Digestive Diseases and Sciences

https://doi.org/10.1007/s10620-020-06109-5

REVIEW

Microbiome and Its Role in Irritable Bowel Syndrome

Mark Pimentel1 · Anthony Lembo2

© Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract
Irritable bowel syndrome (IBS) is an extremely common and often very debilitating chronic functional gastrointestinal disorder.
Despite its prevalence, significant associated healthcare costs, and quality-of-life issues for affected individuals, our understand-
ing of its etiology remained limited. However, it is now evident that microbial factors play key roles in IBS pathophysiology.
Acute gastroenteritis following exposure to pathogens can precipitate the development of IBS, and studies have demonstrated
changes in the gut microbiome in IBS patients. These changes may explain some of the symptoms of IBS, including visceral
hypersensitivity, as gut microbes exert effects on the host immune system and gut barrier function, as well as the brain–gut
axis. Microbial differences also appear to underlie the two main functional categories of IBS: diarrhea-predominant IBS (IBS-
D) is associated with small intestinal bacterial overgrowth, which can be diagnosed by a positive hydrogen breath test, and
constipation-predominant IBS (IBS-C) is associated with increased levels of methanogenic archaea, which can be diagnosed
by a positive methane breath test. Mechanistically, the pathogens that cause gastroenteritis and trigger subsequent IBS develop-
ment produce a common toxin, cytolethal distending toxin B (CdtB), and antibodies raised against CdtB cross-react with the
cytoskeletal protein vinculin and impair gut motility, facilitating bacterial overgrowth. In contrast, methane gas slows intestinal
contractility, which may facilitate the development of constipation. While antibiotics and dietary manipulations have been
used to relieve IBS symptoms, with varying success, elucidating the specific mechanisms by which gut microbes exert their
effects on the host may allow the development of targeted treatments that may successfully treat the underlying causes of IBS.

Keywords Irritable bowel syndrome · Gut microbiome · Acute gastroenteritis · Small intestinal bacterial overgrowth ·
Brain-gut axis · Diet · Antibiotics

Mark Pimentel Anthony Lembo

2
* Mark Pimentel Division of Gastroenterology, Beth Israel Deaconess
[email protected] Hospital, Boston, MA, USA
1
Medically Associated Science and Technology (MAST)
Program, Cedars-Sinai Medical Center, Los Angeles, CA,
USA

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Introduction Post‑infectious IBS

Irritable bowel syndrome (IBS) is a chronic functional gas- Prevalence

trointestinal disorder characterized by abdominal pain and
altered bowel habits, either diarrhea (IBS-D), constipation Reports of post-infectious IBS are not new, although until
(IBS-C), or altering between diarrhea and constipation (IBS- recently these descriptions were sporadic. In the 1960s,
M). Approximately 13% of the world’s population suffers Chaudhary and Truelove described what was then known
from IBS symptoms [1], which results in increased consul- as “irritable colon syndrome” following infectious gastro-
tations, diagnostic procedures, and surgeries. IBS is also enteritis [4]. In 1994, McKendrick and Read reported the
associated with increased medication consumption, reduced development of IBS following two outbreaks of Salmonella
quality of life, and high rates of absenteeism from work and in the UK [5]. Subsequently, multiple infectious gastrointes-
school, and the costs of IBS in the USA alone have been tinal outbreaks have been studied, with the incidence of post-
estimated at over $30 billion [2]. infectious IBS ranging from 3.7 to 36% and lasting up to 6
Despite the prevalence and burden of IBS, its pathobiology and 8 years after the acute illness [6]. In addition to typical
has remained elusive. Early studies focused on gastrointestinal acute gastroenteritis pathogens, even more exotic pathogens
motor disturbances including changes in intestinal transit and are being linked to IBS as well, such as spirochetes [7].
abnormal contractions [3]. Subsequent studies found that many A recent meta-analysis of 45 studies that prospectively
IBS patients experience pain from rectal balloon distention at followed infectious outbreaks found that the pooled inci-
lower thresholds than healthy controls (i.e., visceral hypersen- dence of IBS was 10.1% at 3 or more months after acute
sitivity). Increasing evidence over the past decade suggests that gastroenteritis and 14.5% at more than 12 months after acute
the microbiome may contribute significantly to these findings gastroenteritis [6]. The risk of IBS was 4.2-fold higher in
in IBS. Early recognition that IBS frequently develops after an patients who had acute gastroenteritis in the past 12 months
episode of infectious gastroenteritis led investigators to explore than in those who did not [6]. Several factors increased
the role of bacteria in the pathophysiology of IBS. Uncover- the likelihood of developing IBS (Table 1). Notably, the
ing this role requires the understanding of two parallel paths severity of acute gastroenteritis and female sex were strong
of research into post-infectious IBS and intestinal dysbiosis, predictors. Although the reasons for the higher prevalence
which later merge into a single hypothesis (Fig. 1). of IBS in women remain unproven, a recent genome-wide

