Targeting the gut microbiota for the treatment of irritable bowel syndrome

Abstract

Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder that affects an estimated 11% of people across the world. IBS patients are one of the largest subgroups seen in gastroenterology clinics, exhibit a lesser quality of life, and take greater use of the healthcare system. The exact etiology of IBS remains uncertain. Alterations in the gut microbiome may characterize apotential mechanism in the pathogenesis of IBS. This hypothesis is paralleled by rodent models in which manipulation of the gut microbiota leads to disturbed physiological functions along the brain‐gut axis. Recent research in IBS treatments has redirected its focus towards gu microbiome based therapeutics. In this review, we discuss potential roles of enteric bacteria in the pathogenesis of IBS and its comorbidities. We then explore the manipulation of the enteric microbiota by prebiotics, probiotics, antibiotics, dietary changes, and fecal microbiota transfer. We also discuss the positive and negative effects of these therapeutics on IBS symptoms.

1. INTRODUCTION

Irritable bowel syndrome (IBS) is a functional gastrointestinal disease (FGID) characterized by recurrent abdominal pain, discomfort, and altered bowel habits which do not present with identifiable organic lesions.1 The diagnosis of IBS—according to the Rome IV criteria—requires that patients have had recurrent abdominal pain (at least 1 day/week in the last 3 months) that is related to defecation, an associated change in stool frequency, and/or an associated change in stool form.2. IBS is a common gastrointestinal (GI) disorder with an estimated global prevalence of around 10%.3 Its high prevalence and chronic nature decrease patients' quality of life (QoL)4 and place a significant economic burden on healthcare systems in both western and eastern countries.5, 6, 7, 8, 9

There is a growing body of evidence suggesting a possible role for the gut microbiota in IBS' pathogenesis. IBS has been significantly associated with small intestinal bacterial overgrowth (SIBO) (4% to 78%)10 and prior GI infection (5% to 32%),11 suggesting that enteric dysbiosis (ie, disrupted microbial homeostasis) is a potential pathogenic mechanism of IBS. Next‐generation sequencing has revealed that IBS patients, compared with healthy controls, show significantly lower abundance in enteric Lactobacillus, Bifidobacterium, and Faecalibacterium prausnitzii.12 Fecal microbiota transplantation (FMT) studies in rodents suggest that host‐microbe interactions may lead to IBS development. Touw et al. recently examined the impact on germ‐free (GF) mice provided FMT from mice with pharmacologically‐induced constipation (PIC) as well as from patients with constipation‐predominant IBS (IBS‐C). They found that GF mice receiving FMT from either source have increased abundance of Bacteroides ovatus, Parabacteroides distasonis, and significantly increased GI transit time.13 In another rodent FMT study, mice receiving FMT from either healthy or diarrhea‐predomiant IBS patients (IBS‐D) were found to have taxonomically different microbial compositions.14 Mice receiving IBS‐D stool also showed different serum metabolomic profiles associated with faster GI transit, intestinal barrier dysfunction, and innate immune activation.15 Furthermore, disturbed microbiota profiles are associated with co‐morbidities of IBS, including cognitive changes, anxiety, and depression.16 These studies indicate the gut microbiota's potential to contribute to IBS symptoms as well as to serve as a therapeutic target. In this brief review, we summarize the gut microbiota‐based treatments of IBS, including prebiotics, probiotics, antibiotics, diet, and FMT. We performed a systematic approach in the collection and review of relevant literature. Pubmed was searched from 1999 through to March 2019 with a combination of the following basic and MeSH (medical subject headings) terms: “irritable bowel syndrome” or “functional gastrointestinal disorder” as the population; “probiotics,” “prebiotics,”,“antibiotics,” “diet,” or “fecal transplant” as the intervention; “placebo” or “control” as the comparison; “placebo controlled” or “double‐blind” as the study design. Reference lists of included studies were then manually searched for relevant studies.

