Emerging data from epidemiologic, microbiome, and physiology research in patients with functional bowel disorders (FBDs) provide evidence for a linkage between alterations in the intestinal microbiota and FBDs. However, currently most of the data is based on association studies, and the causality role of the microbiota in these disorders is not established. Growing evidence for compositional changes and the increasing recognition of the association between the intestinal microbiota and gut-brain functions that are relevant to the pathophysiology and/or clinical symptoms of FBDs have led to increased interest in manipulating the intestinal microbiota for the treatment of these disorders.
Key points
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The emerging data from epidemiologic, microbiome, and physiology research in patients with functional bowel disorders (FBDs) provide evidence for a linkage between alterations in the intestinal microbiota and FBDs. However, currently most of the data is based on association studies, and the causality role of the microbiota in these disorders is not established.
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The growing evidence for compositional changes and the increasing recognition of the association between the intestinal microbiota and gut-brain functions that are relevant to the pathophysiology and/or clinical symptoms of FBDs have led to increased interest in manipulating the intestinal microbiota for the treatment of these disorders.
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Several therapeutic interventions targeting the intestinal microbiota have been suggested and are increasingly used in FBDs. These include dietary interventions aiming to modify the intestinal microbiota either directly by altering dietary substrate availability for intraluminal bacterial fermentation, prebiotics and probiotics or indirectly through effects on intestinal motility, transit and osmolarity. Nondietary interventions include antibiotics. Ongoing studies are currently exploring the potential role of fecal microbiota transplantation in patients with FBDs.
Irritable bowel syndrome and functional bowel disorders
Functional bowel disorders (FBDs) are part of the larger group of functional gastrointestinal (GI) disorders characterized by symptoms attributed to the middle and lower GI tract that are not explained by structural or biochemical abnormalities. FBDs are subcategorized into several disorders, including irritable bowel syndrome (IBS), functional bloating, chronic idiopathic constipation, functional diarrhea, and unspecified functional bowel disorder. These disorders are distinguished by symptom-based diagnostic criteria and are traditionally diagnosed on the basis of characteristic GI symptoms and the absence of alarm features suggestive of organic disease.
FBD are highly prevalent in Western countries, with IBS being the most prevalent (10%–20%) and best studied condition. FBDs may have a considerable effect on patients’ quality of life, daily functioning, and work productivity. The high prevalence of the disorders, their chronic nature, and the commonly associated non-GI comorbidities lead to significant utilization of health care services and socioeconomic burden.
The pathogenesis of FBDs is multifactorial and not completely understood. Traditionally, the disorders have been thought to arise from abnormal function along the gut-brain axis with a variety of central and peripheral mechanisms that contribute to the initiation and perturbation of the GI motor and sensory functions leading to chronic, recurrent GI symptoms, including abdominal pain and discomfort, abdominal bloating, diarrhea, constipation, and alternating bowel movements. The intensive research in this area over the past few years has implicated new theories and suggested additional new pathophysiologic mechanisms, including genetic predisposition, peripheral GI factors, extraintestinal neurohormonal and central factors. Psychosocial aspects such as social learning, depression, anxiety, and somatization, are also recognized as important contributing factors, particularly to the clinical severity of the disorders.
Irritable bowel syndrome and functional bowel disorders
Functional bowel disorders (FBDs) are part of the larger group of functional gastrointestinal (GI) disorders characterized by symptoms attributed to the middle and lower GI tract that are not explained by structural or biochemical abnormalities. FBDs are subcategorized into several disorders, including irritable bowel syndrome (IBS), functional bloating, chronic idiopathic constipation, functional diarrhea, and unspecified functional bowel disorder. These disorders are distinguished by symptom-based diagnostic criteria and are traditionally diagnosed on the basis of characteristic GI symptoms and the absence of alarm features suggestive of organic disease.
FBD are highly prevalent in Western countries, with IBS being the most prevalent (10%–20%) and best studied condition. FBDs may have a considerable effect on patients’ quality of life, daily functioning, and work productivity. The high prevalence of the disorders, their chronic nature, and the commonly associated non-GI comorbidities lead to significant utilization of health care services and socioeconomic burden.
The pathogenesis of FBDs is multifactorial and not completely understood. Traditionally, the disorders have been thought to arise from abnormal function along the gut-brain axis with a variety of central and peripheral mechanisms that contribute to the initiation and perturbation of the GI motor and sensory functions leading to chronic, recurrent GI symptoms, including abdominal pain and discomfort, abdominal bloating, diarrhea, constipation, and alternating bowel movements. The intensive research in this area over the past few years has implicated new theories and suggested additional new pathophysiologic mechanisms, including genetic predisposition, peripheral GI factors, extraintestinal neurohormonal and central factors. Psychosocial aspects such as social learning, depression, anxiety, and somatization, are also recognized as important contributing factors, particularly to the clinical severity of the disorders.
