 8 of 14

4. Discussion
While there are substantial data supporting probiotics, prebiotics, and other dietary
supplementation for the treatment of IMIDs, larger better controlled trials need to be performed in
order to further determine the efficacy of each of these treatments on specific patient populations.
Specific professional society guideline recommendations on their clinical use have generally been
lacking, largely due to the heterogeneity of the evidence base. Much, however, can still be extrapolated
from these studies to guide providers for management and researchers for promising avenues to
further explore [21].
There are several possible mechanisms of action by which dietary supplements may have a
therapeutic effect on IBD, including inhibition of microbial pathogens, modification of intestinal
permeability, modulation of the immune response of intestinal epithelia and mucosal immune cells, and
decomposition of luminal pathogenic antigens [89]. Probiotics, for example, attached to the mucosal
surface receptors, can inhibit adhesion and cell invasion by pathogenic bacteria [90,91]. Furthermore,
probiotics have been shown to ferment undigested dietary fibers, producing short-chain fatty acids and
other acid products that may inhibit the growth of pathogens [92,93]. Short-chain fatty acids themselves
have anti-inflammatory properties [94,95]. Probiotics have also been shown to downregulate the
expression of proinflammatory cytokines, such as TNFα, IL1β, and interferon gamma by several
pathways, including the inhibition of NF-κB (nuclear factor kappa-light-chain-enhancer of activated
B cells), modulation of toll like receptor (TLR)-2 signaling, and the PPARγ (peroxisome proliferator
activated receptor gamma) pathway [89]. Despite these mechanistic insights, it is still unclear which
probiotic strains have the most therapeutic potential in treatment of UC and CD. This further supports
the need to conduct cross-analysis and investigation in related IMIDs.
Cocktail strains, such as VSL#3, have the most data supporting adjunctive treatment in IBD,
with some conflicting data on Bifidobacterium and Lactobacillus strains as being potentially useful. The
efficacy of Lactobacillus casei in RA, as well as of Lactobacillus and Bifidobacterium strains in psoriasis,
gives additional supporting evidence and more basis for providers to potentially utilize these strains
for patients with IBD.
Studies assessing the efficacy of prebiotic usage in IBD are more limited, with some data supporting
the use of inulin-type fructans for UC and potentially the use of dietary fiber and fructooligosaccharides
to prevent CD. There are very limited studies detailing the use of prebiotics in other IMIDs. Currently,
given the limited amount of information on prebiotic usage, there is definitely a need for additional
testing to be conducted to assess if it can become a viable adjunctive treatment option. However,
given prior studies suggesting reasonable mechanisms, such as increased anti-inflammatory byproduct
(e.g., butyrate) production in the colon and restoration of microbial diversity, there is solid ground for
additional research.
In regard to other supplements, it appears that vitamin D deficiency is linked to disease
pathogenesis in IBD, RA, and psoriatic disease. Vitamin D regulates gut mucosal immunity by various
means, including the modification of gut epithelial integrity and alteration of T cell development and
function [80,96]. With generally widespread availability of vitamin D testing, various target levels
should be explored in a broad assortment of IMIDs. Omega-3 supplementation has been shown to
inhibit inflammatory cytokine production [97] and to be clinically effective in RA and psoriasis, but
this potential therapy needs further assessment before generalizing to IBD treatment. However, given
the positive results in other IMIDs, particularly RA, future studies may focus on outcomes of omega-3
supplementation in IBD-associated inflammatory arthropathies [75,76]. Curcumin has a medicinal
history of at least 2500 years in Asia and has long been known to have antibacterial properties [81]. There
is evidence of the anti-inflammatory and antioxidant effects of curcumin, including downregulation of
proinflammatory interleukins and cytokines, and inhibition of inflammatory cells. Curcumin has also
been shown to be effective in randomized controlled trials in mild-to-moderate UC and RA, as well
as in mouse models of psoriasis. Overall, the positive effects of curcumin in IMIDs provide further
Nutrients 2020, 12, 2156 9 of 14

support for its use in IBD. In IBD studies, outcomes also differed based on the dose of curcumin
given [83,84], so future additional analyses on dose-dependent changes may be fruitful.
There is strong evidence that the gut microbiota play a crucial role in IBD pathogenesis as well as
in the development of other IMIDs [5–8]. Although conflicting results and a lack of comparability of
available studies often preclude firm guidance, the available supporting data hold promise. Further
research should not only focus on additional investigation of specific bacterial strains but also
combinations of strains and combinations of prebiotics and probiotics, as well as interactions of bacteria
with fungi and viruses.

