The gut microbiome and irritable bowel syndrome

Prebiotics

Prebiotics are undigestible oligosaccharides and polysaccharides—fructooligosaccharides or galactooligosaccharides (GOS)—that promote the growth or activity (or both) of bacteria that impart a health benefit for the host. Early work demonstrated that selected prebiotics promoted the growth of potentially beneficial bifidobacteria while inhibiting the growth of potentially harmful Bacteroides, Clostrida, or Coliforms³⁰. A study by Olesen and Gudmand-Hoyer assessed the effect of high-dose inulin (20 g/day) versus placebo for 12 weeks in patients with IBS³¹. Initial treatment with inulin worsened IBS symptoms in all patients; however, after 12 weeks of treatment, symptoms improved in 58% of the inulin group versus 65% of the placebo group and symptoms worsened in 8% of the inulin group versus 13% of the placebo group, suggesting some level of adaptation in the inulin group. Several other studies using different prebiotics have demonstrated benefit compared with placebo in patients with IBS. Paineau et al. performed a double-blind, placebo-controlled trial in 105 IBS subjects with a short-chain inulin-type fructan dosed at 5 g/day over the course of 6 weeks³². Treatment with the prebiotic reduced the intensity of IBS symptoms and improved quality of life as compared with the placebo. Using GOS, Silk et al. randomly assigned 44 patients with IBS into three groups: receiving 7 g/day GOS, 3.5 g/day GOS and 3.5 g/day placebo, or 7 g/day placebo for 6 weeks³³. The prebiotic significantly improved the composite symptom score, bloating and flatulence, and subject’s global assessment. In those patients receiving GOS, the proportion of bifidobacteria increased in fecal samples. In another study, a novel medical device containing a film-forming agent reticulated protein and a prebiotic mixture of vegetable oligosaccharides and polysaccharides was tested in a multicenter, randomized, placebo-controlled trial³⁴. The researchers found a reduction in abdominal pain (p = 0.017) and flatulence (p = 0.037) with an improvement in quality of life of patients receiving the active treatment (p < 0.0001). Thus, the body of evidence supporting a role for prebiotics as a treatment for IBS is growing. The key will be to understand the dose and duration of prebiotic therapy which encourages the desired effects on the microbiome and improves IBS symptoms without triggering significant symptoms.

Probiotics

Probiotics are live or attenuated microorganisms that alter gut microbial communities in a way that imparts a health benefit to the host. In the case of IBS, probiotics have been suggested to reduce visceral hypersensitivity or exert anti-inflammatory effects^35–37. Probiotics have been extensively studied in IBS patients with variable effects on gut symptoms. The most recent meta-analysis by Ford et al. demonstrated efficacy in IBS patients for improvement of global symptoms, abdominal pain, bloating, and flatulence with a number needed to treat (NNT) of seven³⁸. The relative risk for persistent IBS symptoms for probiotics versus placebo was 0.79 (95% confidence interval [CI] 0.70–0.89). However, this meta-analysis noted that the available evidence could not support recommendations for specific species/strains or combinations of probiotics to treat IBS.

Patients with IBS often have co-morbid psychological distress such as depression or anxiety. Recent studies suggest that IBS and depression share abnormalities in pathophysiology, including dysbiosis, altered intestinal permeability, and gut immune activation³⁹. A number of studies have reported beneficial effects of probiotics on psychological symptoms in healthy individuals⁴⁰. A recent randomized controlled trial found that a “psychobiotic” containing Bifidobacterium longum for 6 weeks improved depression but not anxiety or GI symptoms in patients with IBS to a greater degree than placebo⁴¹. Improvements in depression were associated with changes in brain activation pattern by functional magnetic resonance imaging in the “psychobiotic” group.

Further research is required to establish the optimal single- and multi-strain probiotics for IBS. It is almost certain that host characteristics will influence the likelihood that a specific probiotic will benefit a specific patient with IBS. Understanding and leveraging such predictors of response will be key to optimizing the benefits of probiotics for patients with IBS.