2. PREBIOTICS

Prebiotics are indigestible oligosaccharides and polysaccharides, fructooligosaccharides (FOS) or galactooligosaccharides (GOS) that promote the growth of bacteria, which would convey a health benefit for the host. Prebiotics can provide nutrients for bacteria in the colon, such as Bifidobacteria and Lactobacilli. Both Bifidobacteria and Lactobacilli are decreased in the fecal samples of IBS patients,17 and their abundance can be increased by supplementation with FOS,18 short‐chain FOS,19 and GOS.18

Few studies have investigated the effect of prebiotics on IBS symptoms. Two controlled studies observed no effect of FOS on IBS.20, 21 Another trial showed that low dose (3.5 g/day) supplementation of trans‐GOS supplementation in IBS patients improved stool consistency, flatulence and bloating as well as total symptom score and subjective global assessment. Though a higher dose (7 g/day) only improved subjective global assessment and anxiety scores, both doses significantly increased Bifidobacteria and Lactobacilli abundance.22 Another study investigating the effect of β‐GOS on IBS symptoms found improved flatulence, stool consistency, bloating, and restored Bifidobacterium abundance in both low (3.5 g/d) and high (7 g/d) dose groups. Anxiety scores improved only in the high dose group.23 (See Table 1).

Table 1.

Randomized controlled trials on prebiotics for IBS

Reference	Study design	Sampling patients	Treatment	Main finding
Olesen M.20	Randomized, double‐blind, placebo controlled	Patients with IBS (n = 98)	12 wk of FOS 20 g/d (n = 52) or placebo (n = 46)	No therapeutic value of FOS in IBS
Hunter JO.21	Randomized, crossover, double‐blind, placebo controlled	Patients with IBS‐D (n = 14) and IBS‐C (n = 7)	4 wk FOS 6 g/d then 4 wk of placebo, or vice versa (n = 21)	No therapeutic value of FOS in either IBS‐D or IBS‐C
Silk DB22	Randomized, crossover, single‐blinded, placebo controlled	Patients with IBS‐D (n = 23), IBS‐C (n = 9), or IBS‐A (n = 12)	6 wk placebo followed by 12 wk prebiotic 3.5 g/d (n = 16), prebiotic 7 g/d (n = 14), or placebo (n = 14)	Prebiotic enhanced fecal Bifidobacteria and subjective global assessment
Vulevic J 23	Randomized, crossover, double‐blind, placebo controlled	Adults who suffer with bloating, abdominal pain, and flatulence (n = 83)	2 wk of 1.37 g/d GOS and 2 wk of placebo or vice versa	GOS lower scores for bloating, flatulence, and abdominal pain (vs baseline and placebo)

Abbreviations: FOS: fructooligosaccharide; IBS, irritable bowel syndrome; IBS‐D, IBS with predominant diarrhea; IBS‐C, IBS with predominant constipation; IBS‐A, IBS with a predominant bowel habit which alternates between constipation and diarrhea; GOS, Galactooligosaccharide.

The research to date on the effectiveness of prebiotics in the treatment of IBS remains inconclusive. On the other hand, certain prebiotics may exacerbate IBS symptoms, because they are classified as fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP),24 as discussed in the following section. Nevertheless, the potential for prebiotics to modulate the gut microbiome in the treatment of IBS is worth further exploration.

3. PROBIOTICS

Probiotics are live or attenuated microorganisms that alter gut microbial communities in a way that imparts a health benefit on the host. A recent meta‐analysis of probiotics in the treatment of IBS indicated that short treatment duration (<8 weeks) and the use of low or high doses consistently improve overall IBS symptoms and QoL.25 Single strain probiotics appear to be more effective in improving overall IBS symptoms, but not QoL.25

3.1. Bifidobacterium

!Consistent improvement of bloating and constipation is reported with the use of B infantis,17, 26 B lactis,27 B bifdum,28 and B AnimaliS 29 In two separate placebo‐controlled studies, IBS patients who received B infantis experienced significant improvement from baseline in abdominal pain/discomfort after at least 4 weeks of treatment.17, 26 A separate study, however, found no change in IBS symptoms associated with increasing fecal B infantis abundance.30 Regarding B lactis, it has been shown to reduce maximal abdominal distension, orocecal and colonic transit times, abdominal pain/discomfort, and global IBS symptoms in female IBS‐C patients.27

B Animalis probiotics have been shown in IBS‐C patients to improve bloating within 3 weeks and to improve stool frequency within 6 weeks of treatment.29 In another study, B bifdum was shown in a 4‐week treatment of IBS patients to improve pain, discomfort, distension, bloating, urgency, and QoL.28

An interesting probiotic study involving an fMRI component evaluated the effects of B longum on IBS patients' brain activity and psychological well‐being. While no improvement in GI symptoms was observed compared to placebo, the treatment group did experience an improvement in depression and associated changes in brain activation patterns.31 This study adds to the suggestion that IBS and depression share abnormalities in pathophysiology, including dysbiosis, altered intestinal permeability, and gut immune activation.32 In fact, the beneficial effect of probiotics on psychological symptoms in healthy individuals has been reported.33 (See Table 2)

Table 2.