Fig. 1  Microbial hypothesis in irritable bowel syndrome

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Digestive Diseases and Sciences

Table 1  Risk factors for the development of post-infectious IBS fol- valuable insights, neither Citrobacter nor Trichinella are
lowing acute gastroenteritis. Adapted from Klem et al. Gastroenterol- common causes of human acute gastroenteritis or post-infec-
ogy [6]
tious IBS in the USA. In another model, Sprague–Dawley
Risk factor Pooled OR at rats were infected with Campylobacter jejuni [15], one of the
95% CI (range) most common causes of bacterial gastroenteritis in the USA.
Host-related After recovery from the initial acute infection, most animals
Female gender 2.19 (1.57–3.07) developed altered stool form, increased rectal lymphocytes
Anxiety 1.97 (1.32–2.94) [15], reduced deep muscular plexus interstitial cells of Cajal,
Depression 1.49 (1.17–1.90) and small intestinal bacterial overgrowth [16]. These find-
Somatization 4.05 (2.71–6.03) ings mirrored findings in humans with post-infectious IBS
Neuroticism 3.26 (1.62–6.55) [17]. Interestingly, small intestinal bacterial overgrowth in
Smoking 1.15 (0.90–1.46) humans can result from reductions in migrating motor com-
AGE-related plexes [18] for which the deep muscular plexus interstitial
Abdominal pain 3.26 (1.30–8.14) cells of Cajal are the pacemaker cells.
Antibiotic use 1.69 (1.20–2.37) This new animal model was an important tool to study the
Bloody stool 1.86 (1.14–3.03) development of IBS following acute gastroenteritis. Since C.
Duration of > 7 days 2.62 (1.48–4.61) difficile, C. jejuni, Salmonella, Escherichia coli, and Shigella
Fever 1.21 (0.66–2.23) can all cause IBS [6], identifying a common factor became
Weight loss 1.69 (0.87–3.25) an important goal. One commonality was the production of
cytolethal distending toxin (Cdt). Pokkunuri et al. showed
that animals infected with a genetically modified C. jejuni
association study (GWAS) by Bonfiglio et al. found an asso- lacking CdtB had fewer symptoms (i.e., altered bowel habits)
ciation between variants at the locus 9q31.2 and the risk of and less inflammation (i.e., rectal lymphocytes [17]) com-
IBS in women, a region previously associated with condi- pared to animals exposed to wild-type C. jejuni [19]. These
tions and traits influenced by sex hormones [8]. results suggested the CdtB toxin was required for the devel-
opment of IBS-like phenotypes.
Psychological Factors Subsequent studies found that antibodies to CdtB cross-
react with vinculin [20], an intracellular cytoskeletal protein
Although IBS is frequently associated with stress and anxi- that is an important component of cell adhesion and plays
ety [9], it has been unclear to what extent these contribute to a key role in neuronal cell motility and contractility [21],
the development of IBS, or vice versa. Evidence from stud- particularly in the gastrointestinal tract. Data suggest that
ies in animal models, e.g., the Citrobacter rodentium mouse exposure to CdtB leads to autoimmunity to vinculin [20],
model [10], indicates stress may affect the gut microbiota, supporting an earlier hypothesis that autoimmunity may play
increase gut motility [11], and augment the risk of develop- a role in functional gastrointestinal disorders [22].
ing post-infectious symptoms. Recently, a study of deployed The clinical significance of these discoveries is high-
US military personnel found that, despite significant psy- lighted by the finding that anti-CdtB and anti-vinculin
chological stress in combat zones, acute gastroenteritis dur- antibodies occur more commonly in IBS-D as compared to
ing deployment rather than stress was the most important other conditions that cause diarrhea, including inflammatory
risk factor for IBS development [12]. Furthermore, recent bowel disease (IBD) and celiac disease [23]. When both
evidence indicates that in approximately two-thirds of IBS antibodies are positive, an IBS-D diagnosis can be reached
cases, psychological distress develops after the onset of gas- more confidently [23]. However, sensitivity remained low at
trointestinal symptoms [13]. approximately 50%, likely due to the heterogeneous nature
of IBS-D pathophysiology. The utility of these antibodies in
Post‑infectious IBS Changes the Microbiome diagnosing IBS has been validated in several independent
studies performed in European [24], Latin American [25],
Following the emerging data that linked IBS to acute gastro- and US military [26] populations.
enteritis, animal models were developed. These included the
above-described Citrobacter rodentium mouse model [10], Antibiotics
as well as the Trichinella spiralis mouse model that has been
used to study smooth muscle hypercontractility following Studies have also suggested that prior antibiotics are a risk
parasite infection [14]. While these models have provided factor for IBS. In a case-controlled study, antibiotic use in
the previous year was associated with a three-fold increased

