P- Reviewers: El-Salhy M, Grundmann O, Yang CH S- Editor: Gou SX L- Editor: A E- Editor: Liu XM
Published online Mar 14, 2014. doi: 10.3748/wjg.v20.i10.2456
Revised: December 1, 2013
Accepted: February 20, 2014
Published online: March 14, 2014
Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders, characterized by abdominal pain, bloating, and changes in bowel habits. These symptoms cannot be explained by structural abnormalities and there is no specific laboratory test or biomarker for IBS. Therefore, IBS is classified as a functional disorder with diagnosis dependent on the history taking about manifested symptoms and careful physical examination. Although a great deal of research has been carried out in this area, the pathophysiology of IBS is complex and not completely understood. Multiple factors are thought to contribute to the symptoms in IBS patients; altered gastrointestinal motility, visceral hypersensitivity, and the brain-gut interaction are important classical concepts in IBS pathophysiology. New areas of research in this arena include inflammation, postinfectious low-grade inflammation, genetic and immunologic factors, an altered microbiota, dietary factors, and enteroendocrine cells. These emerging studies have not shown consistent results, provoking controversy in the IBS field. However, certain lines of evidence suggest that these mechanisms are important at least a subset of IBS patients, confirming that IBS symptoms cannot be explained by a single etiological mechanism. Therefore, it is important to keep in mind that IBS requires a more holistic approach to determining effective treatment and understanding the underlying mechanisms.
Core tip: In recent years, several novel mechanisms of irritable bowel syndrome (IBS) that likely relate to previously established IBS theories have been identified. Inflammation and postinfectious low-grade inflammation are emerging areas requiring clarification with regard to IBS pathophysiology. Immunological and genetic predisposition along with altered microbiota are critical in IBS development, while several dietary factors and enteroendocrine cells may also play roles in this syndrome. However, none of these accounts for the full repertoire of IBS symptoms, and the pathophysiology of this condition is not fully understood.
Citation: Lee YJ, Park KS. Irritable bowel syndrome: Emerging paradigm in pathophysiology. World J Gastroenterol 2014; 20(10): 2456-2469
Irritable bowel syndrome is a functional gastrointestinal disorder that manifests symptoms of recurrent abdominal pain associated with changes in bowel habit without organic abnormalities, and its prevalence ranges from 5% to 15%. According to the Rome III Diagnostic Criteria, irritable bowel syndrome (IBS) is defined as a syndrome with recurrent abdominal pain or discomfort occurring at least 3 d per month over a 3-mo span. It is associated with two or more of the following characteristics: (1) improvement with defecation; (2) change in stool frequency with onset; and (3) change in stool form with onset. Many studies in IBS pathophysiology over the past decades have focused on colonic dysmotility, visceral hypersensitivity, and the brain-gut interaction. Recently, however, other mechanisms have been actively studied, including inflammation, post-infectious low-grade inflammation, immunologic factors, altered microbiota, dietary factors and enteroendocrine cells. However, evidence regarding their roles in IBS remains controversial. Recently, the definition of IBS has been challenged by growing evidence of organic abnormalities in patients who satisfy the Rome criteria for IBS[10,11]. Due to these new paradigms, IBS may no longer classify as an absolute functional disorder. In this article, we briefly summarize the classical concepts and follow with a discussion of the recent research pertaining to the new models of IBS pathophysiology. Better understanding of these emerging paradigms will aid the diagnosis and management of IBS.
Gastrointestinal dysmotility is recognized as one of the primary pathophysiological mechanisms in IBS, but it does not fully correlate with symptomatic bowel disturbances. Colonic motor activity in healthy subjects mainly consists of non-propagating and sporadic contractions and progression of intestinal contents by propagating movements termed high-amplitude propagated contractions (HAPCs)[12-14]. The frequent occurrence of HAPCs in IBS patients may explain the frequent bowel movements that cause diarrhea in diarrhea-predominant IBS (D-IBS)[15,16], whereas HAPCs are rarer in patients with constipation-predominant IBS (C-IBS). Colonic transit is generally accelerated in D-IBS and delayed in C-IBS according to several studies; however, reports on the relationship between colonic motility and IBS subtypes are inconsistent. In one survey, 70% of C-IBS and 50% of D-IBS patients noted the feeling of incomplete evacuation. In contrast, more recent data provided evidence that pelvic floor dyssynergia (PFD) causes symptoms characteristic of non-diarrhea predominant IBS (non-D IBS), including straining, incomplete evacuation, blockage, digitation, and anal pain, suggesting that anorectal function tests should be considered in patients with non-D IBS and PFD symptoms.
According to the classical concepts, IBS is caused by visceral hypersensitivity resulting in abdominal pain or discomfort and gastrointestinal motor disorder, which lead to alterations in defecation patterns; i.e., diarrhea or constipation. Numerous studies have demonstrated the link between IBS and increased intestinal sensitivity. Rectal hypersensitivity was proposed as a marker for IBS, and rectal sensory thresholds measured by rectal barostat testing were lower in IBS patients compared to healthy controls after rectal distention. Most research so far has focused on colonic sensitivity[23,24] but hypersensitivity has also been observed in the esophagus, stomach and small intestine with IBS. Many studies have shown visceral sensitivity in IBS to correlate with stress and food intake. Colorectal sensitivity is attenuated in IBS patients after intake of a meal[30,31], and the visceral stimulus is significantly higher during stress in IBS patients than in healthy controls[32,33]. Therefore, visceral hypersensitivity is considered to be the conglomeration of peripheral and central processes, and its determinants are considered to be a combination of intrinsic and environmental factors.
Alterations in the brain-gut axis are a new concept in IBS pathophysiology. Environmental, cognitive, and emotional states can affect intestinal sensory perception[35,36]. Corticotropin-releasing hormone (CRH) is a major mediator of stress responses in the brain-gut axis, affecting the functions of both the brain and the gut[37,38]. Intravenous administration of CRH exacerbated colonic motility, while peripheral administration of a CRH antagonist blocked the stress-induced increase in colonic motility, visceral perception, and negative mood. Several studies have demonstrated brain-gut interactions using brain imaging. For example, Hamaguchi et al showed that distention of the descending colon activated portions of the brain that are highly related to pain recognition and emotion. Mayer et al reported that IBS patients exhibit increased activation of brain regions that potentially correspond to the perception of rectal distension. Finally, Mertz et al showed differences in activation of brain regions in response to a painful rectal stimulus in IBS patients compared to controls.
Recent evidence supports a role for inflammation in IBS pathophysiology and generation of IBS symptoms in a subset of patients. Chadwick et al performed studies of colonoscopic biopsy specimens from patients meeting the Rome criteria for clinical diagnosis of IBS. Immunohistological assessment showed an increased number of activated immunocompetent cells, including T-lymphocytes, neutrophils, and mast cells in the intestinal mucosa, suggesting a role for the mucosal immune system in pathogenesis. Subsequent studies demonstrated an increased frequency of several surrogate markers for inflammation in IBS patients, the most consistent finding being an increased number of mast cells in the gastrointestinal (GI) tracts of IBS patients[4,45-47]. Mast cells are associated with wound healing, defense against pathogens, and hypersensitivity in GI mucosa. They degranulate to release inflammatory and immune mediators, which cause the recruitment of other inflammatory cells into the GI mucosa. Several studies have indicated that increased mast cells in IBS patients may correlate with certain symptoms of IBS, such as bloating and abdominal pain[46,48]. Another finding is the presence of activated T-lymphocytes in mucosal biopsy specimens from IBS patients[4,46,49]. Several studies have demonstrated an increase in the infiltration of lymphocytes in the myenteric plexus of patients compared to healthy controls[46,47,50]. Furthermore, patients with IBS have more activated T-cells in their colonic biopsies and blood samples. T lymphocytes are involved in adaptive immunity and have multiple functions, such as the activation of B lymphocytes and macrophages and the destruction of infected host cells. In addition, enhanced expression of proinflammatory cytokines in peripheral blood mononuclear cells and serum may confer a predisposition to immune activation in patients with IBS. In the following section, we will review the data supporting the role of inflammatory and proinflammatory cytokines in IBS.
IBS-like symptoms seen in ulcerative colitis (UC) patients during the remission phase appear to involve inflammation[55-57]. It is assumed that chronic inflammation in the colon during the remission phase, associated with altered sensory and motor functioning, can lead to IBS-like symptoms[58,59]. Fecal calprotectin was significantly higher in IBD patients displaying IBS-like symptoms than those lacking IBS-like symptoms, indicating the presence of occult inflammation in the former. One group reported elevated levels of beta-defensin 2 peptides (HBD-2) in fecal fluid derived from IBS patients. HBD-2 is an antimicrobial peptide recently implicated in the pathogenesis of inflammatory bowel disease. These results suggest an activation of the mucosal innate defense system toward a proinflammatory response in IBS patients without macroscopic signs of inflammation.
