An Update on Irritable Bowel Syndrome
Abstract
Purpose of review Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder characterized by abdominal discomfort or pain that is accompanied by a disturbance in defecation. Although the exact etiopathogenesis is not completely understood, recent advances in the understanding of the biochemical, physiologic, and biopsychosocial mechanisms of IBS have resulted in exciting new insights as well as therapies. This article will review the recent developments in pathogenesis, diagnosis, and treatment.
Recent findings IBS may be the product of various pathogenic mechanisms which include IBS as a serotonergic disorder; the role of genetics; IBS as an inflammatory state and the potential role of mast cells; IBS as a result of bacterial overgrowth and altered gastrointestinal microbiome; and abnormal pain processing and pain memory. Emerging therapies have developed targeting these mechanisms.
Summary IBS remains a symptom-based diagnosis that can usually be made comfortably based on clinical history without testing in the absence of alarm features. Novel and emerging therapies that are based upon the evolving understanding of the pathophysiology of IBS hold significant promise and for the first time there are potential therapies that may alter the natural history of this disorder.
Recent findings IBS may be the product of various pathogenic mechanisms which include IBS as a serotonergic disorder; the role of genetics; IBS as an inflammatory state and the potential role of mast cells; IBS as a result of bacterial overgrowth and altered gastrointestinal microbiome; and abnormal pain processing and pain memory. Emerging therapies have developed targeting these mechanisms.
Summary IBS remains a symptom-based diagnosis that can usually be made comfortably based on clinical history without testing in the absence of alarm features. Novel and emerging therapies that are based upon the evolving understanding of the pathophysiology of IBS hold significant promise and for the first time there are potential therapies that may alter the natural history of this disorder.
Introduction
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder (FGID) characterized by symptoms of recurrent abdominal pain or discomfort directly associated with disturbances in defecation which are not explained by structural abnormalities. IBS is very common in the North American population with the prevalence estimated to be between 10 and 15%. Although it has not been found to negatively impact survival, IBS continues to account for significant morbidity and heavy utilization of healthcare resources. IBS has been estimated to account for 3.5 million annual physician visits in the USA and is associated with annual direct costs of US$ 1.6 billion and indirect costs of US$ 19.2 billion. These figures are staggering considering that only a minority of those with IBS actually seek care for their symptoms.
Given its prevalence in the community and dramatic impact on both patients and healthcare utilization, there has been a clear impetus to better define the etiopathogenesis of IBS and to identify safe and effective therapies. However, to date, no definitive biomarkers or physiologic disturbances have been identified. As a result, available therapies that address the entire syndrome complex and alter the natural history of IBS have largely been lacking, with most traditional therapies focused on improving individual symptoms that comprise the syndrome.
Despite these limitations, this remains an exciting time as IBS represents an area of intense investigation from multiple directions. Therapy that alters the natural history of IBS has been identified for the first time, and current knowledge of IBS is constantly in evolution. As novel insights into its pathophysiology emerge it seems likely that better therapies will be identified. This article will provide a global review including recent developments in terms of pathogenesis, diagnosis, and emerging therapies for IBS.
Pathogenesis
The discovery of a single unifying pathway of pathogenesis for IBS has been elusive, and there are no definitive biochemical, or physiologic markers. However, one may argue that such a 'holy grail' may not exist for IBS and that its pathogenesis is likely multifactorial in nature. The proposed biopsychosocial model for IBS which views IBS as a product of the cumulative interactions between physiological, psychosocial, behavioral, and environmental factors, seems especially appropriate in this context. Investigation has suggested several likely sets of abnormalities amenable to therapeutic intervention: IBS as a serotonergic disorder; the role of genetics; IBS as an inflammatory state and the potential role of mast cells; IBS as a result of bacterial overgrowth and altered gastrointestinal microbiome; and abnormal pain processing and pain memory.Irritable Bowel Syndrome as a Serotonergic Disorder