Author Contributions: Conceptualization, S.R.S. and J.F.A.; methodology, S.R.S., J.F.A., P.J., Y.J., K.J. and
C.L.; formal analysis, S.R.S., J.F.A., P.J., Y.J., K.J. and C.L.; data curation, S.R.S., J.F.A., P.J., Y.J., K.J. and C.L.;
writing—original draft preparation, S.R.S., J.F.A., P.J., Y.J., K.J. and C.L.; writing—review and editing, S.R.S., J.F.A.,
P.J., Y.J., K.J. and C.L.; supervision, S.R.S. and J.F.A. All authors have read and agreed to the published version of
the manuscript.
Funding: This research was supported by The Leona M. and Harry B. Helmsley Charitable Trust, Grant 2007-04026.
Acknowledgments: The authors acknowledge the Division of Gastroenterology and Hepatology at Stanford
University School of Medicine for supporting the time to complete this research.
Conflicts of Interest: The authors declare no conflict of interest.

References
1. Cani, P.D. Human gut microbiome: Hopes, threats and promises. Gut 2018, 67, 1716–1725. [CrossRef]
[PubMed]
2. Young, V.B. The role of the microbiome in human health and disease: An introduction for clinicians. BMJ
2017, 356. [CrossRef] [PubMed]
3. McDermott, A.J.; Huffnagle, G.B. The microbiome and regulation of mucosal immunity. Immunology 2014,
142, 24–31. [CrossRef] [PubMed]
4. Kuhn, K.A.; Pedraza, I.; Demoruelle, M.K. Mucosal immune responses to microbiota in the development of
autoimmune disease. Rheum. Dis. Clin. N. Am. 2014, 40, 711–725. [CrossRef]
5. Honda, K.; Littman, D.R. The microbiota in adaptive immune homeostasis and disease. Nature 2016, 535,
75–84. [CrossRef]
6. Petersen, C.; Round, J.L. Defining dysbiosis and its influence on host immunity and disease. Cell. Microbiol.
2014, 16, 1024–1033. [CrossRef]
7. Sinha, S.R.; Haileselassie, Y.; Nguyen, L.P.; Tropini, C.; Wang, M.; Becker, L.S.; Sim, D.; Jarr, K.; Spear, E.T.;
Singh, G.; et al. Dysbiosis-Induced Secondary Bile Acid Deficiency Promotes Intestinal Inflammation. Cell
Host Microbe 2020, 27, 659–670. [CrossRef]
8. Pickard, J.M.; Zeng, M.Y.; Caruso, R.; Núñez, G. Gut microbiota: Role in pathogen colonization, immune
responses, and inflammatory disease. Immunol. Rev. 2017, 279, 70–89. [CrossRef]
9. Markowiak, P.; Śliżewska, K. Effects of Probiotics, Prebiotics, and Synbiotics on Human Health. Nutrients
2017, 9, 1021. [CrossRef]
10. Quigley, E.M.M. Prebiotics and Probiotics in Digestive Health. Clin. Gastroenterol. Hepatol. 2019, 17, 333–344.
[CrossRef]
11. Ghishan, F.K.; Kiela, P.R. Vitamins and Minerals in Inflammatory Bowel Disease. Gastroenterol. Clin. N. Am.
2017, 46, 797–808. [CrossRef]
12. Alkhouri, R.H.; Hashmi, H.; Baker, R.D.; Gelfond, D.; Baker, S.S. Vitamin and mineral status in patients with
inflammatory bowel disease. J. Pediatr. Gastroenterol. Nutr. 2013, 56, 89–92. [CrossRef] [PubMed]
13. Ananthakrishnan, A.N. Epidemiology and risk factors for IBD. Nat. Rev. Gastroenterol. Hepatol. 2015, 12,
205–217. [CrossRef]
14. Kalinkovich, A.; Livshits, G. A cross talk between dysbiosis and gut-associated immune system governs the
development of inflammatory arthropathies. Semin. Arthritis Rheum. 2019, 49, 474–484. [CrossRef]
15. Barnas, J.L.; Ritchlin, C.T. Etiology and Pathogenesis of Psoriatic Arthritis. Rheum. Dis. Clin. N. Am. 2015, 41,
643–663. [CrossRef]
Nutrients 2020, 12, 2156 10 of 14

16. Zhang, X.; Zhang, D.; Jia, H.; Feng, Q.; Wang, D.; Liang, D.; Wu, X.; Li, J.; Tang, L.; Li, Y.; et al. The oral and
gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat. Med.