Randomized controlled trials on probiotics for IBS

References	Study design	Sampling patients	Probiotic strain	Treatment groups	Main finding
Whorwell PJ26	Randomized, double‐blinded, placebo‐controlled	IBS patients (n = 362)	B lactis	4 wk of 106 (n = 90), 108 (n = 90), 1010 CFU/d(n = 90), or placebo (n = 92)	B lactis at 10,8 but not 106 or 1010 CFUs/d, significantly improved global symptom compared to placebo.
Guglielmetti S28	Randomized, double‐blinded, placebo‐controlled	IBS patients (n = 122)	B bifdum	4 wk 109 CFU/d (n = 60) or placebo (n = 62)	B bifdum showed a significant improvement in health‐related QoL and reduction of pain/discomfort and distension/bloating compared to placebo.
Guyonnet D29	Randomized, double‐blind, placebo‐controlled	IBS‐C patients (n = 276)	B infantis	6 wk of 1.25 × 1010 CFU/d (n = 137) or placebo (n = 137)	B infantis decreased bloating score compared to placebo.
Agrawal A27	Randomized, double‐blinded, placebo‐controlled	Female IBS‐C patients (n = 32)	B lactis	2 wk of 2.5 × 1010 CFU/d (n = 17) or placebo (n = 15)	B lactis showed a reduction in maximal distension, orocecal and colonic transit times, and overall symptom severity compared to placebo.
Nobaek S34	Randomized, double‐blinded, placebo‐controlled	IBS patients (n = 52)	L plantarum	4 wk of 2 × 1010 CFU/d (n = 25) or placebo (n = 27)	L plantarum reduced flatulence and abdominal pain compared to placebo
Niedzielin K35	Randomized, double‐blinded, placebo‐controlled	IBS‐C (n = 21), IBS‐D (n = 1) and IBS‐A patients(n = 18)	L plantarum	4 wk of 2 × 1010 CFU/d (n = 20) or placebo (n = 20)	L plantarum reduced abdominal pain and improved overall IBS symptoms
Ligaarden SC36	Randomized, crossover, double‐blinded, placebo‐controlled	IBS patients (n = 16)	L plantarum	3 wk of 1010 CFU/d then 3 wk placebo or vice versa	L plantarum showed no therapeutic benefit
Bauserman M37	Randomized, double‐blinded, placebo‐controlled	IBS patients (n = 50)	L rhamnosus	6 wk of 2 × 1010 CFU/d (n = 25) or placebo (n = 25)	L rhamnosus reduced the incidence of perceived abdominal distension, but no therapeutic benefit for IBS patients
Gawronska A38	Randomized, double‐blinded, placebo‐controlled	Children with IBS (n = 37), functional abdominal pain (n = 47), or functional dyspepsia (n = 20)	L rhamnosus	4 wk of 3 × 109 CFU/d (n = 52) or placebo (n = 52)	L rhamnosus reduced pain frequency in children with IBS only
Francavilla R39	Randomized, double‐blinded, placebo‐controlled	Children with IBS (n = 80) or functional abdominal pain (n = 56)	L rhamnosus	8 wk of 3 × 109 CFU/d (n = 69) or placebo (n = 67)	Treatment with L rhamnosus reduced abdominal pain frequency and severity compared to placebo
Niv E41	Randomized, double‐blinded, placebo‐controlled	IBS patients (n = 39)	L reuteri	6 months of 2 × 108 CFU/d (n = 21) or placebo (n = 18)	L reuteri provided no therapeutic benefit to IBS patients
Jadresin O42	Randomized, double‐blinded, placebo‐controlled	Children with chronic abdominal pain (n = 55)	L reuteri	12 wk of 108 CFU/d (n = 26) or placebo (n = 29)	L reuteri the frequency and severity of abdominal pain compared to placebo
Pineton de Chambrun G43	Randomized, double‐blinded, placebo‐controlled	IBS patients (n = 179)	S cerevisiae	8 wk of 8 × 109 CFU/d (n = 86) or placebo (n = 93)	S cerevisiae improved abdominal pain/discomfort compared to placebo.
Spiller R44	Randomized, double‐blinded, placebo‐controlled	IBS patients (n = 269)	S cerevisiae	12 wk of 8 × 109 CFU/d (n = 132) or placebo (n = 131)	S cerevisiae had no therapeutic benefit for IBS patients overall, but had significantly improved abdominal pain and bloating in IBS‐C subjects.
Bafutto M46	Randomized, double‐blinded, placebo‐controlled	IBS‐D patients (n = 53)	S boulardi	30 d of mesalazine only (n = 20), mesalazine with 600 mg/d S boulardi (n = 20), or S boulardi 600 mg/d only (n = 12)	S boulardi was not superior or additive in therapeutic benefit to treatment with mesalazine.
Kim HJ48	Randomized, double‐blinded, placebo‐controlled	IBS‐D patients (n = 25)	VSL #3 (L plantarum, L delbrueckii, L casei, L acidophilus, B breve, B longum, B infantis, and S salivarius)	8 wk of 9 × 1011 lyophilized bacteria/d (n = 12) or matching placebo (n = 13)	VSL #3 showed no effect on abdominal bloating scores compared to placebo.
Kim HJ49	Randomized, double‐blinded, placebo‐controlled	IBS patients (IBS‐D = 20; IBS‐C = 16, and IBS‐A = 12)	VSL #3	8 wk (n = 17) or 4 wk (n = 31) treatment with 9 × 1011 lyophilized bacteria/d (n = 24) or matching placebo (n = 24)	VSL# 3 reduced flatulence and slowed colonic transit in IBS patients
Tsuchiya J50	Single‐blind, placebo controlled, follow up study	IBS patients (n = 68)	SCM‐III (L acidophilus, L helveticus, and Bifidobacterium sp.)	12 wk of SCM‐III 30 mL/d (n = 34) or matching placebo (n = 34)	SCM‐III improved abdominal pain and bloating score compared to placebo.
Lorenzo‐Zuniga V51	Randomized, double‐blinded, placebo‐controlled	IBS‐D patients (n = 84)	I.31 (L plantarum and Pediococcus acidilactici)	6 wk of 1–3 × 1010 (n = 28); 3–6 × 109 CFU (n = 27); and placebo (n = 29)	I.31 Improved gut‐specific anxiety and IBS‐related QoL

