Irritable bowel syndrome (IBS) is a common, heterogeneous disorder characterized by abdominal pain associated with changes in bowel habits. The pathogenesis of IBS is multifactorial and may relate to alterations in the gut microbiota, changes in visceral sensation and motility, and genetic and environmental factors. Administration of systemic antibiotics may increase the risk of IBS by altering gastrointestinal homeostasis. Therapeutic interventions for IBS with diarrhea that are thought to target alterations in the gut microbiota include the nonsystemic antibiotic rifaximin, the medical food serum-derived bovine immunoglobulin, prebiotics, probiotics, and dietary modification. SYN-010 is a modified-release statin formulation that reduces methane production by Methanobrevibacter smithii and is currently in development for the treatment of patients with constipation-predominant IBS. Use of these interventions in the management of patients with IBS may function to restore a healthy gut microbiota and ameliorate symptoms of IBS.
Irritable bowel syndrome (IBS) is a common gastrointestinal (GI) disorder characterized by recurrent abdominal pain associated with alterations in bowel habits.1, 2 The global prevalence of IBS is approximately 11%, affecting more women than men, and adults younger than 50 years of age compared with older adults.1, 3 In 2016, Rome IV redefined the criteria for diagnosis of IBS, to individuals experiencing abdominal pain at least 1 day per week, concurrently meeting at least two of the following three criteria: pain that is related to defecation, pain that is associated with a change in stool frequency, or pain that is associated with change in stool texture.1 Individuals with IBS are further categorized based on their predominant stool pattern: constipation-predominant IBS (IBS-C), diarrhea-predominant IBS (IBS-D), mixed IBS, and unclassified IBS.1
IBS pathogenesis and heterogeneity
IBS is a complex, heterogeneous disorder and its pathogenesis differs from individual to individual.2 Factors linked to IBS symptom development include history of enteric infection, modifications in the gut microbiota, immunomodulation, alterations in brain–gut processing, and changes in visceral sensation and motility.2, 4, 5, 6 Neuroimmunologic signaling in response to a precipitating event at the mucosal surface stimulates communication through multiple pathways that can lead to the development of visceral hypersensitivity and alterations in stool frequency and form.4 However, the factors involved and their relative contributions to the development, frequency, and severity of symptoms differ between individuals.2, 7, 8, 9, 10, 11 Despite decades of research, the specific mechanistic pathways involved in the development of IBS are only beginning to be elucidated. An association with small intestinal bacterial overgrowth (SIBO) has been observed in subpopulations of patients with IBS,5, 12, 13, 14, 15, 16 although a causal relationship between SIBO and IBS remains to be established.17 Nonetheless, changes in the gut microbiota are thought to trigger alterations in gut permeability, motility, visceral perception, and food processing, ultimately resulting in IBS symptoms.6, 18, 19 The goal of the current article is to provide an overview of the role of altered GI homeostasis in IBS and present therapeutic options.
The role of altered gut microbiota in IBS
The term “gut microbiota” represents the totality of microbes that collectively inhabit the GI tract.20 Historically, it has been argued that the average individual contains 10 times more microbial cells than human cells,21, 22 but newer data contest this hypothesis.23 In either case, several trillion microbes are found within the GI tract, and this community plays a central role in the health and function of the GI system.20 Multiple studies have demonstrated altered intestinal microbiota in patients with IBS.24 For example, compared with healthy individuals, brushings of duodenal mucosa in patients with IBS showed significantly lower Bifidobacterium catenulatum counts (P<0.001).25 Furthermore, a 2017 systematic review and meta-analysis demonstrated that patients with IBS (n=360) had significantly less bacterial colonization of Lactobacillus, Bifidobacterium, and Faecalibacterium prausnitzii based on quantitative real-time PCR analysis compared with healthy individuals (n=268; P<0.001, for all comparisons).24
Alterations in the gut microbiota are thought to be associated with changes in GI function that have been observed in patients with IBS.5, 26 For example, fecal aspirates from patients with IBS applied to the colonic mucosa of mice were shown to increase intestinal permeability,27 and the administration of fecal microbiota transplants from patients with IBS to germ-free mice induced alterations in GI motility, as well as hypersensitivity to colonic distension.28, 29 Furthermore, patients with IBS have increased expression of colonic toll-like receptors (TLRs), which are involved in the immune response to enteric bacteria.18 TLR-4 detects lipopolysaccharide (LPS), a component of the cell membrane of Gram-negative bacteria.30 Through intricate signaling pathways, LPS exposure can lead to increased production of proinflammatory cytokines.30 TLR-4 signaling is also important for the health and survival of GI neuronal cells,18, 30 and a lack of TLR-4 signaling can delay GI motility.30 In addition, GI microbes have the potential to modulate the enteroendocrine system;31 specifically, data have suggested that indigenous microbes in healthy individuals produce metabolites that promote serotonin synthesis in the GI tract.31 Serotonin is known to play a role in GI motor and sensory functions,31 and modulation of the gut microbiota may influence serotonin-related GI functions. Overall, these studies suggest that disruptions in gut microbiota may play a causative role in the pathogenesis of IBS.21, 32