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risk of developing IBS [27]. In another case-controlled that combining cytokine profiles with microbiome-directed
study, 83% of patients with new-onset functional GI symp- antibodies might provide optimal results [26]. They also
toms reported antibiotic use with an odds ratio of 1.95 (95% found a strong association between anti-vinculin antibody
CI: 1.2–3.0, p = 0.005) [28]. levels and development of post-Campylobacter IBS [26].

Role of Intestinal Dysbiosis in IBS Small Intestinal Bacterial Overgrowth

and IBS
The concept that the intestinal microbiome was associ-
ated with human disease led investigators to study whether Many, but not all, studies have reported a greater prevalence
alterations in the microbiome could be identified in IBS, of small intestinal bacterial overgrowth in IBS versus con-
and whether these contributed to, or were the result of, the trols based on either glucose or lactulose breath testing [43].
IBS development. Numerous studies have been performed Meta-analyses revealed that breath testing is abnormal in
using varying techniques (quantitative PCR (qPCR), 16S IBS subjects more often than in healthy controls (pooled
rRNA denaturing gradient gel electrophoresis (DGGE), OR 3.45 (95% CI 0.9–12.7) or 4.7 (95% CI 1.7–12.95)),
phylogenetic microarrays, and 16S rRNA gene sequencing) depending on the criteria used to define a positive test [43].
and sample types (fecal samples, duodenal mucosa brush In comparison, only a handful of studies used small bowel
samples, duodenal aspirates, and colonic/rectal mucosal cultures to determine the presence of small intestinal bacte-
biopsy samples) (Table 2). Moreover, some compared IBS rial overgrowth. Posserud et al. showed that coliforms were
subjects to healthy controls, while others examined specific much more common in duodenal aspirates from IBS subjects
IBS subtypes. Comparing these studies, several [29–34], versus healthy controls [44]. However, using older defini-
but not all [35], identified lower microbial diversity or rich- tions of small intestinal bacterial overgrowth (> 105 cfu/mL),
ness in IBS subjects versus healthy controls. At the phylum these differences were not significant. Another study found
level, some found an increase in Firmicutes-to-Bacteroidetes small intestinal bacterial overgrowth was far more predomi-
ratio in IBS subjects, including Rajilic-Stojanovic et al. who nant in IBS patients than in non-IBS patients undergoing
also found decreased Bifidobacterium [36] and Jeffery et al. endoscopy for other reasons [45]. QPCR and deep sequenc-
who also found increased Actinobacteria in IBS samples ing of small bowel aspirates from IBS subjects and controls
[31]. In contrast, Ng et al. found increased Bacteroidetes confirmed these findings [33].