Abbreviations: CFU, colony forming units; IBS, irritable bowel syndrome; IBS‐C, IBS with predominant constipation; IBS‐D, IBS with predominant diarrhea; IBA‐A, IBS with alternating bowel habit; QoL, quality of life.

3.2. Lactobacillus

Placebo‐controlled trials investigating Lactobacillus probiotics have shown improvement in IBS symptoms following treatment with L plantarium, L rhamnosus, L casei, and L reuteri, however, these results are less consistent when compare to studies on Bifidobacterium.

L plantarium has been demonstrated to reduce flatulence and improve stool frequency after 4 weeks of treatment in IBS patients.34, 35 On the other hand, L plantarium has also been shown to be no better than placebo and may have an unfavorable effect on IBS symptoms.36 Likewise, studies show L rhamnosus to be no better than placebo in the treatment of IBS symptoms in adults,37 however, the probiotic may hold a modest benefit for children.38, 39 L rhamnosus in children with IBS or functional pain has been shown to reduce the frequency and severity of abdominal pain.38, 39 Treatment with L casei has been shown to improve stool frequency and consistency in adult IBS and SIBO patients.40 L reuteri has also been studied in the treatment of IBS. While its ability to decrease the intestinal pH to a level unfavorable to most pathogenic bacteria, placebo‐controlled studies show that L reuteri supplementation provides only a marginal improvement in IBS‐related symptoms. L reuteri 41, 42 (See Table 2)