The intestinal microbiota
The microbiota comprising the human GI tract includes a complex community of microorganisms that are collectively referred to as the intestinal microbiota (the total community of organisms in the GI tract). In addition to bacteria, the intestinal microbiota includes archea, fungi, and viruses. Most of the bacteria in the GI tract are represented in 4 major bacterial phyla (divisions): Firmicutes (64%), Bacteroidetes (23%), Proteobacteria (8%) and Actinobacteria (3%). The intestinal bacteria reside in an increasing density along the GI tract, with the highest density of about 10 14 bacteria per gram of luminal content in the colon. There are more than 1000 different bacterial species; however, only about a third of them have been identified and characterized.
The intestinal microbiota is in close interaction with the human host and has a variety of physiologic effects, which are important for human health. At the peripheral level, intestinal commensal and pathogenic bacteria can affect the human host via multiple mechanisms, including by direct stimulation of enteric neurons and immune cells and indirectly via intraluminal metabolic effects. In addition, the intestinal microbiota can influence systemic physiologic processes through epithelial receptor-mediated signaling with effects beyond the GI tract. For example, there is growing evidence for a bidirectional communication between the intestinal microbiota and the central (brain) nervous systems. Indeed, studies in animal models have shown that products of microbiota have the potential to affect the excitability of enteric and vagal afferents neurons as well as brain functions and behavior. Conversely, the enteric mictobiota can be influenced through the brain effects on intestinal motility, secretion, and immune function, thus creating the microbiota-gut-brain axis.
The intestinal microbiota in functional bowel disorders
Several lines of evidence support the relevance and importance of the intestinal microbiota in the pathogenesis and/or the clinical manifestation of FBDs. The first line of evidence comes from epidemiologic observations. Multiple epidemiologic studies have demonstrated that acute interruption of the intestinal microbiota is often associated with an increased risk for persistent functional GI symptoms. Several studies reported the development of persistent IBS symptoms following acute GI bacterial infection despite clearance of the initiating pathogen, a condition referred to as postinfectious IBS (PI-IBS). Indeed, acute gastroenteritis is currently recognized as the strongest identified predictor for the development of IBS with a 6- to 7-fold increased risk and average incidence of about 10%. Although several predisposing factors for the development of persisting PI-IBS have been identified, including prior psychological morbidity, female gender, severity and duration of the initial infection, and the inflammatory/immune response to the infectious event, the mechanisms underlying this disorder are still unclear. Nevertheless, a recent study comparing the intestinal microbiota between patients with or without IBS symptoms 6 months after gastroenteritis, patients with diarrhea-predominant IBS (IBS-D), and healthy controls has demonstrated that the microbiota of patients with PI-IBS is different from healthy controls but similar to the microbiota of patients with IBS-D, suggesting an ongoing postinfection alteration of the intestinal microbiota and possible shared pathophysiologic pathways with IBS-D. Persistent increase in a range of mucosal inflammatory markers has also been reported in these patients.
Another example for the development of persistent functional bowel symptoms following acute interruption of the intestinal microbiota is the use of antibiotics. The association between the use of antibiotics is less established because of relatively limited published data coming mainly from retrospective studies, and the difficult interpretation of the data due to expected differences in the effect of the different types of antibiotics. For example, a large retrospective study of nearly 26,000 patients found that exposure to macrolides or tetracyclines was significantly associated with developing IBS, whereas treatment with cephalosporins or penicillins was not. Nevertheless, a recent prospective case-control study has demonstrated that antibiotic therapy (all types) for extraintestinal infections was significantly associated with FBDs (odds ratio [OR] 1.90; 95% confidence interval [CI] 1.21–2.98) and even more so with IBS (OR 2.30; CI 1.22–4.33).
The association between IBS and small-intestine bacterial overgrowth is commonly reported and has been suggested as a possible cause for IBS; however, the data on this association are nonconclusive, and the relationship is debatable.
The second line of evidence comes from microbiology studies investigating the intestinal microbiota in patients with FBDs. Most of the studies in this area have focused on characterizing the composition of the microbiota in patients with IBS and comparing it to the microbiota in healthy controls. For convenience and practicality reasons, most of this research has been done on fecal samples as a representation of the overall bacterial makeup of the luminal intestinal microbiota. Only a few studies investigated the bacteria residing in the mucosal-associated microbiota, microorganisms in the thin layer of mucus adhering to the surface of the intestinal mucosa. In general, these studies have shown reduced microbial diversity and richness, and increased temporal instability in patients with IBS compared with healthy controls. In addition, they provide evidence for compositional alterations at different levels of bacterial taxonomy. The most repeated observations in this area are increased levels of Firmicutes and decreased levels of Bacteroidetes in patients with IBS compared with healthy controls. However, the differences in the abundance of specific species within these 2 microbial phyla are not consistent across studies. Of interest are reports of decreased levels of bacteria with beneficial metabolic and anti-inflammatory properties, for example, Bifidobacteria, and Faecalibacterium prausnitzii , and increased levels of potentially pathogenic bacteria, for example, Streptococcus spp (associated with increased interleukin-6 [IL-6] levels and stimulation of immune response) and mucin degraders bacteria, for example, members of the Ruminococcus spp in patients with IBS compared with healthy controls.