2015, 21, 895–905. [CrossRef]
17. Salas, A.; Hernandez-Rocha, C.; Duijvestein, M.; Faubion, W.; McGovern, D.; Vermeire, S.; Vetrano, S.;
Vande Casteele, N. JAK-STAT pathway targeting for the treatment of inflammatory bowel disease. Nat. Rev.
Gastroenterol. Hepatol. 2020, 17, 323–337. [CrossRef] [PubMed]
18. Fragoulis, G.E.; McInnes, I.B.; Siebert, S. JAK-inhibitors. New players in the field of immune-mediated
diseases, beyond rheumatoid arthritis. Rheumatol. Oxf. Engl. 2019, 58, i43–i54. [CrossRef] [PubMed]
19. Olivera, P.A.; Lasa, J.S.; Bonovas, S.; Danese, S.; Peyrin-Biroulet, L. Safety of Janus Kinase Inhibitors in
Patients with Inflammatory Bowel Diseases or Other Immune-mediated Diseases: A Systematic Review and
Meta-Analysis. Gastroenterology 2020, 158, 1554–1573. [CrossRef] [PubMed]
20. Bernstein, C.N.; Forbes, J.D. Gut Microbiome in Inflammatory Bowel Disease and Other Chronic
Immune-Mediated Inflammatory Diseases. Inflamm. Intest. Dis. 2017, 2, 116–123. [CrossRef]
21. Su, G.L.; Ko, C.W.; Bercik, P.; Falck-Ytter, Y.; Sultan, S.; Weizman, A.V.; Morgan, R.L. AGA Clinical Practice
Guidelines on the Role of Probiotics in the Management of Gastrointestinal Disorders. Gastroenterology 2020.
[CrossRef] [PubMed]
22. Mack, D.R. Probiotics in Inflammatory Bowel Diseases and Associated Conditions. Nutrients 2011, 3, 245–264.
[CrossRef] [PubMed]
23. Sartor, R.B. Mechanisms of disease: Pathogenesis of Crohn’s disease and ulcerative colitis. Nat. Clin. Pract.
Gastroenterol. Hepatol. 2006, 3, 390–407. [CrossRef] [PubMed]
24. Clavel, T.; Haller, D. Bacteria- and host-derived mechanisms to control intestinal epithelial cell homeostasis:
Implications for chronic inflammation. Inflamm. Bowel Dis. 2007, 13, 1153–1164. [CrossRef]
25. Ganji-Arjenaki, M.; Rafieian-Kopaei, M. Probiotics are a good choice in remission of inflammatory bowel
diseases: A meta analysis and systematic review. J. Cell. Physiol. 2018, 233, 2091–2103. [CrossRef]
26. Peng, L.; Zhong, Y.; Wang, A.; Jiang, Z. Probiotics combined with aminosalicylic acid affiliates remission of
ulcerative colitis: A meta-analysis of randomized controlled trial. Biosci. Rep. 2019, 39. [CrossRef]
27. Sood, A.; Midha, V.; Makharia, G.K.; Ahuja, V.; Singal, D.; Goswami, P.; Tandon, R.K. The probiotic
preparation, VSL#3 induces remission in patients with mild-to-moderately active ulcerative colitis. Clin.
Gastroenterol. Hepatol. 2009, 7, 1202–1209.e1. [CrossRef]
28. Kruis, W.; Fric, P.; Pokrotnieks, J.; Lukás, M.; Fixa, B.; Kascák, M.; Kamm, M.A.; Weismueller, J.; Beglinger, C.;
Stolte, M.; et al. Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is
as effective as with standard mesalazine. Gut 2004, 53, 1617–1623. [CrossRef]
29. Sang, L.-X.; Chang, B.; Zhang, W.-L.; Wu, X.-M.; Li, X.-H.; Jiang, M. Remission induction and maintenance
effect of probiotics on ulcerative colitis: A meta-analysis. World J. Gastroenterol. 2010, 16, 1908–1915.