3.3. Saccharomyces

Improvement in abdominal pain/discomfort has been reported in Saccharomyces (S) cerevisiae and S boulardi yeast strains in IBS patients.43, 44 S cerevisiae has been shown in IBS patients to improve bloating and abdominal pain/discomfort after 4 weeks of treatment.43 A separate study found a similar improvement in abdominal pain/discomfort. However, this was only observed in the IBS‐C subgroup of patients.44 In these two studies, the IBS‐C patients with abdominal pain/discomfort showed a clinically relevant reduction (>10% compared to placebo) of 13.1% in abdominal pain/discomfort and 14.9% reduction in bloating during the second month of supplementation.45 S boulardii has been shown to improve stool frequency and consistency after 4 weeks of treatment in IBS‐D patients,46, 47 an effect that may be enhanced with the anti‐inflammatory drug mesalazine.46 (See Table 2).

3.4. Mixed probiotics

Several probiotics containing multiple bacterial strains have been studied in the treatment of IBS. The probiotic VSL #3, containing several Bifidobacterium, Lactobacillus, and Streptococcus strains, has been evaluated in two randomized controlled trials. VSL#3 supplementation demonstrated a borderline significant reduction in abdominal bloating in IBS‐D patients.48 The same group later recruited IBS patients with significant bloating and found VSL#3 supplementation to reduce both colonic transit time and flatulence scores in the treatment group.49

SCM‐III, another probiotic combination containing L acidophilus, L helveticus, and Bifidobacterium species, was shown to be effective in 80% of IBS patients. Patients experienced an improvement in bloating and abdominal pain whereas those with predominant constipation also experienced an improvement in bowel habit.50

I.31, a probiotic combination containing Pediococcus acidilactici and two L plantarum strains, was shown in IBS‐D patients to significantly increase in IBS‐related QoL and improve gut‐specific anxiety, as measured by a visceral sensitivity questionnaire. Nevertheless, symptom relief showed no significant changes compared to placebo.51 (See Table 2).

Generally, the public usually holds the concept that probiotics are well‐tolerated with little or no complications. However, long‐term use of these medications in IBS patients can increase the occurrence of various adverse effects.47 As microorganisms, probiotics may predispose susceptible patients toward infection, sepsis, and endocarditis. A recent review found Saccharomyces (S) fungemia reported following S boulardi supplementation, Lactobacillus bacteremia following L acidophilus, L casei, and L rhamnossus supplementation, sepsis reported following Lactobacillus, Bifidobacterium, and Saccharomyces supplementation, and endocarditis following L rhamnosus supplementation.52 Brain fog was also recently reported in a study of patients taking probiotics. This brain fog was associated with SIBO as well as elevated serum levels of D‐lactic acid—a byproduct of Lactobacillus and Bifidobacterium fermentation that are typically elevated in patients with short bowel—indicating a link between brain fog, D‐lactic acidosis, and SIBO.53 In this study, brain fog resolved in 80% of patients once probiotics were discontinued.54 Another key challenge in probiotics administration in the treatment of IBS is the variability in a patient's resistance or permissiveness to mucosal probiotic colonization. This variability may be mediated by the host's indigenous microbiota, as a recent study found probiotic strains to encounter a person and strain‐specific colonization resistance. They also noted that probiotic strain expansion in the stool may represent a transient washout of noncolonizing strains and that evaluating mucosal instead of fecal microbiota may be a better indicator of probiotic efficacy.55 Therefore, despite the meta‐analysis' results in favor of probiotics in treating IBS, future research should be focused on the types, strengths, and long term safety the probiotics.

4. ANTIBIOTICS—NEOMYCIN

Neomycin is a nonabsorbable antibiotic which can be used to treat IBS. One trial demonstrated that neomycin‐treated patients experienced a 50% improvement in IBS symptoms and an even greater clinical response was observed if SIBO was eradicated.56 The same group found in a later study that neomycin failed to normalize breath tests in 25% of treated subjects.57 A subgroup analysis revealed that neomycin significantly improves constipation in IBS‐C in a manner that is dependent on the presence and elimination of a positive methane breath test.58 In addition to its relatively low efficacy, neomycin treatment may also produce rapid resistance,59 making patients less responsive to subsequent therapy. Because of this high resistance, neomycin does not have the ideal antibiotic properties needed in a microbiota‐based treatment for IBS.