Several studies investigated the intestinal microbiota in specific subtypes of IBS and attempted to compare the microbiota between clinically relevant IBS subgroups. A recent study using high throughput pyrosequencing of the 16S rRNA gene on fresh fecal samples from a cohort of 60 patients with IBS and 20 healthy controls demonstrated significant differences in the microbiota between subgroups of patients with IBS that were categorized based on clinical symptoms of abdominal bloating and bowel characteristics (diarrhea predominant, constipation predominant, or mixed).
Another recent study investigating both fecal and colonic mucosal microbiotas in patients with chronic constipation found that the colonic mucosal microbiota in constipated patients differ from that of controls with higher abundance of genera from Bacteroidetes in the constipation group. However, although the profile of the colonic mucosal microbiota discriminated between patients with constipation and controls with 94% accuracy, this association was independent of the physiologic measure of colonic transit. In contrast, the profile of the fecal microbiota was associated with colonic transit and methane production but not the clinical diagnosis of constipation.
The latter 2 studies demonstrate 3 important points: (1) Alterations in the intestinal microbiota may have a role in the pathogenesis of specific symptoms (eg, abdominal bloating, constipation) associated with IBS and other FBDs; (2) The intestinal microbiota can affect relevant physiologic functions (eg, intestinal transit) as well as functional GI symptoms via different and independent mechanisms; (3) Both the intestinal luminal microbiota and the mucosa-associated microbiota are relevant and may have different effects on the human host.
The third line of evidence comes from physiologic studies that investigated the effects of the intestinal microbiota on gut-brain axis functions relevant to the pathophysiology of FBDs, including the following:
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GI sensory and motor functions,
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Intestinal barrier,
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Intestinal immune function,
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Intestinal neurohormonal function,
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Psychological factors.
Effects on gastrointestinal Sensorimotor Function
Most of the understanding of the effects of the intestinal microbiota on the GI sensory-motor function comes from animal studies. Early studies in germ-free rats (rats lacking microbiota) have demonstrated profound abnormalities in intestinal motor function including significantly delayed intestinal transit and a prolonged interdigestive migratory motor complex (MMC) period. On the other hand, colonization of germ-free rats with either Lactobacillus acidophilus or Bifidobacterium bifidum partially increases interdigestive MMC activity and small-bowel transit time while colonization with Escherichia coli and Micrococcus luteus delays gut motility. Thus, these studies demonstrate that the intestinal microbiota has an important role in maintaining normal intestinal motor function, and that different members of the intestinal microbiota can have different effects on intestinal motility. Specifically relevant to FBD are more recent studies in which germ-free animals were colonized with fecal material from patients with IBS (ie, microbiota humanized mice). These studies have shown that the transfer of fecal material from patients with IBS to germ-free animals can induce alterations in intestinal transit and greater pain responses to colonic balloon distension (ie, visceral hypersensitivity). Taken together, these studies demonstrate that the 2 relevant physiologic functions of the disorder, abnormal motility and visceral hypersensitivity, are transferable via fecal material, thus supporting the possibility of a causal role for the intestinal microbiota in the pathophysiology of at least those 2 physiologic hallmarks of the disorder.
Effects on Intestinal Barrier
The GI barrier is composed of complex molecular tight junctions, intracellular and surface-membrane proteins that keep the enterocytes tightly sealed and regulate the passage of molecules across the epithelium. Loss of structural and functional integrity of the epithelial barrier could lead to exposure of the mucosa-associated immune system to luminal toxic and immunogenic particles and trigger immunologic responses that could eventually lead to a variety of GI disorders, including inflammatory bowel diseases and functional GI disorders. Alterations in the integrity and function of the intestinal barrier have gained an increased interest as possible factors in the pathogenesis of IBS. Several studies in children and adult patients with IBS have demonstrated increased intestinal permeability in IBS compared with healthy controls. The mechanisms related to the increased permeability in IBS are not clear. However, the observations that certain bacteria ( Vibrio cholera, Clostridium difficile , and toxin-producing strains of E coli ) can increase intestinal permeability, whereas certain probiotics can promote barrier integrity, led to the suggestion that alterations in intestinal microbiota and mucosal immune functions could be important etiologic factors.