There is also evidence of microscopic inflammation in IBS. In our previous study, conducted in 42 IBS patients diagnosed by the Rome II criteria, the microscopic findings of mucosal hyperplasia, lymphocyte aggregation, and increased eosinophil counts were more frequently observed in the IBS group than the control group. Microscopic colitis does not appear to be associated with IBS symptoms. A study in Malaysia also identified microscopic inflammations in D-IBS subjects that did not meet the criteria for classical microscopic colitis. In this study, the most common pathological findings were mixed chronic and acute inflammatory cells, lymphocytes, plasma cells and neutrophils. IBS onset following an episode of gastroenteritis [post-infectious IBS (PI-IBS) is indicative of a role for inflammation in the pathogenesis of IBS (discussed below)]. Although large amount of research focusing on inflammation in the pathophysiology of IBS, as discussed in this section, this concept should be studied further to develop a potential future therapy for IBS.
Recently, numerous studies indicated that bacteriologically confirmed gastroenteritis is critical in the pathogenesis of IBS[5,64,65]. Also called post-infectious IBS (PI-IBS), first proposed by Stewart in 1950, this is a case where IBS symptoms emerge in a patient - who has not previously met the Rome criteria for IBS - following an infectious illness characterized by two or more of the following: fever, vomiting, diarrhea, or a positive bacterial stool culture. Most patients with infectious gastroenteritis recover in a few days, but approximately 10% of patients experience persistent symptoms (e.g., abdominal pain or diarrhea) that progress to IBS. In the meta-analysis by Thabane et al, the odds of developing IBS increased six- to seven-fold in patients with an episode of acute gastroenteritis. The mechanisms of PI-IBS are still not clear, yet studies have indicated that inflammation, genetic polymorphisms in genes associated with immune responses to infectious pathogens, and immune functioning may contribute to the occurrence of PI-IBS.
Low-grade inflammation is recognized as the main pathophysiology of PI-IBS. El-Salhy et al reported that rectal biopsy specimens taken from patient after Campylobacter gastroenteritis showed increases in leucocytes, lymphocytes, mast cells and endocrine cells. Another study reported that 3 mo post-gastroenteritis, patients who had PI-IBS continued to increase their chronic inflammatory cell counts, while those in healthy controls returned to normal levels. Furthermore, several studies demonstrated that intestinal mast cell infiltration and activation following an infection often resulted in mucosal inflammation and the development of PI-IBS[5,73]. Such findings support a relationship between mucosal inflammation and PI-IBS. Development of IBS following non-GI infection has also been reported, and other recent study found that viral and bacterial enteritis outbreaks can lead to PI-IBS in a considerable proportion of patients (13%).
Several lines of evidence indicate that inflammation and immune cells play roles in the intestinal neuroendocrine system, which controls GI sensory-motor function. Dunlop et al identified an association between PI-IBS and the persistence of mucosal abnormalities, enterochromaffin cell (EC) hyperplasia, and increased mucosal permeability, including intestinal inflammation. Increased permeability facilitates transfer of antigens through the intestinal mucosa, which leads to inflammatory cascades characterized by increased immune cell numbers. Serotonin secretion from EC cells, which regulates the gut immune system, can be attenuated by the secretory products of immune cells[78,79].
There are reports of increased levels of the proinflammatory cytokines in plasma levels of PI-IBS patient and significantly greater IL-1β mRNA expression in the rectal mucosa of patients with IBS symptoms following acute gastroenteritis, but not in asymptomatic control subjects[73,80]. Flagellin antibodies were observed more frequently in patients with PI-IBS, indicating that immune activation in response to luminal triggers plays a role in the development of IBS[81,82]. Flagellins are primary triggers of innate and adaptive immunity, thus driving pathogen-induced acute inflammation. These observations suggest that inflammatory responses to infection, rather than the infective pathogen itself, are an important predisposition to the occurrence of PI-IBS.
More recent data indicate an influence of genetics on the development of IBS. A survey of twins in Norway showed that the concordance for IBS in monozygotic twins was significantly higher than in dizygotic twins, providing robust evidence for the involvement of genetic factors in the etiology of IBS. To date over 60 candidate genes have been reported as positively associated with IBS. It should be noted that many of these studies had conflicting results; nevertheless, similar surrogate markers are being examined. Discrepancies may be due to differences in IBS subtypes of the study subjects, or in the processes by which the studies recruited their control groups, or in the laboratory methodologies used. However, it is noteworthy that many of these cases demonstrated genetics as a potential etiological factor. The representative genetic factors for IBS pathophysiology associate with inflammation, neurotransmitters, and bile acid synthesis.
Transient mucosal inflammation is crucial for the manifestation of IBS, despite the original definition of this syndrome that implies the lack of signs of active inflammation. According to the evidence, subsets of IBS patients share genetic susceptibility loci for inflammation. The relatively well-studied IBS gene is TNFSF15, which has been confirmed in genome-wide association studies to mediate mucosal inflammation in IBD. In Crohn’s disease, TNFSF15 is up-regulated with intestinal inflammation and functions in nuclear factor κB activation, potentiation of IL-2 signaling, and secretion of interferon gamma by T lymphocytes. Three cohort studies performed in the United Kingdom, Sweden and the United States, and England identified a significant association between TNFSF15 and IBS. Belmonte et al provided further evidence for altered intestinal immune activation. Increased toll-like receptor (TLR) expression has previously been observed in IBD. In this study, the expression of TLR2 and TLR4 differed significantly among the IBS subtypes. The increased TLR expression in mixed-type IBS patients provoked intracellular signaling pathways that resulted in increased expression of the mucosal proinflammatory cytokines IL-1 and IL-8. Villani et al suggested genetic risk factors for the development of PI-IBS based on a 2300-patient cohort in Walkerton, Ontario. They found that TLR9, IL-6, and CDH1 variants persisted as independent risk factors for PI-IBS. Similarly, Brint et al reported elevated levels of TLR4 and TLR5 level in PI-IBS patients, supporting the involvement of the innate immune system leading to an inflammatory response.
Several studies identified specific genetic polymorphisms in proinflammatory cytokines, which have an influence on GI functions, motility, epithelial permeability, and visceral sensation[95-97]. TNF-alpha is produced by monocyte-derived activated macrophages, and this cytokine plays on important role in chronic inflammatory states such as IBD. According to a study in the Netherlands, increased TNF-alpha levels were significantly more prevalent in IBS patients compared to healthy controls, while no such association was found for polymorphisms in the IL-10 gene, an anti-inflammatory cytokine involved in the regulation of immune and inflammatory responses. Several studies identified that certain IBS patients may be genetically predisposed to decreased production of IL-10 and subsequent development of low-grade inflammatory manifestations of IBS. In a study done in Mexico, the high IL-10 producer genotype is less prevalent in IBS patients than healthy controls. However, in the abovementioned Netherlands study, IL-10 genotypes were similarly distributed among patients with IBD compared to healthy controls. In contrast, in Japanese subjects, the frequency of the IL-10 genotype was significantly higher in IBS-D and UC than that in controls. Although IL-10 might be associated with susceptibility to IBS development, many important questions remain regarding this relationship.
Among the single genetic polymorphisms associated with IBS, the role of the serotonin transporter (SERT) gene polymorphism (SLC6A4) has been relatively well explored in IBS. This polymorphism varys according to geographical region and ethnic population. In a meta-analysis, a genetic polymorphism in the gene region responsible for SERT activity was not associated with IBS. However, subsequent studies reported inconsistent results. Kumar et al did show that a SLC6A4 polymorphism was significantly associated with IBS, and Wang et al found that different SERT genotypes could influence SLC6A4 promoter efficiency and SERT mRNA and protein expression in the colonic mucosa.
G proteins are expressed in all human cells and play a crucial role in signal transduction, particularly ligand-receptor interactions. The G protein is encoded by the GNbeta3 gene. Although, GNbeta3 polymorphisms have been linked to functional dyspepsia, such association was not observed with IBS[104,105]. However, Saito et al reported a significant interaction between the GNbeta3 polymorphism and infection during IBS development, suggesting that IBS is a complex genetic disorder with both a genetic and environmental component for expression of symptoms.
Neuropeptide S (NPS) is a bioactive 20 amino acid peptide that selectively binds and activates the neuropeptide S receptor (NPSR1). NPSR1 induces the production of several neuropeptides, including cholecystokinin, vasoactive intestinal peptide, peptide YY, and somatostatin. NPSR1 variants are associated with gastrointestinal motor and sensory functions that are relevant to IBS.