Providers and patients should be aware that, depending on the claims made by a manufacturer, probiotics can be regulated in the US as a food, dietary supplement, medical food, or drug. This has implications regarding the purity and likelihood that the product contains viable organisms at the time of purchase. For example, dietary supplements are not required to demonstrate safety or efficacy, and there is no need for US Food and Drug Administration (FDA) approval prior to introduction into the marketplace. On the other hand, medical foods and drugs require a higher level of evidence to achieve regulatory approval by the FDA.

Antibiotics

The concept of Yin and Yang would seem to apply to the role of antibiotics in IBS. On the one hand, broad-spectrum antibiotics have been shown to negatively impact the gut microbiota by reducing diversity and potentially beneficial bacteria^42,43. Additionally, there is an association between prior use of macrolides (p = 0.036) and tetracycline (p < 0.025) within 12 months and a new diagnosis of IBS⁴⁴.

On the other hand, there is a robust body of evidence to suggest that non-absorbable antibiotics lead to significant symptom improvement in a subset of patients with IBS. In a meta-analysis of five studies and 1,803 participants, Menees et al. demonstrated that rifaximin was more efficacious than placebo for global IBS symptom improvement (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)⁴⁵. The more recently published Target 3 study reported that 44% of 2,438 patients with IBS-diarrhea (IBS-D) treated with open-label rifaximin (550 mg three times a day for 14 days) experienced a significant improvement in their IBS symptoms. Of those patients who responded to rifaximin, almost 60% developed recurrent IBS symptoms within 18 weeks. In those patients who recurred, retreatment with rifaximin (possible two courses of treatment) led to a significantly greater proportion of responders than placebo^46,47. Overall, the short-term adverse event profile with rifaximin is similar to that of placebo, and stool analyses from the Target 3 study demonstrate short-term depression of diversity and richness⁴⁸ across a broad range of microbes which was largely reversed at study end.

The randomized trials teach us that an empiric course of rifaximin will lead to improvement in fewer than half of IBS-D patients with an NNT of 10. In addition, most responders will recur within a median of 10 weeks, necessitating repeated courses of rifaximin⁴⁶. Finally, variable insurance coverage and high acquisition cost create further barriers to the use of rifaximin. Given these issues, a biomarker that could significantly enrich the likelihood of response of IBS-D patients to rifaximin would be welcome³². Recent studies suggest that identifying IBS patients with bacterial contamination of the small intestine, by either aspiration for quantitative culture or lactulose breath testing, may substantially increase the likelihood of response to oral antibiotics^49–51. Although these studies should be viewed as preliminary and hypothesis generating, they provide evidence that at least some of the benefit of oral antibiotics is derived from effects in the small intestine.

Diet

There has been a surge of interest in dietary interventions to reduce IBS symptoms. Although benefits have been attributed largely to reductions in colonic fermentation or decreased antigen activation of the gut immune system, it is important to consider that diet significantly impacts the composition of the gut microbiome^52–54. For example, reduction in the intake of foods that are high in fermentable oligosaccharides, disaccharides, and monosaccharides and polyols (FODMAP) reduces GI symptoms and improves disease-specific quality of life in patients with IBS^55–58. A recent review of low-FODMAP dietary therapy suggests that at least 50% of patients with IBS report symptomatic benefit⁵⁹.

The mechanisms by which the low-FODMAP diet improves IBS symptoms are likely multifold; however, there is evidence that alterations in the gut microbiome may play a role. Zhou et al. demonstrated that rats fed FODMAPs developed changes in gut microbiota, intestinal permeability, and fecal lipopolysaccharide levels that were associated with the development of visceral hypersensitivity. These abnormalities were reversed by a low-FODMAP diet⁶⁰. On the other hand, some researchers have expressed concerns about the impact of the low-FODMAP diet on the gut microbiome. Recent studies have demonstrated reductions in potentially beneficial fecal bifidobacteria and butyrate levels in IBS patients on a low-FODMAP diet⁶¹. Clearly, further studies assessing the long-term impact of a low-FODMAP diet on the gut microbiome in patients with IBS are needed. In the meantime, it is critical for providers recommending the low-FODMAP diet to recall that elimination is the first of a three-step diet plan. The elimination phase of the diet plan should be viewed as a diagnostic test to identify patients who are sensitive to FODMAPs. Those who respond to a 2- to 6-week trial of FODMAP exclusion should be instructed to reintroduce foods containing individual FODMAPs to determine their sensitivities and allow diversification of their diet in the hopes of improving adherence and minimizing effects on the microbiome. Recent studies suggest that concurrent administration of probiotics can reduce effects on fecal bifidobacteria levels³⁸ and that the use of α-galactosidase supplements may allow some patients with IBS to tolerate GOS⁶².