The relevance of this hypothesis to FBDs is demonstrated by the following 3 studies. In the 2 studies, fecal supernatants from IBS patients were applied in vitro to colonic mucosa from mice or to a model for intestinal barrier (Caco-2 cells system). In both studies, the expression of a tight junction intracellular protein (zonula occludens; ZO-1) decreased and the permeability increased. In the third, more recent study, plasma from patients with IBS-D and healthy controls was applied to the Caco-2 model of intestinal barrier. Interestingly, exposure of plasma from the IBS-D patients to the basolateral cell led to an increase in permeability compared with exposure of plasma from healthy controls, thus suggesting also a possible systemic mechanism. Furthermore, the increased permeability effect in the latter study was attenuated by selective inhibition of mast cell tryptase, and gram-negative bacteria lipopolysaccharides (LPS) thus further support the idea that this effect is mediated by microbiota and immune factors.
Effects on Intestinal Immune Function
Although IBS is not generally considered an inflammatory disease, there is growing evidence for the presence of dysregulated immune function and low-grade inflammation in some patients with IBS. Studies have demonstrated increased colonic infiltration of mucosal inflammatory and immune cells (most consistently reported are mast cells) and increased levels of high-sensitivity C-reactive protein and some inflammatory mediators (eg, IL-6 and IL-8) and inflammatory cytokines in patients with IBS compared with healthy individuals. Abnormal polymorphisms in genes involved in immune and inflammatory responses have also been reported. The interactions between the intestinal immune system and the intestinal microbiota are well documented, and their relation to FBDs is reviewed in detail elsewhere. Important observations in this area are increased expression of Toll-like receptors (TLRs) specifically involved in activation of the innate immune response to enteric bacteria, including TLR4 (involved with recognition of bacterial LPS from gram-negative bacteria) and TLR5 (involved with recognition of flagellin, a common bacterial antigen present in most motile bacteria in the intestine). In line with these observations is the finding that TLR4-deficient mice have a significantly reduced number of enteric neurons and altered GI motility and that activation of TLR4 by enteric microbiota affects the enteric nervous system and intestinal motility. Interestingly, a recent study has suggested that the microbiota effects on GI motility through TLRs could be mediated by affecting the expression of intestinal serotonin or 5-hydroxytryptamine (5-HT) receptors. Also, in line with the observation of increased expression of TLR5 (involved with recognition of bacterial flagellin) is the finding of increased antiflagellin antibodies in IBS patients (mostly in PI-IBS, almost 30%) compared with healthy controls (only 7%). These observations support the hypothesis that the intestinal luminal bacterial antigens could be the trigger of the immune activation that leads to alterations in intestinal physiology and functional bowel symptoms at least in a subset of patients.
Effects on Intestinal Neurohormonal Function
The role of the enteroendocrine system, and particularly the intestinal serotonin system, has been the focus of extensive research over the past decade. Serotonin or 5-HT is a monoamine neurotransmitter produced primarily (90%) by enterochromaffin cells in the GI tract. Indeed, 95% of this potent neurotransmitter is contained in the gut and only 5% in the central nervous system. The locally enteric release of 5-HT acts on specific intestinal receptors to affect multiple GI functions, including intestinal motility, sensation, and secretion. The profound effects of serotonin on GI functions relevant to FBDs have led to the increased interest in targeting serotonin receptors (primarily 5-HT3 and 5-HT4 receptors) for development of pharmacologic interventions for these disorders. An interesting association between the entering serotonergic system and the intestinal microbiota has been recently reported by an important study demonstrating that indigenous spore-forming microbes from mice and healthy human colons can produce specific metabolites that promote GI 5-HT biosynthesis by colonic enterochromaffin cells and that this microbiota-dependent 5-HT effect could have a significant impact on GI motility.
Psychological Factors
Although most patients with FBDs do not meet criteria for diagnosis of psychiatric disorders, emotional distress and psychological difficulties are often clinically observed in these patients, and they are considered as contributing and risk factors for the onset, severity, duration, and response to treatment of the disorders. Although it is not clear whether psychological and emotional distresses precede a diagnosis of FBDs or are consequences of them, they do have the capacity to affect physiologic functions relevant to the pathophysiology of the disorders. The effects of psychological disorders on motor, sensory, barrier, and immune functions are well documented and the relevance of these interactions to FBDs are usually discussed under the concept of gut-brain axis. However, the increasing recognition of the regulatory effects of the intestinal microbiota on the bidirectional interactions between the central nervous system, the enteric nervous system, and the GI tract has broadened this concept, which is now referred to as “microbiota-gut-brain axis.”
The exact mechanisms of these interactions are not yet clear, but data from animal and a few human studies provide evidence for intestinal bacteria effect on pain experience and psychological, emotional, and behavioral disturbances that are often observed in association with FBDs.
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