The most well-documented line of evidence linking disruption of GI microbial homeostasis to the development of IBS symptoms comes from the literature on postinfectious IBS (PI-IBS), in which the reported rates of prior GI infection in patients with PI-IBS ranged between 10% and 53%.33, 34 A systematic review reported that an acute GI illness increased the risk of PI-IBS by 7-fold.35 Patients who develop PI-IBS do not fully downregulate their normal inflammatory responses to a GI infection.36 These patients, therefore, have ongoing GI inflammation characterized by increased rectal mucosal epithelial lymphocytes and cytokine upregulation.36 Persistent inflammation can also cause increased intestinal permeability that leads to further immune system activation and GI inflammation.36 Furthermore, genetic studies suggest that patients who develop PI-IBS may have an innate susceptibility to an infectious trigger or to the development of ongoing GI dysfunction.37
Similarly, a prospective community-based study has shown that systemic antibiotic exposure can increase the risk of developing IBS symptoms by at least 3-fold, presumably through alterations in GI homeostasis.38 A retrospective analysis of medical records at a single institution noted that a significantly greater percentage of patients who had received a macrolide or tetracycline antibiotic during the previous year developed IBS compared with patients who did not develop IBS (P=0.04 and P<0.02, respectively).39
An alternative pathway connecting the gut microbiota and IBS has developed from studies that associated IBS with SIBO. Several studies have reported that patients with IBS have a higher prevalence of SIBO compared with healthy individuals.12, 40, 41, 42 The prevalence of SIBO in patients with IBS was reported to range between 46% and 50%.42, 43 Breath test results were approximately 10 times more likely to be positive in patients with IBS compared with age- and sex-matched controls,40 and culture of duodenal aspirates—considered the gold standard for SIBO determination—revealed that patients with IBS-D had higher total bacterial counts compared with healthy individuals, as well as different sets of predominant bacterial species.15, 44 In addition, eradication of SIBO has been shown to correlate with improvement in IBS symptoms.42 Therefore, it is plausible that both the absolute number and types of microbes are important in maintaining gut homeostasis, and that SIBO plays a role in the pathogenesis of IBS in a subset of patients.15, 44
Food represents another plausible factor in the pathogenesis of IBS. Most patients experience a triggering or exacerbation of IBS symptoms when they eat a meal.45 Foods may directly affect gut microbial composition.46 Patients with IBS consuming a diet low in fermentable oligo-, di-, monosaccharides, and polyols (FODMAP) for 3 weeks had an increase in richness and diversity of fecal Actinobacteria species, whereas a high FODMAP diet was associated with decreased numbers of gas-consuming bacteria.46 Food can also influence intestinal motility, sensation, and neural activity,47 and the gut microbiota may have a role in some of these effects. For example, when gut microbes ingest dietary components, they can produce potential symptom-inducing metabolites.48 Fat and digested proteins can increase bile acid excretion, which leads to increased intestinal motility and colonic secretion of water and electrolytes.48, 49, 50 In the colon, bacterial fermentation of oligosaccharides into carbon dioxide and hydrogen can lead to sensations of pain and bloating, with reflex response of the diaphragm and anterior abdominal wall resulting in distension.51, 52 Hydrogen can be used to form methane by anaerobic archaea, such as Methanobrevibacter smithii,48, 53 and evidence suggests that methane slows GI motility and may contribute to constipation.53 In fact, excess methanogenesis has been purported as a plausible pathogenic mechanism for the development of IBS-C.53 A better understanding of these mechanisms has, and will continue, to result in new treatment modalities for this disorder.
IBS is a complex disease with a high prevalence.1 The pathogenesis of the disease is likely multifactorial.2 Available data suggest that gut microbiota contribute to disease pathogenesis and expression in multiple ways, including effects on GI immune system activation and inflammation, membrane permeability, intestinal motility, gut-brain communication, and gas production. Treatment options aimed at restoring a healthy GI tract microbial environment are available or are being evaluated. Further research on the potential benefits of available and treatments in development, including an understanding of their effects on the pathophysiologic mechanisms of IBS, is warranted.
Technical editorial and medical writing assistance were provided by Mary Beth Moncrief, PhD, and Sophie Bolick, PhD, for Synchrony Medical Communications, LLC, West Chester, PA, USA, under the direction of the authors. Funding for this support was provided by Salix Pharmaceuticals, Bridgewater, NJ, USA. No remuneration for the development of the article was received.