Fecal microbial transplant

The success of re-establishing intestinal homeostasis with fecal microbial transplant (FMT) in recurrent Clostridium difficile infection has inspired investigators with an interest in IBS. The first open-label single-center study involved 13 patients with IBS by Rome III criteria who underwent an esophagogastroduodenoscopy (EGD) to have 50–100 mL donor stool infused into the distal duodenum or proximal jejunum⁶³. A total of 70% of participants reported resolution or improvement of symptoms with one adverse event of transiently increased flatus. Holvoet et al. performed an open-label single-center FMT study (unknown route) in 12 patients with refractory IBS (Rome III criteria) with intermittent diarrhea and severe bloating⁶⁴. A total of 75% achieved adequate relief of global IBS symptoms, and 78% of responders continued to report significant relief at 1 year. Fecal microbial analysis demonstrated a tendency toward higher Streptococcus counts at baseline in donors compared with patients (p = 0.011). There was also a trend for higher baseline counts of Streptococcus in successful donors compared with unsuccessful donors and higher microbiota enrichment in responders. In the last open-label single-center study, Mizuno et al. enrolled 10 IBS patients (Rome III criteria) who underwent FMT via colonoscopy⁶⁵. The primary end point was a change in the Bristol Stool Form Scale, and a clinical response was defined as normalization to types 3 or 4. A total of 60% of participants experienced a clinical response, and fecal samples from responders displayed increased microbial diversity. Interestingly, the authors found that donor abundance of Bifidobacterium correlated with the therapeutic efficacy of FMT, but a similar increase in participant Bifidobacterium did not correlate with FMT success. Most recently, Johnsen et al. completed the first double-blind, randomized, placebo-controlled, single-center study in moderate-to-severe IBS-D or IBS-M (Rome III criteria) participants (n = 83)⁶⁶. The primary end point was symptom relief of more than 75 points assessed by the IBS Severity Scoring System 3 months after FMT. With either fresh or frozen donor feces for active treatment or the participant’s own feces for placebo, FMT was delivered via colonoscopy. A total of 65% of participants receiving active treatment versus 43% receiving the placebo demonstrated response at 3 months (p = 0.049); 12 months after FMT, 56% of participants receiving active treatment versus 36% of 28 receiving placebo had a durable response (p = 0.075). No serious adverse events were attributed to FMT. However, no microbiota assessment analysis was available for this trial. Most recently, preliminary results from 3 additional randomized, controlled trials were presented at Digestive Diseases Week 2018. A single center trial from Belgium in 64 IBS patients with significant bloating reported a statistically significant benefit of nasojejunal administration of donor stool vs. the patient’s own stool for the primary outcome of adequate relief of IBS and bloating symptoms at 12 weeks (49% vs. 29%, p=0.004)⁶⁷. Unfortunately, 2 additional randomized, controlled trials reported negative results^68,69. A multi-center study from the US which compared oral ingestion of encapsulated stool from healthy donors or placebo in IBS-D patients found no difference in clinical response rate between groups at week 12 (FMT 48% vs. placebo 63%, p=0.32)⁶⁸. A final study in 52 IBS patients from Denmark reported no statistically significant benefit in IBS symptoms from encapsulated, orally administered donor stool vs. placebo at 12 weeks⁶⁹. Thus, the efficacy of FMT for IBS remains to be clearly established. Many questions including mechanism of action, proper donor selection, route of administration, durability of response, and short and long term safety require further study before FMT can be considered a mainstream treatment for IBS.