The endocannabinoid system, involved in motility, sensation, secretion[110,111] and inflammatory[112,113] functions in the gastrointestinal tract, has been proposed as a mechanism in the development of IBS. The endocannabinoid anandamide is inactivated by the fatty acid amide hydrolase (FAAH), and single nucleotide polymorphisms (SNPs) in the FAAH gene (C385A) have been associated with accelerated colonic transit time in D-IBS.
Genetic variation in the genes controlling bile acid synthesis may contribute to abnormal bowel pattern and symptoms in IBS. Bile acid malabsorption stimulates colonic motility and secretion and has been associated with D-IBS. Hepatic bile acid synthesis is partially controlled by feedback inhibition via the fibroblast growth factor 19 (FGF19); FGF19 binds to the FGF receptor 4 and the co-receptor Klotho-beta (KLB), leading to suppression of the rate-limiting enzyme in bile acid synthesis. Wong et al reported that a SNP in the KLB gene (rs17618244), is associated with accelerated colonic transit in IBS-D. A previous study suggested that the G protein-coupled bile acid receptor 1 (GpBAR1/TGR5) is expressed in myenteric, cholinergic, nitrergic neurons in the colon and in the proximal small intestine, indicating that bile acids may alter intestinal and colonic motility. Camilleri et al demonstrated that variations in TGR5 might contribute to altered SBT and colonic transit in D-IBS patients.
The intestinal microbiota has recently been assumed to be an important predisposition factor for IBS. The most convincing evidence is that IBS can develop in predisposed persons who have experienced gastroenteritis. Other evidence indicates that bacteria may contribute to the pathophysiology of IBS, since luminal- and mucosa-associated microbiota can influence their host via immunomicrobial interactions. In addition, small intestinal bacterial overgrowth (SIBO) has been implicated in a subset of IBS patients.
Earlier studies found that the intestinal microbiota in IBS patients differs from that in healthy individuals, with a decrease in the Bifidobacterium spp. population and an increase in the Enterobacter population being the most consistent findings[120,121]. In a study using real-time PCR assays, results included significantly lower counts of Lactobacilli in D-IBS than C-IBS specimens, lower counts of Bifidobacterium spp. in D-IBS than the other groups, and significantly higher counts of Veillonella spp. counts in the C-IBS group than healthy controls. High-throughput analysis of 16S ribosomal RNA gene cloning and sequencing identified that the fecal microbiota is considerably altered in IBS, as IBS patients have lower Lactobacillus and Bifidobacterium spp. counts than healthy subjects. Subsequent molecular studies confirmed that IBS patients have fecal microbiota differing from normal subjects[124-126]. Results regarding the intestinal microbiota in IBS are difficult to interpret due to the heterogeneity of the conditions and the observation that alterations of the intestinal microbiota may not be consistent across each subtype of IBS. Furthermore, the precise role of the luminal vs the mucosal-associated microbiota in IBS remains uncertain. Nevertheless, previous evidence consistently showed differences in the bacterial composition of feces between IBS and normal controls. Changes in the intestinal flora might result in the proliferation of species that produce more gas[127,128] during the development of IBS symptoms that bring about gas-induced distension. The direct effects of bacterial production on colonic contractility, intestinal myoelectrical activity, and pain response[131,132] have been identified in several in vitro studies. Also, a role for the microbiota in the induction of IBS symptoms is supported by the findings that probiotics improve flatulence and abdominal distension[133,134] and that rifaximin provides significant improvements in IBS symptoms, including bloating, abdominal pain, and loose or watery stools.
A growing body of research implicates SIBO in the symptoms of IBS, but this issue remains under debate. SIBO proved to be more prevalent in patients with IBS patients[136-138], and its eradication with antibiotics relieved the symptoms of IBS[139-142]. The presence of SIBO might be associated with abnormalities in small intestinal motor function. Pimentel et al found that patients with IBS and SIBO experience few, if any, phase III events during short-term manometric measurements compared to controls. In contrast, Posserud et al performed intestinal manometry and culturing of intestinal aspirates taken from IBS and control groups, found that IBS subjects have fewer Major Migrating Complex phase III events compared to patients without SIBO. However, there were no differences in other motility parameters, and no correlation between bacterial numbers and the pattern of IBS symptoms was detected. SIBO is typically diagnosed via indirect methods, such as positive early glucose or lactulose breath tests, and the accuracy of these methods is arguable. These diagnostic limitations have resulted in wide range of reports for SIBO prevalence (10% to 84%) in patients with IBS[145,146]. Regardless, slightly elevated intestinal bacterial numbers are inarguably more prevalent in IBS patients, and so further studies of this area are required.
Although the “response to food” is not included in the diagnostic criteria for IBS, most patients claim their symptoms are triggered by certain foods, which are then avoided to alleviate symptoms[147,148]. Many researchers have focused on the role of diet in IBS in recent years. Also, guidance on diet management for patients with IBS has been revealed as improving their quality of life and symptoms[149,150]. The sensory component of the gastrocolonic reflex following nutrient intake is exaggerated in IBS patients, and IBS patients with intraluminal lipids exhibited impaired intestinal gas clearance because of an upregulated reflex inhibition in small bowel transit. One study demonstrated that postprandial GI disorders in IBS patients might be associated with cellular immune function along the neuroendocrine-immune axis. Furthermore, altered autonomic responses after a meal might cause exacerbated postprandial symptoms in IBS patients.
Many IBS patients report that their symptoms are associated with specific foods; thus, the possibility of food allergies causing IBS symptoms has been proposed. Food allergy/hypersensitivity is defined as an allergic response in susceptible individuals following ingestion of a specific food (e.g., cow’s milk, peanuts, soybeans)[154,155]. However, there is little evidence that food allergies play a role in IBS. Several studies have reported that fructose-sorbitol malabsorption frequently occurs in IBS patients, but the results were similar in healthy volunteers; further, the response to a low lactose diet was disappointingly low in IBS patients experiencing lactose malabsorption, indicating a lack of obvious association between food allergy and IBS[156,157]. Several lines of evidence indicate that an altered immune response and inflammation may be involved in food hypersensitivity in IBS patients. There are reports of IgG-mediated food hypersensitivity and improved IBS symptoms when patients are placed on elimination diets[158-160]. Carroccio et al[161,162] demonstrated in IBS patients with food hypersensitivity an activation of serum basophils after stimulation with food antigens and increased levels of fecal eosinophil cationic proteins and tryptases. However, further investigations are necessary to validate the accuracy of the methods used in these studies before any claims can be made.
Food intolerances are defined as non-toxic and non-immune-mediated adverse reactions to food or to the presence of pharmacological agents within food, including histamines, sulfates, monosodium glutamate, serotonin, norepinephrine and tyramine. Food intolerance is a possible factor underlying the pathogenesis of IBS, according to the finding that symptoms improved with an elimination diet. However, subsequent studies showed little benefit from these diets[165,166]. Although specific food intolerances in IBS have been explored through patient questionnaires[167,168], the role of food intolerance in IBS remains questionable due to the lack of a reliable methodology and well-designed trials. Well-designed studies with standardized protocols are thus necessary.
A recently proposed mechanism by which dietary factors might contribute to IBS symptoms suggests that poor absorption of nutrients influence GI function and sensation through osmotic actions and colonic fermentation. Short-chain carbohydrates, such as fructose and dietary starch, are poorly absorbed, causing a number of ingested carbohydrates to enter the distal small bowel and colon. Consequently, these provide substrates for short-chain fatty acid (SCFA) generation by bacterial fermentation and increase the osmotic pressure. The short-chain carbohydrates called Fermentable Oligo-saccharides, Di-saccharides, Mono-saccharides And Polyols (FODMAPs) contribute to IBS; however, IBS symptoms in such cases are triggered by luminal distension that induces abdominal pain, bloating, flatus, and altered bowel habits. A number of studies suggesting effects of dietary manipulation, particularly elimination of FODMAPs, further support the importance of poor nutrient absorption in the development of IBS symptoms[171,172]. In addition, fecal SCFA were increased in D-IBS. SCFA stimulate colonic transit and motility via intraluminal release of 5-hydroxytryptamine (5-HT) and high-amplitude propagated colonic contractions, according to in vivo studies.
Limited data also suggest that changes in intestinal microbiota may be relevant for fermentation of nonabsorbable nutrients. Tana et al showed that an altered GI microbiota contributes to the higher levels of SCFA and abdominal symptoms in IBS. In addition, many studies have explored the effect of dietary fiber on IBS symptoms. Although dietary fiber has commonly been a standard recommendation for patients with IBS, some evidence suggests that it may aggravate symptoms of IBS, such as flatulence, bloating and abdominal pain[76,127,128]. In a recent meta-analysis, patients administered fiber in their diets had persistent or unimproved symptoms compared to control groups that ingested placeboes or lower fiber diets. Some investigators suggest that insoluble fiber intake does not significantly improve IBS symptoms, whereas soluble fiber intake can effectively improve overall IBS symptoms[178,179]. These results suggest that not all types of fiber are equally influential on IBS.