[CrossRef]
30. Fedorak, R.N.; Feagan, B.G.; Hotte, N.; Leddin, D.; Dieleman, L.A.; Petrunia, D.M.; Enns, R.; Bitton, A.;
Chiba, N.; Paré, P.; et al. The probiotic VSL#3 has anti-inflammatory effects and could reduce endoscopic
recurrence after surgery for Crohn’s disease. Clin. Gastroenterol. Hepatol. 2015, 13, 928–935. [CrossRef]
31. Kaur, L.; Gordon, M.; Baines, P.A.; Iheozor-Ejiofor, Z.; Sinopoulou, V.; Akobeng, A.K. Probiotics for induction
of remission in ulcerative colitis. Cochrane Database Syst. Rev. 2020, 3. [CrossRef] [PubMed]
32. Mallon, P.; McKay, D.; Kirk, S.; Gardiner, K. Probiotics for induction of remission in ulcerative colitis. Cochrane
Database Syst. Rev. 2007, CD005573. [CrossRef]
33. Tursi, A.; Brandimarte, G.; Papa, A.; Giglio, A.; Elisei, W.; Giorgetti, G.M.; Forti, G.; Morini, S.; Hassan, C.;
Pistoia, M.A.; et al. Treatment of Relapsing Mild-to-Moderate Ulcerative Colitis With the Probiotic VSL#3
as Adjunctive to a Standard Pharmaceutical Treatment: A Double-Blind, Randomized, Placebo-Controlled
Study. Am. J. Gastroenterol. 2010, 105, 2218–2227. [CrossRef] [PubMed]
34. Petersen, A.M.; Mirsepasi, H.; Halkjær, S.I.; Mortensen, E.M.; Nordgaard-Lassen, I.; Krogfelt, K.A.
Ciprofloxacin and probiotic Escherichia coli Nissle add-on treatment in active ulcerative colitis: A double-blind
randomized placebo controlled clinical trial. J. Crohns Colitis 2014, 8, 1498–1505. [CrossRef] [PubMed]
35. Schultz, M.; Timmer, A.; Herfarth, H.H.; Sartor, R.B.; Vanderhoof, J.A.; Rath, H.C. Lactobacillus GG in
inducing and maintaining remission of Crohn’s disease. BMC Gastroenterol. 2004, 4, 5. [CrossRef] [PubMed]
36. Lactobacillus Rhamnosus GG (ATCC 53103) in Mild-Moderately Active UC Patients ClinicalTrials.gov.
Available online: https://clinicaltrials.gov/ct2/show/NCT04102852 (accessed on 2 June 2020).
Nutrients 2020, 12, 2156 11 of 14

37. A Study to Assess Efficacy and Safety of SER-287 in Adults with Active Mild-to-Moderate Ulcerative Colitis
(ECO-RESET) ClinicalTrials.gov. Available online: https://clinicaltrials.gov/ct2/show/NCT03759041 (accessed
on 2 June 2020).
38. Matsuoka, K.; Uemura, Y.; Kanai, T.; Kunisaki, R.; Suzuki, Y.; Yokoyama, K.; Yoshimura, N.; Hibi, T. Efficacy
of Bifidobacterium breve Fermented Milk in Maintaining Remission of Ulcerative Colitis. Dig. Dis. Sci. 2018,
63, 1910–1919. [CrossRef]
39. Malchow, H.A. Crohn’s disease and Escherichia coli. A new approach in therapy to maintain remission of
colonic Crohn’s disease? J. Clin. Gastroenterol. 1997, 25, 653–658. [CrossRef]
40. Marteau, P.; Lémann, M.; Seksik, P.; Laharie, D.; Colombel, J.F.; Bouhnik, Y.; Cadiot, G.; Soulé, J.C.;
Bourreille, A.; Metman, E.; et al. Ineffectiveness of Lactobacillus johnsonii LA1 for prophylaxis of
postoperative recurrence in Crohn’s disease: A randomised, double blind, placebo controlled GETAID trial.
Gut 2006, 55, 842–847. [CrossRef]
41. Van Gossum, A.; Dewit, O.; Louis, E.; de Hertogh, G.; Baert, F.; Fontaine, F.; DeVos, M.; Enslen, M.; Paintin, M.;
Franchimont, D. Multicenter randomized-controlled clinical trial of probiotics (Lactobacillus johnsonii, LA1)
on early endoscopic recurrence of Crohn’s disease after lleo-caecal resection. Inflamm. Bowel Dis. 2007, 13,
135–142. [CrossRef]
42. Bourreille, A.; Cadiot, G.; Le Dreau, G.; Laharie, D.; Beaugerie, L.; Dupas, J.-L.; Marteau, P.; Rampal, P.;
Moyse, D.; Saleh, A.; et al. Saccharomyces boulardii does not prevent relapse of Crohn’s disease. Clin.