abundance and decreased Actinobacteria abundance in IBS Recent data suggest that elevated methane gas production,
subjects versus healthy controls, with probiotic treatment generated predominantly by archaeal species, can influence
reducing the genus Bacteroides to levels similar to controls intestinal motor activity and leads to intestinal slowing and
[32]. A recent meta-analysis of stool qPCR studies iden- constipation [46, 47]. In humans, the predominant archaeon
tified consistent findings of lower levels of Lactobacillus, and methane producer is Methanobrevibacter smithii [48].
Bifidobacterium, and Faecalibacterium prausnitzii in IBS In a double-blind, randomized, placebo-controlled trial [49],
subjects [37]. Using a machine learning procedure, a recent a combination of rifaximin and neomycin could be used to
study identified a microbial profile in patients with severe eradicate methane on breath test in up to 85% of subjects,
IBS characterized by decreased microbial richness, lower resulting in significant improvements in gastrointestinal
levels of exhaled methane, and a Bacteroides-enriched ente- symptoms including constipation severity, straining, and
rotype [38]. bloating [49]. A recent consensus now considers methane
One of the stronger links between IBS and the intesti- (as a surrogate for excess intestinal colonization with metha-
nal microbiota is the finding that the transfer of stool from nogens) as important in the assessment of constipation and
IBS-D patients to animals induces changes similar to those IBS-C [50].
in IBS, including altered intestinal motility, innate immune-
activation and increased intestinal permeability, and vis- Brain–Gut–Microbiome Axis
ceral hypersensitivity [39]. IBS patients also appear to
have increased expression of intestinal Toll-like receptors The brain–gut axis has been widely described as impor-
(TLRs) [40, 41], which are important mediators of intesti- tant to the understanding of IBS [3]. IBS is associated
nal immune response to gut microbes—specifically, TLR4 with alterations in gut motility, gut barrier function,
is implicated in recognition of bacterial lipopolysaccha- immune regulation, and visceral hypersensitivity, all of
ride (LPS) and TLR5 is implicated in flagellin recognition which can be affected by the gut microbiome [42, 51, 52].
[42]. Pike et al. suggested that differences in host immune For example, increased serum levels of bacterial LPS
responses may predict the likelihood of developing IBS, with and anti-flagellin antibodies have been demonstrated in
or without antecedent acute gastroenteritis, and concluded IBS-D subjects, indicating impaired gut barrier function

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Table 2  Microbiome analysis studies in IBS