Patients with celiac disease (CD) often experience IBS-like symptoms[180,181]. Therefore, it has been proposed that IBS patients should be routinely examined for CD[163,181]. Certain evidence suggests that dietary gluten intolerance also occurs in patients with IBS, and those whose symptoms improve with such diets may have a genetic susceptibility to gluten[182,183]. However, two groups of investigators recently published contrasting results. Vazquez-Roque et al conducted randomized controlled trials in D-IBS patients consuming gluten-free diets vs gluten-containing diets. The group consuming gluten showed increased stool frequency, small intestinal permeability, and reduced mRNA expression of tight-junction proteins in bowel mucosa compared to the patients consuming the gluten-free diet. However, Biesiekierski et al reported that gluten might be not be a specific trigger of GI symptoms in IBS patients, as most patients’ symptoms were not exacerbated with gluten exposure; there was no evidence of specific or dose-dependent effects of gluten in the expression of serum and fecal markers of intestinal inflammation/injury and immune activation. Further studies are being conducted to determine the role of gluten intolerance in IBS.
Abnormalities in neuroendocrine peptides and amines derived from enteroendocrine cells can cause disturbances in digestion, GI motility and sensation in IBS patients[76,186]. These abnormalities are stimulated by gut luminal content, contributing to the development of symptoms in IBS. Enteroendocrine cells release various bioactive substances, including gastrin, secretin, stomatostatin, cholecystokinin, chromogranins and serotonin. Enterochromaffin cells, which are scattered throughout the GI mucosa, are the dominant type of enteroendocrine cells; they synthesize, store, and release serotonin in response to luminal stimuli. Serotonin affects motility, sensation, and secretion in the gut through the activation of receptors present on enteric nerves and sensory afferents. Studies demonstrated an increase in the release of serotonin in patients with D-IBS[189,190] and PI-IBS, while impaired release was found in patients with C-IBS[191,192]. The increased release of 5-HT triggered by luminal stimuli activates immune cells supporting the role of 5-HT in gut inflammation.
In addition to serotonin, enteroendocrine cells release chromogranin and secretogranin, which can influence several GI functions, such as immune modulation and inflammation. El-Salhy et al[193-195] showed that decreased density of chromogranin A (CgA)-containing cells was found in duodenum, terminal ileum and colonic mucosa of IBS patients. Whereas, other studies demonstrated that serum CgA levels increase in IBS patients[196,197]. Recently, Ohman et al showed that IBS patients with rapid colonic transit have higher levels of fecal CgA, secretogranin (Sg)II, and SgIII, but lower levels of chromogranin B, compared to healthy subjects. Based on the data, granins could serve as useful biomarkers of IBS; however, the role of granins in IBS has not been revealed.
There is abundant evidence supporting the claim that IBS should no longer be considered an absolute idiopathic functional disease. In recent years, attention has been directed towards the role of inflammation, gut microbiota, immunity, genetics, dietary factors, and enteroendocrine cells. As a result, IBS is regarded as a multifactorial condition that affects individuals differentially. Understanding these mechanisms will be useful for the development of a more specific, individualized treatment strategy and for the clinical management of IBD patients.
|1.||Camilleri M, Lasch K, Zhou W. Irritable bowel syndrome: methods, mechanisms, and pathophysiology. The confluence of increased permeability, inflammation, and pain in irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol. 2012;303:G775-G785. [PubMed] [DOI]|
|2.||Ballou SK, Keefer L. Multicultural considerations in the diagnosis and management of irritable bowel syndrome: a selective summary. Eur J Gastroenterol Hepatol. 2013;25:1127-1133. [PubMed] [DOI]|
|3.||Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology. 2006;130:1480-1491. [PubMed] [DOI]|
|4.||Guilarte M, Santos J, de Torres I, Alonso C, Vicario M, Ramos L, Martínez C, Casellas F, Saperas E, Malagelada JR. Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum. Gut. 2007;56:203-209. [PubMed] [DOI]|
|5.||Mearin F, Pérez-Oliveras M, Perelló A, Vinyet J, Ibañez A, Coderch J, Perona M. Dyspepsia and irritable bowel syndrome after a Salmonella gastroenteritis outbreak: one-year follow-up cohort study. Gastroenterology. 2005;129:98-104. [PubMed]|
|6.||van der Veek PP, van den Berg M, de Kroon YE, Verspaget HW, Masclee AA. Role of tumor necrosis factor-alpha and interleukin-10 gene polymorphisms in irritable bowel syndrome. Am J Gastroenterol. 2005;100:2510-2516. [PubMed] [DOI]|
|7.||Simrén M, Barbara G, Flint HJ, Spiegel BM, Spiller RC, Vanner S, Verdu EF, Whorwell PJ, Zoetendal EG. Intestinal microbiota in functional bowel disorders: a Rome foundation report. Gut. 2013;62:159-176. [PubMed] [DOI]|
|8.||Barrett JS, Gibson PR. Fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) and nonallergic food intolerance: FODMAPs or food chemicals? Therap Adv Gastroenterol. 2012;5:261-268. [PubMed] [DOI]|
|9.||Ohman L, Stridsberg M, Isaksson S, Jerlstad P, Simrén M. Altered levels of fecal chromogranins and secretogranins in IBS: relevance for pathophysiology and symptoms? Am J Gastroenterol. 2012;107:440-447. [PubMed] [DOI]|
|10.||Talley NJ, Spiller R. Irritable bowel syndrome: a little understood organic bowel disease? Lancet. 2002;360:555-564. [PubMed] [DOI]|
|11.||Martínez C, Lobo B, Pigrau M, Ramos L, González-Castro AM, Alonso C, Guilarte M, Guilá M, de Torres I, Azpiroz F. Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier. Gut. 2013;62:1160-1168. [PubMed] [DOI]|
|12.||Narducci F, Bassotti G, Gaburri M, Morelli A. Twenty four hour manometric recording of colonic motor activity in healthy man. Gut. 1987;28:17-25. [PubMed]|
|13.||Bassotti G, Gaburri M. Manometric investigation of high-amplitude propagated contractile activity of the human colon. Am J Physiol. 1988;255:G660-G664. [PubMed]|
|14.||RITCHIE JA, ARDRAN GM, TRUELOVE SC. Motor activity of the sigmoid colon of humans. A combined study by intraluminal pressure recording and cineradiography. Gastroenterology. 1962;43:642-668. [PubMed]|
|15.||Chey WY, Jin HO, Lee MH, Sun SW, Lee KY. Colonic motility abnormality in patients with irritable bowel syndrome exhibiting abdominal pain and diarrhea. Am J Gastroenterol. 2001;96:1499-1506. [PubMed] [DOI]|
|16.||Choi MG, Camilleri M, O’Brien MD, Kammer PP, Hanson RB. A pilot study of motility and tone of the left colon in patients with diarrhea due to functional disorders and dysautonomia. Am J Gastroenterol. 1997;92:297-302. [PubMed]|
|17.||Whitehead WE, Engel BT, Schuster MM. Irritable bowel syndrome: physiological and psychological differences between diarrhea-predominant and constipation-predominant patients. Dig Dis Sci. 1980;25:404-413. [PubMed]|
|18.||Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical review on irritable bowel syndrome. Gastroenterology. 2002;123:2108-2131. [PubMed] [DOI]|