Gastroenterol. Hepatol. 2013, 11, 982–987. [CrossRef]
43. Alipour, B.; Homayouni-Rad, A.; Vaghef-Mehrabany, E.; Sharif, S.K.; Vaghef-Mehrabany, L.;
Asghari-Jafarabadi, M.; Nakhjavani, M.R.; Mohtadi-Nia, J. Effects of Lactobacillus casei supplementation
on disease activity and inflammatory cytokines in rheumatoid arthritis patients: A randomized double-blind
clinical trial. Int. J. Rheum. Dis. 2014, 17, 519–527. [CrossRef]
44. Zamani, B.; Golkar, H.R.; Farshbaf, S.; Emadi-Baygi, M.; Tajabadi-Ebrahimi, M.; Jafari, P.; Akhavan, R.;
Taghizadeh, M.; Memarzadeh, M.R.; Asemi, Z. Clinical and metabolic response to probiotic supplementation
in patients with rheumatoid arthritis: A randomized, double-blind, placebo-controlled trial. Int. J. Rheum.
Dis. 2016, 19, 869–879. [CrossRef] [PubMed]
45. Mandel, D.R.; Eichas, K.; Holmes, J. Bacillus coagulans: A viable adjunct therapy for relieving symptoms of
rheumatoid arthritis according to a randomized, controlled trial. BMC Complement. Altern. Med. 2010, 10, 1.
[CrossRef] [PubMed]
46. Navarro-López, V.; Martínez-Andrés, A.; Ramírez-Boscá, A.; Ruzafa-Costas, B.; Núñez-Delegido, E.;
Carrión-Gutiérrez, M.A.; Prieto-Merino, D.; Codoñer-Cortés, F.; Ramón-Vidal, D.; Genovés-Martínez, S.;
et al. Efficacy and Safety of Oral Administration of a Mixture of Probiotic Strains in Patients with Psoriasis:
A Randomized Controlled Clinical Trial. Acta Derm. Venereol. 2019, 99, 1078–1084. [CrossRef] [PubMed]
47. Häger, J.; Bang, H.; Hagen, M.; Frech, M.; Träger, P.; Sokolova, M.V.; Steffen, U.; Tascilar, K.; Sarter, K.;
Schett, G.; et al. The Role of Dietary Fiber in Rheumatoid Arthritis Patients: A Feasibility Study. Nutrients
2019, 11, 2392. [CrossRef]
48. Valcheva, R.; Koleva, P.; Martínez, I.; Walter, J.; Gänzle, M.G.; Dieleman, L.A. Inulin-type fructans improve
active ulcerative colitis associated with microbiota changes and increased short-chain fatty acids levels.
Gut Microbes 2019, 10, 334–357. [CrossRef]
49. Proudman, S.M.; James, M.J.; Spargo, L.D.; Metcalf, R.G.; Sullivan, T.R.; Rischmueller, M.; Flabouris, K.;
Wechalekar, M.D.; Lee, A.T.; Cleland, L.G. Fish oil in recent onset rheumatoid arthritis: A randomised,
double-blind controlled trial within algorithm-based drug use. Ann. Rheum. Dis. 2015, 74, 89–95. [CrossRef]
50. Kristensen, S.; Schmidt, E.B.; Schlemmer, A.; Rasmussen, C.; Johansen, M.B.; Christensen, J.H. Beneficial effect
of n-3 polyunsaturated fatty acids on inflammation and analgesic use in psoriatic arthritis: A randomized,
double blind, placebo-controlled trial. Scand. J. Rheumatol. 2018, 47, 27–36. [CrossRef]
51. Salesi, M.; Farajzadegan, Z. Efficacy of Vitamin D in patients with active rheumatoid arthritis receiving
methotrexate therapy. Rheumatol. Int. 2012, 32, 2129–2133. [CrossRef]
52. Amalraj, A.; Varma, K.; Jacob, J.; Divya, C.; Kunnumakkara, A.B.; Stohs, S.J.; Gopi, S. A Novel Highly
Bioavailable Curcumin Formulation Improves Symptoms and Diagnostic Indicators in Rheumatoid Arthritis
Patients: A Randomized, Double-Blind, Placebo-Controlled, Two-Dose, Three-Arm, and Parallel-Group
Study. J. Med. Food 2017, 20, 1022–1030. [CrossRef]
Nutrients 2020, 12, 2156 12 of 14

53. Vaghef-Mehrabany, E.; Alipour, B.; Homayouni-Rad, A.; Sharif, S.-K.; Asghari-Jafarabadi, M.; Zavvari, S.
Probiotic supplementation improves inflammatory status in patients with rheumatoid arthritis. Nutrition
2014, 30, 430–435. [CrossRef] [PubMed]