Serotonin, or 5-hydroxytryptamine (5-HT), is a biogenic monoamine neurotransmitter that is largely contained within the gastrointestinal tract in enterochromaffin cells. Enterochromaffin cells release 5-HT in response to luminal stimuli, such as the passage of chyme, with 5-HT having a wide range of gastrointestinal effects given that receptor subtypes are found on smooth muscle, enteric neurons, and enterocytes. Given the integral role of 5-HT in gut signaling and function, there has been growing interest in its potential role in IBS. Recent findings appear to suggest that disruption of serotonergic equilibrium may have a role in IBS which include increased postprandial levels of circulating 5-HT in patients with diarrhea-predominant IBS (D-IBS); elevated platelet-depleted plasma 5-HT levels in both fasting and fed states in patients with D-IBS; lack of elevation in plasma 5-HT after meal ingestion in patients with constipation-predominant IBS (C-IBS); and decreased mucosal 5-hydroxyindoleacetic acid (5-HIAA)/5-HT ratio in those with C-IBS. These findings suggest there may be relative 5-HT excess in D-IBS and 5-HT insufficiency in C-IBS. Furthermore, the role of serotonin transporter (SERT) function has been of interest given findings of reduced mucosal SERT activity in IBS. However, the role of SERT function in IBS is unclear, as a recent report did not find any differences in mucosal expression of SERT in patients with IBS.Perhaps some of the most compelling evidence that IBS is a serotonergic disorder stems from results from 5-HT receptor modulating agents as therapies in IBS; specifically, alosetron and tegaserod. Both alosetron and tegaserod were withdrawn from the U.S. market due to serious adverse events with constipation and ischemic colitis and postmarketing reports of higher cerebrovascular and cardiac events, respectively. Nonetheless, both appeared to be effective therapeutic agents in IBS (and alosetron was re-released in the USA). As a 5-HT3 antagonist, alosetron was shown to be an effective agent in the treatment of D-IBS with improvements in global IBS symptoms, relief of abdominal pain, improvement of both frequency and consistency of bowel movements, inhibition of intestinal secretion, delay of colonic transit time, and central effects that may have resulted in beneficial effects on sensation in D-IBS. Tegaserod, a selective partial agonist of the 5-HT4 receptor has been shown to improve global IBS symptoms and constipation in C-IBS patients. Despite the significant adverse events associated with alosetron and those potentially reported for tegaserod, their consistently demonstrated effectiveness as targeted therapies for IBS is supported by the literature. They have served to further strengthen the hypothesis that serotonin is key in the pathophysiology of IBS, which has led to the development of other novel serotonergic agents.
Irritable Bowel Syndrome and Genetics
The possible role of genetics and putative susceptibility loci for IBS has been an area of growing investigation and interest. Multiple family studies have consistently reported that familial aggregation occurs in IBS. Furthermore, the majority of twin studies have demonstrated a significant genetic liability in IBS. Although it remains unclear whether these findings are secondary to common genetic versus early environmental factors, there has been an active interest in various candidate genes. Notable gene polymorphisms include the β3 subunit of the G protein (GNβ3) and the serotonin transporter-linked polymorphic region (5-HTT LPR) which is located in the promoter region of the SERT gene. Unfortunately, these polymorphisms have not been found to be associated with the clinical phenotype of IBS. Various other polymorphisms have been investigated with similar negative findings; although limitations of small sample sizes and lack of replication of findings for certain polymorphisms are inherent in many of these studies. Despite these limitations, a genetic approach to IBS remains an exciting area of exploration. Future direction of investigation includes genome-wide approaches and further delineation of the role of epigenetic factors in IBS.Irritable Bowel Syndrome as an Inflammatory Condition and the Possible Role of Mast Cells
There is increasing evidence emerging on the role of low-grade inflammation in the pathogenesis of IBS, and in particular, the role of mast cells. Mast cells play a critical role in normal immune function and respond to antigen stimuli through degranulation resulting in the release of the inflammatory mediators histamine and tryptase. Numerous studies have reported on the increased number of mast cells found throughout the gastrointestinal tract in patients with IBS. Furthermore, both the degree of cellularity of mucosal mast cells and proximity to sensory nerves have been found to be correlated with abdominal pain in IBS. Increased mast cell activity, as measured by release of histamine and tryptase, has also been reported in patients with IBS. These findings have resulted in interest not only in the role of mast cells in IBS, but also the potential therapeutic role of mast cell stabilizers in IBS (Fig. 1).| Mast cell activation results in degranulation with release of histamine and tryptase which interact with enteric nerves and may result in symptoms of irritable bowel syndrome Ketotifen is a mast cell stabilizer that prevents degranulation, thus making it an agent of interest in the treatment of IBS. IBS, irritable bowel syndrome. |
Figure 1.
Mast cell activation results in degranulation with release of histamine and tryptase which interact with enteric nerves and may result in symptoms of irritable bowel syndrome
Ketotifen is a mast cell stabilizer that prevents degranulation, thus making it an agent of interest in the treatment of IBS. IBS, irritable bowel syndrome.
Ketotifen is a mast cell stabilizer that prevents degranulation, thus making it an agent of interest in the treatment of IBS. IBS, irritable bowel syndrome.