4.1. Rifaximin

Rifaximin can be an ideal antibiotic for IBS since it is nonabsorbable, gut‐specific, has a low bacterial resistance profile, limited side effects, and broad‐spectrum coverage. There is a growing body of evidence pointing toward the benefit of a short course of treatment with rifaximin in global IBS symptom improvement. A recent meta‐analysis of five studies and 1803 patients showed that rifaximin was more effective than placebo in the improvement of IBS patients' global symptom scores (odds ratio [OR] = 1.57, 95% CI =1.22‐2.01, therapeutic gain = 9.8%, NNT = 10.2) and bloating (OR = 1.55, 95% CI = 1.23‐1.96, therapeutic gain = 9.9%, NNT = 10.1).60 Retreatment with rifaximin may be indicated once IBS symptoms recur. A recently published target three study on the use of rifaximin found 44% of 2438 IBS‐D patients to have experienced a significant improvement in IBS symptoms. Among responders, 60% developed recurrent IBS symptoms within 18 weeks; however, retreatment with rifaximin led to a significantly greater proportion of responders.61 Given that less than half of IBS patients in these studies experienced a long‐term benefit from repeated rifaximin use, more widespread clinical use of rifaximin will require a reliable biomarker, such as the lactulose or methane breath test, to identify patients with the greatest likelihood of response. FDA has approved Rifaxamin in treating IBS since May 2017.

Rifaximin and neomycin can be combined to reduce GI levels of methane; a byproduct of methanogenic bacteria which slows GI motility that is implicated in the pathogenesis of IBS‐C.62 One retrospective study found combination treatment with rifaximin and neomycin in IBS‐C patients reduced constipation, and this was directly associated with an eradicated methane breath test.63 By the way, methanogenic bacteria may also be targeted using SYN‐010, a modified release statin.64 One study demonstrated that 4 weeks of SYN‐010 in IBS patients to reduce methane levels from baseline as well as to improve abdominal pain and stool frequency.62

The treatment of IBS symptoms may benefit from certain antibiotics, however, antibiotics may even contribute toward the initial onset of IBS symptoms. There is an association between prior macrolide (P = .036) and tetracycline (P < .025) use within 12 months of a new diagnosis of IBS.65 In a study investigating over 2700 Swedish children, antibiotic usage during girls' first and second year of life increased the risk of developing chronic abdominal pain at 12‐years‐old (OR 1.65; 95% CI: 1.09‐2.49).66 What is more, the use of antibiotics induces the same kind of dysbiosis that predisposes patients toward developing IBS.67 Nevertheless, there exists a subset of IBS patients whose symptoms improve with antibiotics. Such patients' IBS symptoms may be partly related to a small intestine bacterial overgrowth (SIBO), the presence of which can be confirmed by a lactulose breath test.68

5. DIET

5.1. Low FODMAP diet

The microbiota may contribute toward the clinical efficacy of diet‐based treatments for IBS. The most well‐studied dietary therapy to date focuses on reducing the consumption of FODMAP, known as the low FODMAP diet (LFD).69, 70, 71, 72 The luminal microbiome rapidly ferments FODMAPs, precipitating luminal distension through water secretion and gas production.25 An LFD, therefore, may help to alleviate symptoms of abdominal pain, bloating, and flatus production in IBS patients. Systematic reviews demonstrate the clinical effectiveness of the LFD in IBS patients,73, 74 however, the diet has a paradoxical effect on the microbiota; a reduced luminal Bifidobacteria concentration.75, 76, 77 Compared to healthy individuals, the baseline luminal concentration of Bifidobacteria is lower in IBS patients.17 The improvement in IBS symptoms observed following an LFD is paradoxical because the LFD reduces Bifidobacteria's abundance whereas prebiotics and probiotics increase it. LFD combined with probiotic supplementation prevents the associated reduction in Bifidobacteria.75

The microbiota may serve as a potential biomarker in identifying those patients most likely to benefit from LFD. Chumpitazi et al. assessed IBS patients' microbiota at baseline and found responders to LFD to be enriched in microbes from several taxa with a more substantial saccharolytic potential (eg, Bacteroides, Ruminococcaceae, and Faecalibacterium prausnitzii).78