Study Subjects, samples, and techniques Principal findings

Kerckhoffs et al. [78] Fecal and duodenal mucosa brush samples Lower Bifidobacteria counts in duodenum and fecal
41 IBS and 26 healthy controls samples in IBS
FISH; qPCR for Bifidobacteria
Codling et al. [29] Fecal and colonic mucosa samples Lower microbial diversity in IBS
47 IBS and 33 healthy controls
16S rRNA D ­ GGEa
Kerckhoffs et al. [79] Fecal and duodenal mucosa brush samples Higher levels of Pseudomonas aeruginosa in duode-
37 IBS and 20 healthy controls nal and fecal samples in IBS
16S rRNA D ­ GGEa and qPCR
Ponnusamy et al. [35] Fecal samples Higher diversity of total bacteria, Bacteroidetes and
11 IBS and 8 non-IBS Lactobacillus in IBS
16S rRNA D ­ GGEa and qPCR Lower diversity of Bifidobacter and Clostridium coc-
coides in IBS
Rajilic-Stojanovic et al. [36] Fecal samples Twofold increase in Firmicutes-to-Bacteroidetes ratio
62 IBS (varied subtypes) and 46 healthy controls in IBS
Phylogenetic microarray and qPCR 1.5-fold increase in Dorea, Ruminococcus, and
Clostridium spp.
1.5-fold decrease in Bifidobacterium and Faecalibac-
terium spp
Fourfold decrease in methanogens
Saulnier et al. 2011 Fecal samples Higher levels of Gammaproteobacteria in IBS, includ-
22 pediatric IBS and 22 healthy controls ing higher Haemophilus parainfluenzae
16S rRNA gene sequencing Novel Ruminococcus-like microbe associated with
IBS
Carroll et al. [30] Fecal samples Reduced microbial richness in D-IBS
23 D-IBS and 23 healthy controls Increased levels of Enterobacteriaceae in D-IBS
16S rRNA gene sequencing Decreased levels of Fecalibacterium genera in D-IBS
Jeffery et al. [31] Fecal samples Lower microbial diversity in IBS
37 IBS (varied subtypes) and 20 healthy controls Wide-ranging microbial changes in a subset of
16S rRNA gene sequencing IBS (N = 22) including increased Firmicutes and
decreased Bacteroidetes among other findings
Ng et al. [32] Rectal biopsies Lower microbial diversity in IBS at genus but not
10 IBS and 10 healthy controls OTU level
16S rRNA gene sequencing Increased Bacteroidetes and Synergistetes in IBS
Decreased Actinobacteria and Cyanobacteria in IBS
Rangel et al. [80] Fecal samples and mucosal biopsies Lower Clostridiales in mucosal samples in IBS
35 IBS and 16 healthy controls Many differences in IBS in fecal samples
Phylogenetic microarray Notable findings including increases in Actinobacte-
ria, Bacilli, several Clostridium clusters and Proteo-
bacteria and a decrease in Bacteroidetes
Giamarellos-Bourboulis et al. [33] Duodenal aspirates Lower microbial diversity in IBS
74 IBS, 163 non-healthy non-IBS, and 21 healthy Increased Escherichia/Shigella and Aeromonas in IBS
for qPCR Decreased Acinetobacter, Citrobacter and Microvir-
5 IBS and 5 healthy for 16S rRNA gene sequencing gula in IBS
Tap et al. [38] Fecal samples and mucosal biopsies Using classic approaches, no differences between IBS
Cohort 1: 110 IBS, 39 healthy controls and healthy
Cohort 2: 29 IBS, 17 healthy controls Computational statistics identified a microbial
16S rRNA gene sequencing signature in severe IBS including methanogens and
enriched by Clostridiales or Prevotella
Maharshak et al. [34] Fecal samples and mucosal biopsies Decreased richness in IBS fecal samples only
23 D-IBS and 24 healthy subjects Faecalibacterium lower in D-IBS
16S rRNA gene sequencing Dorea higher in D-IBS
a
DGGE denaturing gradient gel electrophoresis