Bacterial Overgrowth and Altered Gastrointestinal Microbiotome
The gastrointestinal microbiota is comprised of two distinct ecosystems: luminal bacteria that are associated with feces or food particles and mucosa-associated bacteria that are bound to the mucus layer adjacent to the intestinal epithelium. The gastrointestinal microbiota has been proposed to play a critical role in gastrointestinal homeostasis, and has been proposed to have host effects from immune–microbial interactions. The theorized importance of the gut microbiota has led to investigations which seek to detect either quantitative or qualitative alterations of the microbiota in IBS.Small intestinal bacterial overgrowth (SIBO) has been proposed as a quantitative alteration of the gut microbiota that results in symptoms of IBS. The role of SIBO in IBS has been supported by evidence that SIBO based on breath testing is highly prevalent in patients with symptoms of IBS, and that treatment of presumed SIBO resulted in improvements in global symptoms of IBS, abdominal pain, bloating, and diarrhea. However, these findings have not been supported by other studies. Furthermore, there is considerable controversy regarding the most appropriate standard by which to diagnosis SIBO, breath tests versus small bowel aspirates and culture. Although a recent systematic review and meta-analysis reported the prevalence of SIBO in patients with symptoms of IBS to be between 4% and 64%, the significant heterogeneity among studies, funnel plot asymmetry, as well as attenuation of significant findings based upon SIBO criteria used, limited any conclusions that could be drawn. Despite this uncertainty, it certainly is notable that recent preliminary studies have found rifaximin, a nonabsorbable oral antibiotic, to be effective in not only improving D-IBS symptoms, but also may have sustained effects after cessation of therapy. Regardless of the uncertainty surrounding SIBO in IBS, quantitative disturbances of the gastrointestinal microbiota in IBS appears plausible and treatment algorithms have been proposed for IBS based on the SIBO hypothesis.
Qualitative changes of the gut microbiota in IBS have also come under scrutiny. One recent study not only found higher levels of Lactobacillus and Veillonella in fecal samples of patients with IBS, but also found higher levels of acetic acid, propionic acid, and total organic acids as well. Furthermore, the levels of acetic and propionic acids were both associated with more severe symptoms and impaired quality of life (QoL). These findings support the concept that both quantitative as well as qualitative changes within the gut microbiota may have contributory roles in the pathogenesis of IBS.
Diagnosis of Irritable Bowel Syndrome: Are we there yet?
Given the lack of definitive sine qua non biomarkers that firmly indicate a diagnosis of IBS, it remains a clinical diagnosis that is largely founded on symptom-based criteria. Since its first development in 1988, the Rome Criteria for IBS has undergone modifications and revisions that have resulted in its current iteration, Rome III. Although there is a lack of validation studies of Rome III, two recent well performed meta-analyses investigated the performance characteristics of the Manning criteria, Rome I and Rome II criteria in discriminating patients with organic disease. The studies had similar findings indicating that all three diagnostic criteria are of moderate utility in distinguishing those patients at high or low risk for organic disease. However, both studies found improved specificity when alarm signs were included with gastrointestinal symptoms. Therefore, symptom-based diagnostic criteria can be used to make a positive clinical diagnosis of IBS and in the absence of alarm symptoms, it is reasonable to prescribe indicated therapies without referring for evaluation to exclude organic disease. A diagnostic algorithm for IBS from the Rome Foundation summarizes the approach. Future studies are needed to provide validation of the Rome III criteria, and as suggested by some, should possibly include latent class analysis studies that incorporate additional diagnostic markers (e.g. endoscopy) in conjunction with the Rome criteria for predicting IBS status.Traditional Therapies
The traditional approach to therapy for IBS has been largely limited to an individual symptom-specific approach. Such symptom-based therapies have had limited efficacy in treating the entire syndrome complex and have had no impact on the natural history of the disorder. These therapies include the use of bulking agents, antidiarrheals, and antispasmodics.Bulking Agents
Bulking agents traditionally used in the treatment of IBS have included soluble fibers such as psyllium, ispaghula, and calcium polycarbophil. Although commonly used in clinical practice, historically, the evidence for the role of bulking agents in IBS has been limited. However, recent meta-analyses have consistently reported the effectiveness of bulking agents in improving global IBS symptoms and reducing symptom severity. Despite these findings, bulking agents have not been demonstrated to improve quality of life in IBS. Given their benign safety profile, bulking agents appear to be an appropriate initial therapy in those with mild symptoms.Antidiarrheals