|19.||Talley NJ, Zinsmeister AR, Melton LJ. Irritable bowel syndrome in a community: symptom subgroups, risk factors, and health care utilization. Am J Epidemiol. 1995;142:76-83. [PubMed]|
|20.||Prott G, Shim L, Hansen R, Kellow J, Malcolm A. Relationships between pelvic floor symptoms and function in irritable bowel syndrome. Neurogastroenterol Motil. 2010;22:764-769. [PubMed] [DOI]|
|21.||Barbara G, De Giorgio R, Stanghellini V, Cremon C, Salvioli B, Corinaldesi R. New pathophysiological mechanisms in irritable bowel syndrome. Aliment Pharmacol Ther. 2004;20 Suppl 2:1-9. [PubMed] [DOI]|
|22.||Bouin M, Plourde V, Boivin M, Riberdy M, Lupien F, Laganière M, Verrier P, Poitras P. Rectal distention testing in patients with irritable bowel syndrome: sensitivity, specificity, and predictive values of pain sensory thresholds. Gastroenterology. 2002;122:1771-1777. [PubMed]|
|23.||Posserud I, Syrous A, Lindström L, Tack J, Abrahamsson H, Simrén M. Altered rectal perception in irritable bowel syndrome is associated with symptom severity. Gastroenterology. 2007;133:1113-1123. [PubMed] [DOI]|
|24.||Bradette M, Delvaux M, Staumont G, Fioramonti J, Bueno L, Frexinos J. Evaluation of colonic sensory thresholds in IBS patients using a barostat. Definition of optimal conditions and comparison with healthy subjects. Dig Dis Sci. 1994;39:449-457. [PubMed]|
|25.||Costantini M, Sturniolo GC, Zaninotto G, D’Incà R, Polo R, Naccarato R, Ancona E. Altered esophageal pain threshold in irritable bowel syndrome. Dig Dis Sci. 1993;38:206-212. [PubMed]|
|26.||Zighelboim J, Talley NJ, Phillips SF, Harmsen WS, Zinsmeister AR. Visceral perception in irritable bowel syndrome. Rectal and gastric responses to distension and serotonin type 3 antagonism. Dig Dis Sci. 1995;40:819-827. [PubMed]|
|27.||Accarino AM, Azpiroz F, Malagelada JR. Selective dysfunction of mechanosensitive intestinal afferents in irritable bowel syndrome. Gastroenterology. 1995;108:636-643. [PubMed]|
|28.||Walker LS, Garber J, Smith CA, Van Slyke DA, Claar RL. The relation of daily stressors to somatic and emotional symptoms in children with and without recurrent abdominal pain. J Consult Clin Psychol. 2001;69:85-91. [PubMed]|
|29.||Awad RA, Camacho S, Martín J, Ríos N. Rectal sensation, pelvic floor function and symptom severity in Hispanic population with irritable bowel syndrome with constipation. Colorectal Dis. 2006;8:488-493. [PubMed] [DOI]|
|30.||Simrén M, Abrahamsson H, Björnsson ES. An exaggerated sensory component of the gastrocolonic response in patients with irritable bowel syndrome. Gut. 2001;48:20-27. [PubMed]|
|31.||Simrén M, Agerforz P, Björnsson ES, Abrahamsson H. Nutrient-dependent enhancement of rectal sensitivity in irritable bowel syndrome (IBS). Neurogastroenterol Motil. 2007;19:20-29. [PubMed] [DOI]|
|32.||Dickhaus B, Mayer EA, Firooz N, Stains J, Conde F, Olivas TI, Fass R, Chang L, Mayer M, Naliboff BD. Irritable bowel syndrome patients show enhanced modulation of visceral perception by auditory stress. Am J Gastroenterol. 2003;98:135-143. [PubMed] [DOI]|
|33.||Posserud I, Agerforz P, Ekman R, Björnsson ES, Abrahamsson H, Simrén M. Altered visceral perceptual and neuroendocrine response in patients with irritable bowel syndrome during mental stress. Gut. 2004;53:1102-1108. [PubMed] [DOI]|
|34.||Gunnarsson J, Simrén M. Peripheral factors in the pathophysiology of irritable bowel syndrome. Dig Liver Dis. 2009;41:788-793. [PubMed] [DOI]|
|35.||Wilhelmsen I. Brain-gut axis as an example of the bio-psycho-social model. Gut. 2000;47 Suppl 4:iv5-i7; discussion iv10. [PubMed]|
|36.||Murray CD, Flynn J, Ratcliffe L, Jacyna MR, Kamm MA, Emmanuel AV. Effect of acute physical and psychological stress on gut autonomic innervation in irritable bowel syndrome. Gastroenterology. 2004;127:1695-1703. [PubMed]|
|37.||Fukudo S. Role of corticotropin-releasing hormone in irritable bowel syndrome and intestinal inflammation. J Gastroenterol. 2007;42 Suppl 17:48-51. [PubMed] [DOI]|
|38.||Fukudo S, Saito K, Sagami Y, Kanazawa M. Can modulating corticotropin releasing hormone receptors alter visceral sensitivity? Gut. 2006;55:146-148. [PubMed] [DOI]|
|39.||Fukudo S, Nomura T, Hongo M. Impact of corticotropin-releasing hormone on gastrointestinal motility and adrenocorticotropic hormone in normal controls and patients with irritable bowel syndrome. Gut. 1998;42:845-849. [PubMed]|
|40.||Sagami Y, Shimada Y, Tayama J, Nomura T, Satake M, Endo Y, Shoji T, Karahashi K, Hongo M, Fukudo S. Effect of a corticotropin releasing hormone receptor antagonist on colonic sensory and motor function in patients with irritable bowel syndrome. Gut. 2004;53:958-964. [PubMed]|
|41.||Hamaguchi T, Kano M, Rikimaru H, Kanazawa M, Itoh M, Yanai K, Fukudo S. Brain activity during distention of the descending colon in humans. Neurogastroenterol Motil. 2004;16:299-309. [PubMed] [DOI]|
|42.||Mayer EA, Berman S, Suyenobu B, Labus J, Mandelkern MA, Naliboff BD, Chang L. Differences in brain responses to visceral pain between patients with irritable bowel syndrome and ulcerative colitis. Pain. 2005;115:398-409. [PubMed] [DOI]|
|43.||Mertz H, Morgan V, Tanner G, Pickens D, Price R, Shyr Y, Kessler R. Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distention. Gastroenterology. 2000;118:842-848. [PubMed]|
|44.||Chadwick VS, Chen W, Shu D, Paulus B, Bethwaite P, Tie A, Wilson I. Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology. 2002;122:1778-1783. [PubMed]|
|45.||O'Sullivan M, Clayton N, Breslin NP, Harman I, Bountra C, McLaren A, O’Morain CA. Increased mast cells in the irritable bowel syndrome. Neurogastroenterol Motil. 2000;12:449-457. [PubMed]|
|46.||Cremon C, Gargano L, Morselli-Labate AM, Santini D, Cogliandro RF, De Giorgio R, Stanghellini V, Corinaldesi R, Barbara G. Mucosal immune activation in irritable bowel syndrome: gender-dependence and association with digestive symptoms. Am J Gastroenterol. 2009;104:392-400. [PubMed] [DOI]|
|47.||Piche T, Saint-Paul MC, Dainese R, Marine-Barjoan E, Iannelli A, Montoya ML, Peyron JF, Czerucka D, Cherikh F, Filippi J. Mast cells and cellularity of the colonic mucosa correlated with fatigue and depression in irritable bowel syndrome. Gut. 2008;57:468-473. [PubMed] [DOI]|
|48.||Akbar A, Yiangou Y, Facer P, Walters JR, Anand P, Ghosh S. Increased capsaicin receptor TRPV1-expressing sensory fibres in irritable bowel syndrome and their correlation with abdominal pain. Gut. 2008;57:923-929. [PubMed] [DOI]|
|49.||Ohman L, Isaksson S, Lundgren A, Simrén M, Sjövall H. A controlled study of colonic immune activity and beta7+ blood T lymphocytes in patients with irritable bowel syndrome. Clin Gastroenterol Hepatol. 2005;3:980-986. [PubMed]|
|50.||Törnblom H, Lindberg G, Nyberg B, Veress B. Full-thickness biopsy of the jejunum reveals inflammation and enteric neuropathy in irritable bowel syndrome. Gastroenterology. 2002;123:1972-1979. [PubMed] [DOI]|
|51.||Ohman L, Isaksson S, Lindmark AC, Posserud I, Stotzer PO, Strid H, Sjövall H, Simrén M. T-cell activation in patients with irritable bowel syndrome. Am J Gastroenterol. 2009;104:1205-1212. [PubMed] [DOI]|
|52.||Martínez C, González-Castro A, Vicario M, Santos J. Cellular and molecular basis of intestinal barrier dysfunction in the irritable bowel syndrome. Gut Liver. 2012;6:305-315. [PubMed] [DOI]|