54. Chen, Y.-H.; Wu, C.-S.; Chao, Y.-H.; Lin, C.-C.; Tsai, H.-Y.; Li, Y.-R.; Chen, Y.-Z.; Tsai, W.-H.; Chen, Y.-K.
Lactobacillus pentosus GMNL-77 inhibits skin lesions in imiquimod-induced psoriasis-like mice. J. Food
Drug Anal. 2017, 25, 559–566. [CrossRef] [PubMed]
55. Groeger, D.; O’Mahony, L.; Murphy, E.F.; Bourke, J.F.; Dinan, T.G.; Kiely, B.; Shanahan, F.; Quigley, E.M.M.
Bifidobacterium infantis 35624 modulates host inflammatory processes beyond the gut. Gut Microbes 2013, 4,
325–339. [CrossRef] [PubMed]
56. Davani-Davari, D.; Negahdaripour, M.; Karimzadeh, I.; Seifan, M.; Mohkam, M.; Masoumi, S.J.; Berenjian, A.;
Ghasemi, Y. Prebiotics: Definition, Types, Sources, Mechanisms, and Clinical Applications. Foods 2019, 8, 92.
[CrossRef]
57. Silva, J.P.B.; Navegantes-Lima, K.C.; Oliveira, A.L.B.; Rodrigues, D.V.S.; Gaspar, S.L.F.; Monteiro, V.V.S.;
Moura, D.P.; Monteiro, M.C. Protective Mechanisms of Butyrate on Inflammatory Bowel Disease. Curr.
Pharm. Des. 2018, 24, 4154–4166. [CrossRef]
58. Mohammed Vashist, N.; Samaan, M.; Mosli, M.H.; Parker, C.E.; MacDonald, J.K.; Nelson, S.A.; Zou, G.Y.;
Feagan, B.G.; Khanna, R.; Jairath, V. Endoscopic scoring indices for evaluation of disease activity in ulcerative
colitis. Cochrane Database Syst. Rev. 2018, 1. [CrossRef]
59. Casellas, F.; Borruel, N.; Torrejón, A.; Varela, E.; Antolin, M.; Guarner, F.; Malagelada, J.-R. Oral
oligofructose-enriched inulin supplementation in acute ulcerative colitis is well tolerated and associated
with lowered faecal calprotectin. Aliment. Pharmacol. Ther. 2007, 25, 1061–1067. [CrossRef]
60. Faghfoori, Z.; Shakerhosseini, R.; Navai, L.; Somi, M.H.; Nikniaz, Z.; Abadi, A. Effects of an Oral
Supplementation of Germinated Barley Foodstuff on Serum CRP Level and Clinical Signs in Patients
with Ulcerative Colitis. Health Promot. Perspect. 2014, 4, 116–121. [CrossRef]
61. Lindsay, J.O.; Whelan, K.; Stagg, A.J.; Gobin, P.; Al-Hassi, H.O.; Rayment, N.; Kamm, M.A.; Knight, S.C.;
Forbes, A. Clinical, microbiological, and immunological effects of fructo-oligosaccharide in patients with
Crohn’s disease. Gut 2006, 55, 348–355. [CrossRef] [PubMed]
62. Benjamin, J.L.; Hedin, C.R.H.; Koutsoumpas, A.; Ng, S.C.; McCarthy, N.E.; Hart, A.L.; Kamm, M.A.;
Sanderson, J.D.; Knight, S.C.; Forbes, A.; et al. Randomised, double-blind, placebo-controlled trial of
fructo-oligosaccharides in active Crohn’s disease. Gut 2011, 60, 923–929. [CrossRef]
63. Ananthakrishnan, A.N.; Khalili, H.; Konijeti, G.G.; Higuchi, L.M.; de Silva, P.; Korzenik, J.R.; Fuchs, C.S.;
Willett, W.C.; Richter, J.M.; Chan, A.T. A prospective study of long-term intake of dietary fiber and risk of
Crohn’s disease and ulcerative colitis. Gastroenterology 2013, 145, 970–977. [CrossRef]
64. Forbes, J.D.; Van Domselaar, G.; Bernstein, C.N. The Gut Microbiota in Immune-Mediated Inflammatory
Diseases. Front. Microbiol. 2016, 7. [CrossRef] [PubMed]
65. Franco, A.S.; Freitas, T.Q.; Bernardo, W.M.; Pereira, R.M.R. Vitamin D supplementation and disease activity
in patients with immune-mediated rheumatic diseases. Medicine (Baltimore) 2017, 96. [CrossRef] [PubMed]
66. Zuccotti, E.; Oliveri, M.; Girometta, C.; Ratto, D.; Di Iorio, C.; Occhinegro, A.; Rossi, P. Nutritional strategies
for psoriasis: Current scientific evidence in clinical trials. Eur. Rev. Med. Pharmacol. Sci. 2018, 22, 8537–8551.