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and resultant bacterial translocation to the circulation [53], antibiotics to treat IBS may represent the strongest argu-
which in turn leads to immune responses and inflamma- ment for the role of bacteria in IBS.
tion. Interestingly, this increase in serum anti-flagellin Neomycin was one of the first antibiotics to be studied
antibodies correlated with patient anxiety scores [53], systematically for IBS. In a randomized double-blind pla-
underscoring the central link between gut and brain. The cebo-controlled trial of 111 IBS patients fulfilling standard
reductions in bifidobacteria identified in some IBS stud- diagnostic criteria comparing neomycin to placebo, neo-
ies [35, 36] have also been associated with impaired gut mycin resulted in a 35% improvement in composite scores
barrier function (possibly mediated through TLRs [40, of IBS symptoms, compared with only 11% for placebo
41] and/or tight junction proteins). Altered signaling by (p < 0.05) [62]. Although neomycin alone was somewhat
muscle-residing macrophages and secretion of cytokines, effective in treating IBS, it is used less often due to side
both of which may be influenced by the gut microbiota, effects.
have also been suggested to affect inflammatory responses Rifaximin is a non-systemic antibiotic for which a num-
and gut motility, possibly via effects on the interstitial cells ber of mechanisms of action have been proposed, includ-
of Cajal [54] that again are mediated by TLR signaling ing potential anti-inflammatory actions, and is the most
[55]. Lastly, serotonin (produced by intestinal enterochro- comprehensively studied antibiotic explored in the treat-
maffin cells) and histamine (produced by mast cells in the ment of IBS-D. In two identically designed phase III trials,
mucosa) have been shown to affect inflammation and intes- a single 2-week treatment with rifaximin 550 mg three
tinal barrier integrity [56], and serotonin has also been times daily in patients with non-constipated IBS resulted
implicated in visceral hypersensitivity. Gut microbiota in significantly more patients reporting adequate relief of
appear to modulate serotonin production [57], suggesting IBS (p = 0.01) and bloating (p = 0.005) [63]. Improvement
another potential mechanism by which gut microbes may in symptoms persisted for up to 10 weeks following ces-
affect the gut–brain axis and potentially contribute to IBS sation of treatment [63]. In a more recent phase III trial to
symptoms. assess the safety and efficacy of repeat rifaximin treatment,
Recently, it has become apparent that beyond their inter- 692 IBS-D patients who initially responded to rifaximin
action with the gut, microbes can influence the brains of and then relapsed were randomized to double-blind rifaxi-
their hosts including links to psychological symptoms [58]. min or placebo for 14 days. More patients were found to
For example, colonization of germ-free mice with micro- respond to retreatment with rifaximin than placebo (38.1%
biota from IBS-D patients with anxiety resulted in anxiety- vs. 31.5%) [64].
like behavior in those mice but not in mice colonized with A meta-analysis of clinical trials found rifaximin to be
microbiota from IBS-D patients without anxiety or with more efficacious than placebo for global IBS symptom
healthy controls [59]. In a recent human study, changes in improvement (OR = 1.57; 95% CI = 1.22, 2.01; therapeu-
the microbiome of IBS patients appeared to determine pat- tic gain = 9.8%; number needed to treat (NNT = 10.2),
terns of brain activation [60]. These findings help to inte- with mild heterogeneity (p = 0.25, I(2) = 26%) [65].
grate the seemingly disparate brain–gut axis and microbial Importantly, rifaximin appears to have an acceptable
theories of IBS. side-effect profile with no difference in overall adverse
events between the antibiotic and placebo groups. While
the mechanism of rifaximin is not entirely determined, a
Treating the Microbiome in IBS rodent model revealed that rifaximin reduces bacterial lev-
els in the small intestine, particularly the duodenum, but
Given the mounting evidence that microbes have a role in has lesser and more transient effects on colonic microbes,
IBS, research has examined many avenues of microbial with stool coliform counts recovering within 3 days of ces-
manipulation including antibiotics, probiotics, and dietary sation of treatment [66]. Due to its safety, rifaximin was
changes. approved by the FDA for the treatment of IBS-D.

Antibiotics Probiotics

The growing role of the microbiome in IBS became the Probiotics are widely available and may benefit patients with
basis for trials using antibiotic approaches to treat IBS. IBS through mechanisms that include modifying gut bacte-
Most studies have used poorly absorbed antibiotics, rial communities, mucosal immune function, mucosal bar-
neomycin or rifaximin in particular, to elicit this effect. rier function, function of neuroendocrine cells, and fermen-
Another study showed that norfloxacin was successful tation [67]. Though clinical trials have evaluated the efficacy
in relieving IBS symptoms, including small intestinal of probiotics in IBS patients, most suffer from serious
bacterial overgrowth [61]. In some ways, the success of methodological flaws. A recent meta-analysis that included