|53.||Liebregts T, Adam B, Bredack C, Röth A, Heinzel S, Lester S, Downie-Doyle S, Smith E, Drew P, Talley NJ. Immune activation in patients with irritable bowel syndrome. Gastroenterology. 2007;132:913-920. [PubMed] [DOI]|
|54.||Dinan TG, Quigley EM, Ahmed SM, Scully P, O’Brien S, O’Mahony L, O’Mahony S, Shanahan F, Keeling PW. Hypothalamic-pituitary-gut axis dysregulation in irritable bowel syndrome: plasma cytokines as a potential biomarker? Gastroenterology. 2006;130:304-311. [PubMed] [DOI]|
|55.||Keohane J, O’Mahony C, O’Mahony L, O’Mahony S, Quigley EM, Shanahan F. Irritable bowel syndrome-type symptoms in patients with inflammatory bowel disease: a real association or reflection of occult inflammation? Am J Gastroenterol. 2010;105:1788, 1789-1794; quiz 1795. [PubMed] [DOI]|
|56.||Isgar B, Harman M, Kaye MD, Whorwell PJ. Symptoms of irritable bowel syndrome in ulcerative colitis in remission. Gut. 1983;24:190-192. [PubMed]|
|57.||Minderhoud IM, Oldenburg B, Wismeijer JA, van Berge Henegouwen GP, Smout AJ. IBS-like symptoms in patients with inflammatory bowel disease in remission; relationships with quality of life and coping behavior. Dig Dis Sci. 2004;49:469-474. [PubMed]|
|58.||Vivinus-Nébot M, Frin-Mathy G, Bzioueche H, Dainese R, Bernard G, Anty R, Filippi J, Saint-Paul MC, Tulic MK, Verhasselt V. Functional bowel symptoms in quiescent inflammatory bowel diseases: role of epithelial barrier disruption and low-grade inflammation. Gut. 2013;Epub ahead of print. [PubMed] [DOI]|
|59.||Collins SM, Piche T, Rampal P. The putative role of inflammation in the irritable bowel syndrome. Gut. 2001;49:743-745. [PubMed]|
|60.||Langhorst J, Junge A, Rueffer A, Wehkamp J, Foell D, Michalsen A, Musial F, Dobos GJ. Elevated human beta-defensin-2 levels indicate an activation of the innate immune system in patients with irritable bowel syndrome. Am J Gastroenterol. 2009;104:404-410. [PubMed] [DOI]|
|61.||Aldhous MC, Noble CL, Satsangi J. Dysregulation of human beta-defensin-2 protein in inflammatory bowel disease. PLoS One. 2009;4:e6285. [PubMed] [DOI]|
|62.||Park KS, Ahn SH, Hwang JS, Cho KB, Chung WJ, Jang BK, Kang YN, Kwon JH, Kim YH. A survey about irritable bowel syndrome in South Korea: prevalence and observable organic abnormalities in IBS patients. Dig Dis Sci. 2008;53:704-711. [PubMed] [DOI]|
|63.||Abboud R, Pardi DS, Tremaine WJ, Kammer PP, Sandborn WJ, Loftus EV. Symptomatic overlap between microscopic colitis and irritable bowel syndrome: a prospective study. Inflamm Bowel Dis. 2013;19:550-553. [PubMed] [DOI]|
|64.||Schwille-Kiuntke J, Enck P, Zendler C, Krieg M, Polster AV, Klosterhalfen S, Autenrieth IB, Zipfel S, Frick JS. Postinfectious irritable bowel syndrome: follow-up of a patient cohort of confirmed cases of bacterial infection with Salmonella or Campylobacter. Neurogastroenterol Motil. 2011;23:e479-e488. [PubMed] [DOI]|
|65.||Thabane M, Kottachchi DT, Marshall JK. Systematic review and meta-analysis: The incidence and prognosis of post-infectious irritable bowel syndrome. Aliment Pharmacol Ther. 2007;26:535-544. [PubMed] [DOI]|
|66.||Stewart GT. Post-dysenteric colitis. Br Med J. 1950;1:405-409. [PubMed]|
|67.||Dunlop SP, Jenkins D, Spiller RC. Distinctive clinical, psychological, and histological features of postinfective irritable bowel syndrome. Am J Gastroenterol. 2003;98:1578-1583. [PubMed] [DOI]|
|68.||Camilleri M, Carlson P, McKinzie S, Zucchelli M, D’Amato M, Busciglio I, Burton D, Zinsmeister AR. Genetic susceptibility to inflammation and colonic transit in lower functional gastrointestinal disorders: preliminary analysis. Neurogastroenterol Motil. 2011;23:935-e398. [PubMed] [DOI]|
|69.||Swan C, Duroudier NP, Campbell E, Zaitoun A, Hastings M, Dukes GE, Cox J, Kelly FM, Wilde J, Lennon MG. Identifying and testing candidate genetic polymorphisms in the irritable bowel syndrome (IBS): association with TNFSF15 and TNFα. Gut. 2013;62:985-994. [PubMed] [DOI]|
|70.||Ringel Y, Carroll IM. Alterations in the intestinal microbiota and functional bowel symptoms. Gastrointest Endosc Clin N Am. 2009;19:141-150, vii. [PubMed] [DOI]|
|71.||El-Salhy M, Gundersen D, Hatlebakk JG, Hausken T. Low-grade inflammation in the rectum of patients with sporadic irritable bowel syndrome. Mol Med Rep. 2013;7:1081-1085. [PubMed] [DOI]|
|72.||Gwee KA, Leong YL, Graham C, McKendrick MW, Collins SM, Walters SJ, Underwood JE, Read NW. The role of psychological and biological factors in postinfective gut dysfunction. Gut. 1999;44:400-406. [PubMed]|
|73.||Wang LH, Fang XC, Pan GZ. Bacillary dysentery as a causative factor of irritable bowel syndrome and its pathogenesis. Gut. 2004;53:1096-1101. [PubMed] [DOI]|
|74.||McKeown ES, Parry SD, Stansfield R, Barton JR, Welfare MR. Postinfectious irritable bowel syndrome may occur after non-gastrointestinal and intestinal infection. Neurogastroenterol Motil. 2006;18:839-843. [PubMed] [DOI]|
|75.||Zanini B, Ricci C, Bandera F, Caselani F, Magni A, Laronga AM, Lanzini A. Incidence of post-infectious irritable bowel syndrome and functional intestinal disorders following a water-borne viral gastroenteritis outbreak. Am J Gastroenterol. 2012;107:891-899. [PubMed] [DOI]|
|76.||El-Salhy M. Irritable bowel syndrome: diagnosis and pathogenesis. World J Gastroenterol. 2012;18:5151-5163. [PubMed] [DOI]|
|77.||Dunlop SP, Jenkins D, Neal KR, Spiller RC. Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in postinfectious IBS. Gastroenterology. 2003;125:1651-1659. [PubMed]|
|78.||Spiller R. Serotonin, inflammation, and IBS: fitting the jigsaw together? J Pediatr Gastroenterol Nutr. 2007;45 Suppl 2:S115-S119. [PubMed] [DOI]|
|79.||Khan WI, Ghia JE. Gut hormones: emerging role in immune activation and inflammation. Clin Exp Immunol. 2010;161:19-27. [PubMed] [DOI]|
|80.||Gwee KA, Collins SM, Read NW, Rajnakova A, Deng Y, Graham JC, McKendrick MW, Moochhala SM. Increased rectal mucosal expression of interleukin 1beta in recently acquired post-infectious irritable bowel syndrome. Gut. 2003;52:523-526. [PubMed]|
|81.||Schoepfer AM, Schaffer T, Seibold-Schmid B, Müller S, Seibold F. Antibodies to flagellin indicate reactivity to bacterial antigens in IBS patients. Neurogastroenterol Motil. 2008;20:1110-1118. [PubMed] [DOI]|
|82.||Cremon C, Pallotti F, Bacchilega M, Stanghellini V, Corinaldesi R, Barbara G. Antiflagellin antibodies suggest infective participation in irritable bowel syndrome pathogenesis. Expert Rev Gastroenterol Hepatol. 2008;2:735-740. [PubMed] [DOI]|
|83.||Gewirtz AT. Flag in the crossroads: flagellin modulates innate and adaptive immunity. Curr Opin Gastroenterol. 2006;22:8-12. [PubMed]|
|84.||Bengtson MB, Rønning T, Vatn MH, Harris JR. Irritable bowel syndrome in twins: genes and environment. Gut. 2006;55:1754-1759. [PubMed] [DOI]|
|85.||Saito YA. The role of genetics in IBS. Gastroenterol Clin North Am. 2011;40:45-67. [PubMed] [DOI]|
|86.||Romero-Valdovinos M, Gudiño-Ramírez A, Reyes-Gordillo J, Martínez-Flores WA, Ramírez-Miranda ME, Maravilla P, Olivo-Díaz A. Interleukin-8 and -10 gene polymorphisms in irritable bowel syndrome. Mol Biol Rep. 2012;39:8837-8843. [PubMed] [DOI]|
|87.||Gonsky R, Deem RL, Targan SR. Multiple activating and repressive cis-promoter regions regulate TNFSF15 expression in human primary mononuclear cells. Cytokine. 2013;63:36-42. [PubMed] [DOI]|
|88.||Zhang H, Massey D, Tremelling M, Parkes M. Genetics of inflammatory bowel disease: clues to pathogenesis. Br Med Bull. 2008;87:17-30. [PubMed] [DOI]|