The short‐term LFD studies indicate a clinical response in 79%‐82% of IBS patients. On the other hand, there is a much lower response rate of 29%‐53% observed in long‐term LFD studies. Many gaps remain in the clinical implementation of LFD, such as accounting for cultural factors, eating habits, and nutritional adequacy which may influence the diet's acceptability to patients.79 The elimination of FODMAPs in the long‐term may lead to deficiencies in several nutrients, including calcium, iron, folate, vitamins, natural antioxidants, and dietary fibers. Additionally, certain prebiotics (as mentioned above) may cause an imbalance of gut microbiota and result in unknown health consequences. Instead, a short‐term LFD diet may minimize these risks while providing relief of IBS symptoms. (See Table 3).

Table 3.

Randomized controlled trials on dietary interventions for IBS

Referencs	Study design	Sampling patients	Treatment groups	Main finding
Chumpitazi BP78	Double‐blind crossover trial	Children with IBS (n = 33)	LFD for 48 h then typical American diet for 48 h or vice versa	LFD induced fewer daily abdominal pain episodes, while more episodes during with the typical American diet
Biesiekierski JR82	Double‐blind, placebo controlled, rechallenge trial	IBS patients (n = 34)	1 week of diet containing 16 g gluten/d (n = 19) or control (n = 15).	Gluten diet worsened Overall symptoms, pain, and bloating, stool consistency, and tiredness
Vazquez‐Roque MI81	Double‐blind, placebo controlled, randomized control trial	IBS‐D patients (n = 45)	Gluten‐containing (n = 22) or gluten‐free (n = 23) for 4 wk	Gluten containing diet had more bowel movements/d
Biesiekierski JR86	Placebo‐controlled, cross‐over rechallenge trial	IBS patients with non‐celiac wheat sensitivity (n = 37)	2 wk LFD followed by 1 week of diet containing 16 g gluten/d, 2 g gluten/d or control of 14 g whey protein/d	Following LFD, no specific or dose‐dependent effects were associated with the re‐introduction of gluten

Abbreviations: IBS, irritable bowel syndrome; LFD, low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet; IBS‐D, IBS with predominant diarrhea.

5.2. Gluten‐free diet

Several studies have demonstrated significant improvements in IBS symptoms after the avoidance of gluten/wheat.80, 81, 82 This improvement with the gluten‐free diet may be related to a non‐celiac wheat sensitivity (NCWS), a sensitivity characterized by intestinal and extra‐intestinal symptoms associated with the ingestion of wheat‐containing food in subjects for whom a celiac disease or wheat allergy has been excluded.83

It is thought that wheat‐related components, such as fructans, wheat germ agglutinins, or amylase alpha‐trypsin inhibitors,84 may underlie NCWS‐related IBS symptoms by inducing low‐grade inflammation, altering barrier function, and the consequences of fermentation.85 In one study, IBS patients on an LFD were reintroduced to varying amounts of gluten (0, 2, or 16 g/day). Symptoms worsened to a similar degree regardless of the presence or amount of gluten,86 suggesting that the fructan/FODMAP content of wheat‐related components may be more critical than gluten in the generation of IBS symptoms. Given the possible role of FODMAPs in NCWS, one would suppose that a gluten‐free diet induces similar changes to the gut microbiota as seen following LFD, however, a symptom‐free gluten‐free diet does not restore a deficiency in Bifidobacterium. Additionally, the gluten‐free diet decreases the abundance of several bacterial genera, including Ruminococcus (which is essential for the degradation of starch) and especially Veillonellaceae (a pro‐inflammatory, lactate fermenting bacteria that shows increased abundance in IBS patients).87

Nonetheless, there exists a subgroup of IBS patients with suspected food intolerances, including NCWS, who may benefit from dietary exclusion. The gold standard assessment of specific food intolerance is the double‐blind, placebo‐controlled food challenge.88 However, this is difficult to operationalize in clinical trials and clinical practice. A recent review evaluated several diagnostic modalities which measure food‐based immunologic reactions in the GI tract to understand the mechanisms by which specific foods lead to symptoms.89 (See Table 3).