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15 controlled trials concluded that probiotics reduce pain a structured reintroduction of FODMAP-containing foods,
and symptom severity scores with a relative risk ratio for which allows the individual to tailor their diets. The com-
adequate improvement of IBS of 2.14 (95% CI: 1.08–4.26; plexity of the low-FODMAP diet and the need for a struc-
p = 0.03) [68]. Despite this observed improvement, the opti- tured food reintroduction phase emphasize the critical role of
mal strain, dose, formulation, and duration of therapy have a properly trained dietician in the IBS care team [74]. More
not yet been determined. importantly, a recent study indicated that a low-FODMAP
In probably the most notable study using probiotics to diet can reduce stool microbiome diversity [75], a finding
treat IBS, Bifidobacter infantis 35624 led to significant usually attributed to an “unhealthy” microbiome. Thus,
improvements in abdominal pain/discomfort, bloating/ long-term treatment with of low FODMAP requires further
distention, and/or bowel movement difficulty compared study.
with placebo (p < 0.05) in a randomized, blinded placebo-
controlled trial conducted in IBS patients [69]. Few stud- Fecal Microbiota Transplantation
ies have evaluated the effects of probiotics specifically in
subtypes of IBS, although a recent placebo-controlled trial Fecal transplantation has been an exciting area of therapeu-
evaluated a probiotic combination of three lactobacilli, three tics, with most benefit seen in recurring C. difficile colitis. A
bifidobacteria, and Streptococcus thermophiles for 8 weeks recent Norwegian study found that when stool from healthy
in 50 patients with IBS-D. A significantly greater percent- individuals was transplanted into IBS-D patients during
age of patients receiving the probiotic combination reported colonoscopy, clinically meaningful improvement in symp-
adequate relief of IBS compared to placebo (48% vs. 12%, toms (defined as a decrease in the IBS-SSS score of > 75
p = 0.01 reporting adequate relief for > 50% of weeks). Stool points) occurred in 65% (36 out 75) of patients at 3 months
consistency also improved significantly with probiotics ver- compared with 43% (12 out 28) of patients receiving their
sus placebo [70]. own stool. Patients had better results if they received fro-
zen rather than fresh fecal microbiota transplantation [76].
Effects of Diets for IBS on the Microbiome However, another recent study found that while fecal trans-
plantation did alter the gut microbiome in IBS subjects,
The low-FODMAP (fermentable oligo-, di-, and monosac- those receiving placebo reported greater symptom relief
charides and polyols) diet has gained the most attention in than those receiving fecal transplantation [77]. The level of
recent years in part on the basis that it restricts consump- current interest in this subject is evidenced by three recently
tion of food that promotes microbial fermentation in the presented abstracts. On balance, results are not promising,
gut. The main dietary sources of FODMAPs include dairy, but these data await scrutiny after peer-reviewed publication.
wheat and other grains, many fruits and vegetables, and These variable results illustrate that further data are needed
artificial sweeteners. Accumulating evidence from retro- before considering this approach in clinical practice.
spective and prospective controlled trials suggests dietary
FODMAP restriction is associated with reduced fermenta-
tion and significant symptom improvement in a subset of Conclusions
IBS sufferers [71]. Restriction of both fructose and fructans
appears necessary to achieve the full clinical benefits [72]. There is ever-growing evidence supporting the role of
In a randomized sham-controlled single-blind crossover trial microbes in the pathophysiology of IBS (Table 3). It is
among IBS patients who had not previously tried dietary clear from an immense body of literature that exposure to a
manipulation, participants reported a significant reduction pathogen can be an important initiating event in the devel-
in overall gastrointestinal symptom scores compared to those opment of IBS, leading to a series of downstream events
on a standard Australian diet (22.8 vs., 44.9; range 0–100, that may culminate in a change in gut colonization in IBS
p < 0.001) [71]. Patients of all IBS subtypes had greater sat- patients (Fig. 1). These data form the basis of a new micro-
isfaction with stool consistency while on the low-FODMAP bial hypothesis in the pathogenesis of IBS. To date, antibi-
diet, but IBS-D (n = 10) was the only subtype with improve- otics and diet have been first-generation attempts to correct
ment in altered fecal frequency [71]. A recent meta-analy- microbial perturbations and provide relief from IBS symp-
sis that included six clinical trials found that IBS patients toms. The evolving story of the microbiome has opened up
administered a low-FODMAP diet had significant reduction the potential for new treatments for IBS, which target the
in abdominal pain, bloating, and diarrhea [73]. Long-term underlying cause rather than focusing only on symptom
follow-up (i.e., > 4 weeks) is lacking. remediation. The hope is that the future of IBS research will
One challenge with the low-FODMAP diet is long- reduce suffering, cut costs, and avoid unnecessary testing.
term use. Response to full FODMAP restriction is usu- In addition, further research is needed to explore potential
ally assessed after 4–6 weeks. Responders then engage in means of preventing IBS. While these include protecting