|89.||Zucchelli M, Camilleri M, Andreasson AN, Bresso F, Dlugosz A, Halfvarson J, Törkvist L, Schmidt PT, Karling P, Ohlsson B. Association of TNFSF15 polymorphism with irritable bowel syndrome. Gut. 2011;60:1671-1677. [PubMed] [DOI]|
|90.||Swan CDN, Campbell E, Hastings M, Neal KR, Dukes GE, Whorwell PJ, Hall I, Spiller RC. Association of proinflammatory genetic polymorphisms with the irritable bowel syndrome (IBS): phenotype and genotype correlation (Abstract). Gastroenterology. 2011;140:S525.|
|91.||Belmonte L, Beutheu Youmba S, Bertiaux-Vandaële N, Antonietti M, Lecleire S, Zalar A, Gourcerol G, Leroi AM, Déchelotte P, Coëffier M. Role of toll like receptors in irritable bowel syndrome: differential mucosal immune activation according to the disease subtype. PLoS One. 2012;7:e42777. [PubMed] [DOI]|
|92.||Cario E, Podolsky DK. Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect Immun. 2000;68:7010-7017. [PubMed]|
|93.||Villani AC, Lemire M, Thabane M, Belisle A, Geneau G, Garg AX, Clark WF, Moayyedi P, Collins SM, Franchimont D. Genetic risk factors for post-infectious irritable bowel syndrome following a waterborne outbreak of gastroenteritis. Gastroenterology. 2010;138:1502-1513. [PubMed] [DOI]|
|94.||Brint EK, MacSharry J, Fanning A, Shanahan F, Quigley EM. Differential expression of toll-like receptors in patients with irritable bowel syndrome. Am J Gastroenterol. 2011;106:329-336. [PubMed] [DOI]|
|95.||Bashashati M, Rezaei N, Andrews CN, Chen CQ, Daryani NE, Sharkey KA, Storr MA. Cytokines and irritable bowel syndrome: where do we stand? Cytokine. 2012;57:201-209. [PubMed] [DOI]|
|96.||Akiho H, Deng Y, Blennerhassett P, Kanbayashi H, Collins SM. Mechanisms underlying the maintenance of muscle hypercontractility in a model of postinfective gut dysfunction. Gastroenterology. 2005;129:131-141. [PubMed]|
|97.||Al-Sadi R, Boivin M, Ma T. Mechanism of cytokine modulation of epithelial tight junction barrier. Front Biosci (Landmark Ed). 2009;14:2765-2778. [PubMed]|
|98.||Rugtveit J, Brandtzaeg P, Halstensen TS, Fausa O, Scott H. Increased macrophage subset in inflammatory bowel disease: apparent recruitment from peripheral blood monocytes. Gut. 1994;35:669-674. [PubMed]|
|99.||Gonsalkorale WM, Perrey C, Pravica V, Whorwell PJ, Hutchinson IV. Interleukin 10 genotypes in irritable bowel syndrome: evidence for an inflammatory component? Gut. 2003;52:91-93. [PubMed]|
|100.||Shiotani A, Kusunoki H, Kimura Y, Ishii M, Imamura H, Tarumi K, Manabe N, Kamada T, Hata J, Haruma K. S100A expression and interleukin-10 polymorphisms are associated with ulcerative colitis and diarrhea predominant irritable bowel syndrome. Dig Dis Sci. 2013;58:2314-2323. [PubMed] [DOI]|
|101.||Van Kerkhoven LA, Laheij RJ, Jansen JB. Meta-analysis: a functional polymorphism in the gene encoding for activity of the serotonin transporter protein is not associated with the irritable bowel syndrome. Aliment Pharmacol Ther. 2007;26:979-986. [PubMed] [DOI]|
|102.||Kumar S, Ranjan P, Mittal B, Ghoshal UC. Serotonin transporter gene (SLC6A4) polymorphism in patients with irritable bowel syndrome and healthy controls. J Gastrointestin Liver Dis. 2012;21:31-38. [PubMed]|
|103.||Wang YM, Chang Y, Chang YY, Cheng J, Li J, Wang T, Zhang QY, Liang DC, Sun B, Wang BM. Serotonin transporter gene promoter region polymorphisms and serotonin transporter expression in the colonic mucosa of irritable bowel syndrome patients. Neurogastroenterol Motil. 2012;24:560-565, e254-255. [PubMed] [DOI]|
|104.||Saito YA, Locke GR, Zimmerman JM, Holtmann G, Slusser JP, de Andrade M, Petersen GM, Talley NJ. A genetic association study of 5-HTT LPR and GNbeta3 C825T polymorphisms with irritable bowel syndrome. Neurogastroenterol Motil. 2007;19:465-470. [PubMed] [DOI]|
|105.||Andresen V, Camilleri M, Kim HJ, Stephens DA, Carlson PJ, Talley NJ, Saito YA, Urrutia R, Zinsmeister AR. Is there an association between GNbeta3-C825T genotype and lower functional gastrointestinal disorders? Gastroenterology. 2006;130:1985-1994. [PubMed] [DOI]|
|106.||Saito YA, Larson JJ, Atkinson EJ, Ryu E, Almazar AE, Petersen GM, Talley NJ. The role of 5-HTT LPR and GNβ3 825C& gt; T polymorphisms and gene-environment interactions in irritable bowel syndrome (IBS). Dig Dis Sci. 2012;57:2650-2657. [PubMed] [DOI]|
|107.||Camilleri M, Carlson P, Zinsmeister AR, McKinzie S, Busciglio I, Burton D, Zucchelli M, D'Amato M. Neuropeptide S Receptor Induces Neuropeptide Expression and Associates With Intermediate Phenotypes of Functional Gastrointestinal Disorders. Gastroenterology. 2010;138:98-107. [DOI]|
|108.||Camilleri M, Carlson P, McKinzie S, Grudell A, Busciglio I, Burton D, Baxter K, Ryks M, Zinsmeister AR. Genetic variation in endocannabinoid metabolism, gastrointestinal motility, and sensation. Am J Physiol Gastrointest Liver Physiol. 2008;294:G13-G19. [PubMed] [DOI]|
|109.||Camilleri M. Genetics of human gastrointestinal sensation. Neurogastroenterol Motil. 2013;25:458-466. [PubMed] [DOI]|
|110.||Tyler K, Hillard CJ, Greenwood-Van Meerveld B. Inhibition of small intestinal secretion by cannabinoids is CB1 receptor-mediated in rats. Eur J Pharmacol. 2000;409:207-211. [PubMed]|
|111.||MacNaughton WK, Van Sickle MD, Keenan CM, Cushing K, Mackie K, Sharkey KA. Distribution and function of the cannabinoid-1 receptor in the modulation of ion transport in the guinea pig ileum: relationship to capsaicin-sensitive nerves. Am J Physiol Gastrointest Liver Physiol. 2004;286:G863-G871. [PubMed] [DOI]|
|112.||Li YY, Cao MH, Goetz B, Chen CQ, Feng YJ, Chen CJ, Kasparek MS, Sibaev A, Storr M, Kreis ME. The dual effect of cannabinoid receptor-1 deficiency on the murine postoperative ileus. PLoS One. 2013;8:e67427. [PubMed] [DOI]|
|113.||Kimball ES, Schneider CR, Wallace NH, Hornby PJ. Agonists of cannabinoid receptor 1 and 2 inhibit experimental colitis induced by oil of mustard and by dextran sulfate sodium. Am J Physiol Gastrointest Liver Physiol. 2006;291:G364-G371. [PubMed] [DOI]|
|114.||Wedlake L, A’Hern R, Russell D, Thomas K, Walters JR, Andreyev HJ. Systematic review: the prevalence of idiopathic bile acid malabsorption as diagnosed by SeHCAT scanning in patients with diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2009;30:707-717. [PubMed] [DOI]|
|116.||Wong BS, Camilleri M, Carlson PJ, Guicciardi ME, Burton D, McKinzie S, Rao AS, Zinsmeister AR, Gores GJ. A Klothoβ variant mediates protein stability and associates with colon transit in irritable bowel syndrome with diarrhea. Gastroenterology. 2011;140:1934-1942. [PubMed] [DOI]|
|117.||Poole DP, Godfrey C, Cattaruzza F, Cottrell GS, Kirkland JG, Pelayo JC, Bunnett NW, Corvera CU. Expression and function of the bile acid receptor GpBAR1 (TGR5) in the murine enteric nervous system. Neurogastroenterol Motil. 2010;22:814-825, e227-228. [PubMed] [DOI]|
|118.||Camilleri M, Vazquez-Roque MI, Carlson P, Burton D, Wong BS, Zinsmeister AR. Association of bile acid receptor TGR5 variation and transit in health and lower functional gastrointestinal disorders. Neurogastroenterol Motil. 2011;23:995-999, e458. [PubMed] [DOI]|
|119.||Parkes GC, Brostoff J, Whelan K, Sanderson JD. Gastrointestinal microbiota in irritable bowel syndrome: their role in its pathogenesis and treatment. Am J Gastroenterol. 2008;103:1557-1567. [PubMed] [DOI]|