6. FMT

FMT consists in the infusion of a fecal suspension from a healthy donor into the gastrointestinal tract of a GI patient to restore the natural intestinal microflora. FMT has been well studied as a safe and effective treatment of recurrent Clostridium difficile infection.90 Moreover, studies have been done for the management of inflammatory bowel disease,91 metabolic disorders,92 as well as IBS.

A review of six FMT studies found that the treatment of IBS with FMT was beneficial in 28 of the 48 (58%) patients treated.93 Successful FMT treatment for IBS may depend on host‐microbiome characteristics, as it has been shown that Bifidobacterium rich donors can more efficiently induce symbiosis in IBS patients.94

As of now, there are two double‐blind, placebo‐controlled FMT studies. A recent study included 52 IBS patient using oral FMT or placebo capsules. They found that the FMT capsule had led to increased enteric biodiversity in the experimental group. Even so, it was the placebo, not the FMT group, that showed greater symptom relief (P = .012) and improved QoL (P = .003).95 Another study by including 90 IBS patients found significant symptom improvement with freshly prepared, frozen FMT delivered through colonoscopy into the colon when compared to placebo (P = .049).96 These conflicting findings warrant the investigation of various factors which may contribute toward the efficacy of FMT, such as the method of bowel preparation, route of delivery, duration of treatment, and the number of fecal bacteria delivered.

As of yet, FMT‐based treatments for FGID are not widely accepted among gastroenterologists, as they are concerned about a lack of evidence and safety issues.97 The effectiveness of FMT must be further investigated with more double‐blind, placebo‐controlled studies (See Table 4).

Table 4.

Randomized controlled trials on fecal microbiota transplantation for IBS

References	Study design	Sampling patients	Treatment groups	Main finding
Halkjaer SI95	Randomized, double‐blind placebo‐controlled	IBS‐patients (n = 52)	FMT capsules (n = 26) or placebo capsules once daily for 12 d	Placebo improved IBS symptom severity and IBS‐related QoL than FMT capsules
Johnsen PH96	Randomized, double‐blind placebo‐controlled	IBS‐patients (n = 83)	Active FMT (n = 55) or placebo FMT (n = 23) delivered via endoscopy	Active FMT is more responsive than placebo (65% vs 43%, P = .049)

Abbreviations: FMT: fecal microbiota transplantation. QoL: quality of life; IBS, irritable bowel syndrome.

7. CONCLUSIONS

IBS is a highly prevalent illness with unclear pathophysiology. Multiple factors can be responsible for the IBS pathogenesis. Gut microbiota may contribute to the pathogenesis of IBS by affecting the GI immune system, mucosal permeability, intestinal motility, visceral sensation, gut‐brain communication, and fermentation in the gut. Therapy targeting the gut microbiota may provide a promising treatment modality for IBS (Figure 1). However, there are potential drawbacks to each of these treatments. Prebiotics are often associated with unwanted abdominal symptoms and there is no strong evidence supporting their efficacy. Probiotics may hold a benefit for IBS symptoms, but the studies reviewed have heterogeneous methodologies. More studies are required to determine the effectiveness of probiotics regarding the probiotic type, dosage, side effects, treatment duration, and identification of suitable candidates. It is also unclear whether long‐term or chronic therapy using antibiotics or LFD can lead to unfavorable health effects. More controlled trials on FMT are required to build up the most effective regimen and route of administration for the treatment of IBS.

Figure 1.

Summary of treatment and etiology of IBS centered around the enteric bacteria. High FODMAP diets, excessive prebiotics, and antibiotics may lead to dysbiosis of the enteric bacteria. Such alterations in the gut microbiota may put patients at risk of IBS development and such co‐morbidities as psychiatric distress. FODMAPs and prebiotics are substrates for fermentation by the enteric bacteria, potentially leading to excessive gas production, abdominal pain, and flatulence. Several lines of research are directed toward treating IBS by returning the enteric bacteria to a homeostatic balance, including the appropriate usage of probiotics, antibiotics, prebiotics, fecal transplants, and dietary changes. IBS, irritable bowel syndrome; FODMAP, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols

Herndon CC, Wang Y‐P, Lu C‐L. Targeting the gut microbiota for the treatment of irritable bowel syndrome. Kaohsiung J Med Sci. 2020;36:160–170. 10.1002/kjm2.12154