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Table 3  Evidence supporting a role for the microbiome in IBS

Category Evidence

Epidemiology
Meta-analyses support that IBS can be precipitated by acute gastroenteritis
Diagnostics
Breath test abnormalities more common in IBS suggesting SIBO
Duodenal culture demonstrates excess coliforms suggesting SIBO
Stool microbial analyses demonstrate differences from healthy stool
Serum antibodies to AGE toxin higher in IBS than IBD
Some microbiome patterns associated with visceral hyperalgesia
M. smithii (methane production) linked to constipation-predominant IBS
Visceral hypersensitivity can be transplanted
Diet
Restricting fermentables in IBS appears to reduce symptoms
Antibiotics
Antibiotics improve symptoms in a subset of IBS with lasting effects
Probiotics
Some probiotics show benefits in IBS

IBS irritable bowel syndrome, IBD inflammatory bowel disease, AGE acute gastroenteritis, SIBO small intestinal bacterial overgrowth

against acute gastroenteritis through good hygiene, using • Alterations in the gut microbiome may lead to impaired
precautions when traveling, and facilitating good water, sani- gut barrier function, which in turn may affect the brain–
tation and hygiene practices even after natural disasters, also gut axis and potentially contribute to IBS symptoms.
important is identifying ways to prevent the progression to • A low-FODMAP diet may result in improvements in
IBS, including chemoprophylaxis possibly in combination abdominal pain, bloating, and diarrhea in IBS-D patients,
with screening for additional risk factors such as predic- but longer-term follow-up studies are needed to deter-
tive cytokine and antibody panels. This review supports the mine the effects on gut microbiome composition and
concept that IBS is, at least in some patients, a microbiome- diversity.
associated condition with promising therapies in the future
based on a growing understanding of the disorder.

Compliance with Ethical Standards

Key Messages
Conflict of interest MP is a consultant for and has received grant sup-
port from Salix Pharmaceuticals. MP also consults for US Medical
• Post-infectious IBS following acute gastroenteritis is trig-
and Shire. MP has equity in and consults for Gemelli Biotech, Naia
gered by the development of antibodies to the bacterial Pharmaceuticals, and Synthetic Biologics. Cedars-Sinai has licensing
toxin CdtB which, through molecular mimicry, leads to agreements with Bausch Health, Naia Pharmaceuticals, Synthetic Bio-
the development of autoimmunity to the host protein vin- logics and Gemelli Biotech. AL has served on the advisory boards for
Allergen, Salix Pharmaceuticals, Valeant Pharmaceuticals, Alkermes,
culin. Arena, Aoen Biopharma, Takeda, Bioamerica and Ironwood Pharma-
• Anti-CdtB and anti-vinculin antibodies are useful in ceuticals.
diagnosing IBS-D and distinguishing it from other causes
of diarrhea such as IBD and celiac disease.
• The gut microbiome is altered in IBS subjects. Specific
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