Loperamide is a traditional antidiarrheal that has been used in the treatment of diarrhea-predominant IBS. Although it has consistently demonstrated effectiveness in improving stool characteristics and improving diarrhea, it has not been shown to be effective in ameliorating IBS symptoms or abdominal pain. Therefore, loperamide appears to have a limited role in the treatment of D-IBS.Antispasmodics
Many have historically theorized that the symptoms of IBS arise from excitability and even 'spasm' of the colonic smooth muscle. This led to the development of multiple agents that were directed at modulating the colonic smooth muscle and globally were termed 'antispasmodics'. A recent well performed meta-analysis reporting on the efficacy of antispasmodics reported a relative risk (RR) of persistent symptoms after therapy with antispasmodics compared with placebo of 0.68 (95% CI 0.57–0.81) with a number-needed-to-treat (NNT) to prevent symptoms of IBS of five. Hyoscine and peppermint oil appear to be the most effective agents in this class.Emerging Therapies
With the developing understanding of the mechanisms and mediators involved in gastrointestinal motility and secretory function, novel therapies are emerging that hold much promise. In this section we will discuss promising therapies for IBS that include new generation 5-HT4 agonists; novel 5-HT3 antagonists; secretagogues; anti-inflammatory agents; peripheral visceral analgesics; and a centrally acting benzodiazepine receptor modulator.Serotonergic Agents
As discussed earlier, previous serotonergic agents have been effective in the treatment of IBS but have been limited by serious adverse effects and most have been taken off the U.S. market. However, novel serotonergic agents, specifically the 5-HT4 agonist prucalopride, appear promising as therapeutic agents that may avoid the shortcomings of their predecessors.Prucalopride is a 5-HT4 agonist with high selectivity and affinity that has had promising findings without significant adverse events in patients with chronic constipation, which include accelerating colonic transit, improving bowel function and the frequency of bowel movements, improving satisfaction with bowel movements, decreasing perceived severity of constipation, and improving constipation-related QoL. Should these findings extend similarly for patients with C-IBS, then prucalopride may become an important therapy in the near future.
Secretagogues
Chloride ion (Cl−) channels have an integral role in the transport and secretion of fluids throughout the gastrointestinal tract. Specific Cl− channels investigated include the type 2 chloride channels (ClC-2) found on the apical cell membrane of the intestines as well as the cystic fibrosis transmembrane regulator (CFTR) Cl− channels that are found on the luminal membrane of enterocytes.Lubiprostone, a bicyclic fatty-acid derivative of prostaglandin E1 and an activator of ClC-2 channels, is thought to increase secretion of intestinal fluid and thereby have a positive enterokinetic effect on the small intestine and colon. It is currently approved in the USA for the treatment of C-IBS in women.
Linaclotide is a 'first-in-class' guanylate cyclase-C (GC-C) agonist that activates GC-C receptors located on the luminal membrane of enterocytes which results in activation of CFTR and leads to increased intestinal chloride, bicarbonate, and fluid secretion. Linaclotide has been found to significantly accelerate ascending colon transit time, improve ease of stool passage, improve stool consistency, and increase stool frequency in women with C-IBS. Furthermore, there is growing evidence of its beneficial effects on stool frequency and even QoL in patients with chronic constipation.
Anti-inflammatory Agents
As described earlier, there is increasing interest in the role of low grade inflammation in the pathogenesis of IBS. As the role of mast cells has been of particular interest, ketotifen, a mast cell stabilizer, has been investigated as a possible agent in IBS. A recent preliminary report found that it increased the threshold for discomfort in patients with IBS and visceral hypersensitivity versus 'normosensitive' IBS patients, significantly decreased abdominal pain and other IBS symptoms including bloating and diarrhea, and improved QoL. However, the exact mechanism of its beneficial effects was unclear as the number of mast cells in rectal biopsies and spontaneous release of tryptase was actually lower in the IBS patients versus healthy controls in the study, and the degree of histamine and tryptase release was not altered by ketotifen.The use of other anti-inflammatory agents in IBS has been limited and with mixed results. Prednisolone has been investigated in one randomized, double-blind, placebo-controlled trial in postinfectious IBS and was ineffective in improving symptoms. However, mesalazine (5-aminosalicylic acid), an anti-inflammatory agent traditionally used in the treatment of inflammatory bowel disease, has had positive preliminary findings in IBS. One recent randomized, double-blind, placebo-controlled trial of mesalazine in IBS patients found that it significantly reduced colonic immune cells, inhibited mast cells, and increased general well being without serious adverse events; however, it did not significantly alter abdominal pain, bloating, or bowel habits.
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