[CrossRef] [PubMed]
67. Rossi, R.E.; Whyand, T.; Murray, C.D.; Hamilton, M.I.; Conte, D.; Caplin, M.E. The role of dietary supplements
in inflammatory bowel disease: A systematic review. Eur. J. Gastroenterol. Hepatol. 2016, 28, 1357–1364.
[CrossRef]
68. Calder, P.C. Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical
relevance. Biochim. Biophys. Acta 2015, 1851, 469–484. [CrossRef]
69. Lev-Tzion, R.; Griffiths, A.M.; Leder, O.; Turner, D. Omega 3 fatty acids (fish oil) for maintenance of remission
in Crohn’s disease. Cochrane Database Syst. Rev. 2014, CD006320. [CrossRef]
70. Seidner, D.L.; Lashner, B.A.; Brzezinski, A.; Banks, P.L.C.; Goldblum, J.; Fiocchi, C.; Katz, J.; Lichtenstein, G.R.;
Anton, P.A.; Kam, L.Y.; et al. An oral supplement enriched with fish oil, soluble fiber, and antioxidants for
corticosteroid sparing in ulcerative colitis: A randomized, controlled trial. Clin. Gastroenterol. Hepatol. 2005,
3, 358–369. [CrossRef]
71. James, M.; Proudman, S.; Cleland, L. Fish oil and rheumatoid arthritis: Past, present and future. Proc. Nutr.
Soc. 2010, 69, 316–323. [CrossRef]
Nutrients 2020, 12, 2156 13 of 14

72. Millsop, J.W.; Bhatia, B.K.; Debbaneh, M.; Koo, J.; Liao, W. Diet and psoriasis, part III: Role of nutritional
supplements. J. Am. Acad. Dermatol. 2014, 71, 561–569. [CrossRef]
73. Yang, S.-J.; Chi, C.-C. Effects of fish oil supplement on psoriasis: A meta-analysis of randomized controlled
trials. BMC Complement. Altern. Med. 2019, 19, 354. [CrossRef] [PubMed]
74. Brakenhoff, L.K.P.M.; van der Heijde, D.M.; Hommes, D.W. IBD and arthropathies: A practical approach to
its diagnosis and management. Gut 2011, 60, 1426–1435. [CrossRef] [PubMed]
75. Vavricka, S.R.; Schoepfer, A.; Scharl, M.; Lakatos, P.L.; Navarini, A.; Rogler, G. Extraintestinal Manifestations
of Inflammatory Bowel Disease. Inflamm. Bowel Dis. 2015, 21, 1982–1992. [CrossRef] [PubMed]
76. Mangin, M.; Sinha, R.; Fincher, K. Inflammation and vitamin D: The infection connection. Inflamm. Res. 2014,
63, 803–819. [CrossRef] [PubMed]
77. López-Muñoz, P.; Beltrán, B.; Sáez-González, E.; Alba, A.; Nos, P.; Iborra, M. Influence of Vitamin D Deficiency
on Inflammatory Markers and Clinical Disease Activity in IBD Patients. Nutrients 2019, 11, 1059. [CrossRef]
[PubMed]
78. Soleymani, T.; Hung, T.; Soung, J. The role of vitamin D in psoriasis: A review. Int. J. Dermatol. 2015, 54,
383–392. [CrossRef] [PubMed]
79. Siddiqui, M.A.; Al-Khawajah, M.M. Vitamin D3 and psoriasis: A randomized double-blind placebo-controlled
study. J. Dermatol. Treat. 1990, 1, 243–245. [CrossRef]
80. Fletcher, J.; Cooper, S.C.; Ghosh, S.; Hewison, M. The Role of Vitamin D in Inflammatory Bowel Disease:
Mechanism to Management. Nutrients 2019, 11, 1019. [CrossRef]
81. Kocaadam, B.; Şanlier, N. Curcumin, an active component of turmeric (Curcuma longa), and its effects on
health. Crit. Rev. Food Sci. Nutr. 2017, 57, 2889–2895. [CrossRef]
82. He, Y.; Yue, Y.; Zheng, X.; Zhang, K.; Chen, S.; Du, Z. Curcumin, inflammation, and chronic diseases: How
are they linked? Mol. Basel Switz. 2015, 20, 9183–9213. [CrossRef]
83. Lang, A.; Salomon, N.; Wu, J.C.Y.; Kopylov, U.; Lahat, A.; Har-Noy, O.; Ching, J.Y.L.; Cheong, P.K.;
Avidan, B.; Gamus, D.; et al. Curcumin in Combination With Mesalamine Induces Remission in Patients
With Mild-to-Moderate Ulcerative Colitis in a Randomized Controlled Trial. Clin. Gastroenterol. Hepatol.
2015, 13, 1444–1449.e1. [CrossRef] [PubMed]
84. Kedia, S.; Bhatia, V.; Thareja, S.; Garg, S.; Mouli, V.P.; Bopanna, S.; Tiwari, V.; Makharia, G.; Ahuja, V. Low
dose oral curcumin is not effective in induction of remission in mild to moderate ulcerative colitis: Results
from a randomized double blind placebo controlled trial. World J. Gastrointest. Pharmacol. Ther. 2017, 8,
147–154. [CrossRef] [PubMed]
85. Javadi, M.; Khadem Haghighian, H.; Goodarzy, S.; Abbasi, M.; Nassiri-Asl, M. Effect of curcumin nanomicelle
on the clinical symptoms of patients with rheumatoid arthritis: A randomized, double-blind, controlled trial.
Int. J. Rheum. Dis. 2019, 22, 1857–1862. [CrossRef] [PubMed]
86. Chandran, B.; Goel, A. A randomized, pilot study to assess the efficacy and safety of curcumin in patients
with active rheumatoid arthritis. Phytother. Res. 2012, 26, 1719–1725. [CrossRef]
87. Campbell, N.K.; Fitzgerald, H.K.; Malara, A.; Hambly, R.; Sweeney, C.M.; Kirby, B.; Fletcher, J.M.; Dunne, A.
Naturally derived Heme-Oxygenase 1 inducers attenuate inflammatory responses in human dendritic cells
and T cells: Relevance for psoriasis treatment. Sci. Rep. 2018, 8. [CrossRef] [PubMed]
88. Sun, J.; Zhao, Y.; Hu, J. Curcumin Inhibits Imiquimod-Induced Psoriasis-Like Inflammation by Inhibiting
IL-1beta and IL-6 Production in Mice. PLoS ONE 2013, 8. [CrossRef]
89. Bai, A.-P.; Ouyang, Q. Probiotics and inflammatory bowel diseases. Postgrad. Med. J. 2006, 82, 376–382.
[CrossRef]
90. Schultz, M.; Schölmerich, J.; Rath, H.C. Rationale for probiotic and antibiotic treatment strategies in
inflammatory bowel diseases. Dig. Dis. Basel Switz. 2003, 21, 105–128. [CrossRef]
91. Bernet, M.F.; Brassart, D.; Neeser, J.R.; Servin, A.L. Lactobacillus acidophilus LA 1 binds to cultured human
intestinal cell lines and inhibits cell attachment and cell invasion by enterovirulent bacteria. Gut 1994, 35,
483–489. [CrossRef]
92. Babakissa, C.; Colomb, V.; Andrieux, C.; Cherbuy, C.; Vaugelade, P.; Bernard, F.; Popot, F.; Corriol, O.;
Ricour, C.; Duée, P.-H.; et al. Luminal fermentation and colonocyte metabolism in a rat model of enteral
nutrition. Dig. Dis. Sci. 2003, 48, 1339–1345. [CrossRef]
Nutrients 2020, 12, 2156 14 of 14

93. Le Blay, G.; Michel, C.; Blottière, H.M.; Cherbut, C. Prolonged intake of fructo-oligosaccharides induces
a short-term elevation of lactic acid-producing bacteria and a persistent increase in cecal butyrate in rats.
J. Nutr. 1999, 129, 2231–2235. [CrossRef] [PubMed]
94. Wilson, A.J.; Gibson, P.R. Short-chain fatty acids promote the migration of colonic epithelial cells in vitro.
Gastroenterology 1997, 113, 487–496. [CrossRef] [PubMed]
95. Liu, Q.; Shimoyama, T.; Suzuki, K.; Umeda, T.; Nakaji, S.; Sugawara, K. Effect of sodium butyrate on reactive
oxygen species generation by human neutrophils. Scand. J. Gastroenterol. 2001, 36, 744–750. [CrossRef]
[PubMed]
96. De Souza, H.S.P.; Fiocchi, C. Immunopathogenesis of IBD: Current state of the art. Nat. Rev. Gastroenterol.
Hepatol. 2016, 13, 13–27. [CrossRef]
97. Endres, S.; Ghorbani, R.; Kelley, V.E.; Georgilis, K.; Lonnemann, G.; van der Meer, J.W.; Cannon, J.G.;
Rogers, T.S.; Klempner, M.S.; Weber, P.C. The effect of dietary supplementation with n-3 polyunsaturated
fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. N. Engl. J. Med.
1989, 320, 265–271. [CrossRef] [PubMed]

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