|120.||Balsari A, Ceccarelli A, Dubini F, Fesce E, Poli G. The fecal microbial population in the irritable bowel syndrome. Microbiologica. 1982;5:185-194. [PubMed]|
|121.||Si JM, Yu YC, Fan YJ, Chen SJ. Intestinal microecology and quality of life in irritable bowel syndrome patients. World J Gastroenterol. 2004;10:1802-1805. [PubMed]|
|122.||Malinen E, Rinttilä T, Kajander K, Mättö J, Kassinen A, Krogius L, Saarela M, Korpela R, Palva A. Analysis of the fecal microbiota of irritable bowel syndrome patients and healthy controls with real-time PCR. Am J Gastroenterol. 2005;100:373-382. [PubMed] [DOI]|
|123.||Kassinen A, Krogius-Kurikka L, Mäkivuokko H, Rinttilä T, Paulin L, Corander J, Malinen E, Apajalahti J, Palva A. The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects. Gastroenterology. 2007;133:24-33. [PubMed] [DOI]|
|124.||Zoetendal EG, Rajilic-Stojanovic M, de Vos WM. High-throughput diversity and functionality analysis of the gastrointestinal tract microbiota. Gut. 2008;57:1605-1615. [PubMed] [DOI]|
|125.||Krogius-Kurikka L, Lyra A, Malinen E, Aarnikunnas J, Tuimala J, Paulin L, Mäkivuokko H, Kajander K, Palva A. Microbial community analysis reveals high level phylogenetic alterations in the overall gastrointestinal microbiota of diarrhoea-predominant irritable bowel syndrome sufferers. BMC Gastroenterol. 2009;9:95. [PubMed] [DOI]|
|126.||Carroll IM, Ringel-Kulka T, Keku TO, Chang YH, Packey CD, Sartor RB, Ringel Y. Molecular analysis of the luminal- and mucosal-associated intestinal microbiota in diarrhea-predominant irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol. 2011;301:G799-G807. [PubMed] [DOI]|
|127.||King TS, Elia M, Hunter JO. Abnormal colonic fermentation in irritable bowel syndrome. Lancet. 1998;352:1187-1189. [PubMed]|
|128.||Dear KL, Elia M, Hunter JO. Do interventions which reduce colonic bacterial fermentation improve symptoms of irritable bowel syndrome? Dig Dis Sci. 2005;50:758-766. [PubMed]|
|129.||Bär F, Von Koschitzky H, Roblick U, Bruch HP, Schulze L, Sonnenborn U, Böttner M, Wedel T. Cell-free supernatants of Escherichia coli Nissle 1917 modulate human colonic motility: evidence from an in vitro organ bath study. Neurogastroenterol Motil. 2009;21:559-566, e16-17. [PubMed] [DOI]|
|130.||Lesniewska V, Rowland I, Laerke HN, Grant G, Naughton PJ. Relationship between dietary-induced changes in intestinal commensal microflora and duodenojejunal myoelectric activity monitored by radiotelemetry in the rat in vivo. Exp Physiol. 2006;91:229-237. [PubMed] [DOI]|
|131.||Kamiya T, Wang L, Forsythe P, Goettsche G, Mao Y, Wang Y, Tougas G, Bienenstock J. Inhibitory effects of Lactobacillus reuteri on visceral pain induced by colorectal distension in Sprague-Dawley rats. Gut. 2006;55:191-196. [PubMed] [DOI]|
|132.||Rousseaux C, Thuru X, Gelot A, Barnich N, Neut C, Dubuquoy L, Dubuquoy C, Merour E, Geboes K, Chamaillard M. Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat Med. 2007;13:35-37. [PubMed] [DOI]|
|133.||Spiller R. Review article: probiotics and prebiotics in irritable bowel syndrome. Aliment Pharmacol Ther. 2008;28:385-396. [PubMed] [DOI]|
|134.||Brenner DM, Moeller MJ, Chey WD, Schoenfeld PS. The utility of probiotics in the treatment of irritable bowel syndrome: a systematic review. Am J Gastroenterol. 2009;104:1033-149; quiz 1050. [PubMed] [DOI]|
|135.||Pimentel M, Lembo A, Chey WD, Zakko S, Ringel Y, Yu J, Mareya SM, Shaw AL, Bortey E, Forbes WP. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med. 2011;364:22-32. [PubMed] [DOI]|
|136.||Lupascu A, Gabrielli M, Lauritano EC, Scarpellini E, Santoliquido A, Cammarota G, Flore R, Tondi P, Pola P, Gasbarrini G. Hydrogen glucose breath test to detect small intestinal bacterial overgrowth: a prevalence case-control study in irritable bowel syndrome. Aliment Pharmacol Ther. 2005;22:1157-1160. [PubMed] [DOI]|
|137.||Nucera G, Gabrielli M, Lupascu A, Lauritano EC, Santoliquido A, Cremonini F, Cammarota G, Tondi P, Pola P, Gasbarrini G. Abnormal breath tests to lactose, fructose and sorbitol in irritable bowel syndrome may be explained by small intestinal bacterial overgrowth. Aliment Pharmacol Ther. 2005;21:1391-1395. [PubMed] [DOI]|
|138.||Shah ED, Basseri RJ, Chong K, Pimentel M. Abnormal breath testing in IBS: a meta-analysis. Dig Dis Sci. 2010;55:2441-2449. [PubMed] [DOI]|
|139.||Pimentel M, Chow EJ, Lin HC. Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol. 2000;95:3503-3506. [PubMed] [DOI]|
|140.||Pimentel M, Chow EJ, Lin HC. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome. a double-blind, randomized, placebo-controlled study. Am J Gastroenterol. 2003;98:412-419. [PubMed] [DOI]|
|141.||Majewski M, McCallum RW. Results of small intestinal bacterial overgrowth testing in irritable bowel syndrome patients: clinical profiles and effects of antibiotic trial. Adv Med Sci. 2007;52:139-142. [PubMed]|
|142.||Weinstock LB, Fern SE, Duntley SP. Restless legs syndrome in patients with irritable bowel syndrome: response to small intestinal bacterial overgrowth therapy. Dig Dis Sci. 2008;53:1252-1256. [PubMed] [DOI]|
|143.||Pimentel M, Soffer EE, Chow EJ, Kong Y, Lin HC. Lower frequency of MMC is found in IBS subjects with abnormal lactulose breath test, suggesting bacterial overgrowth. Dig Dis Sci. 2002;47:2639-2643. [PubMed]|
|144.||Posserud I, Stotzer PO, Björnsson ES, Abrahamsson H, Simrén M. Small intestinal bacterial overgrowth in patients with irritable bowel syndrome. Gut. 2007;56:802-808. [PubMed] [DOI]|
|145.||Peery AF, Dellon ES, Lund J, Crockett SD, McGowan CE, Bulsiewicz WJ, Gangarosa LM, Thiny MT, Stizenberg K, Morgan DR. Burden of gastrointestinal disease in the United States: 2012 update. Gastroenterology. 2012;143:1179-1187.e1-3. [PubMed] [DOI]|
|146.||Walters B, Vanner SJ. Detection of bacterial overgrowth in IBS using the lactulose H2 breath test: comparison with 14C-D-xylose and healthy controls. Am J Gastroenterol. 2005;100:1566-1570. [PubMed] [DOI]|
|147.||Halpert A, Dalton CB, Palsson O, Morris C, Hu Y, Bangdiwala S, Hankins J, Norton N, Drossman D. What patients know about irritable bowel syndrome (IBS) and what they would like to know. National Survey on Patient Educational Needs in IBS and development and validation of the Patient Educational Needs Questionnaire (PEQ). Am J Gastroenterol. 2007;102:1972-1982. [PubMed] [DOI]|
|148.||Böhn L, Störsrud S, Törnblom H, Bengtsson U, Simrén M. Self-reported food-related gastrointestinal symptoms in IBS are common and associated with more severe symptoms and reduced quality of life. Am J Gastroenterol. 2013;108:634-641. [PubMed] [DOI]|
|149.||Ostgaard H, Hausken T, Gundersen D, El-Salhy M. Diet and effects of diet management on quality of life and symptoms in patients with irritable bowel syndrome. Mol Med Rep. 2012;5:1382-1390. [PubMed] [DOI]|
|150.||Mazzawi T, Hausken T, Gundersen D, El-Salhy M. Effects of dietary guidance on the symptoms, quality of life and habitual dietary intake of patients with irritable bowel syndrome. Mol Med Rep. 2013;8:845-852. [PubMed] [DOI]|
|151.||Salvioli B, Serra J, Azpiroz F, Malagelada JR. Impaired small bowel gas propulsion in patients with bloating during intestinal lipid infusion. Am J Gastroenterol. 2006;101:1853-1857. [PubMed] [DOI]|
|152.||Elsenbruch S, Holtmann G, Oezcan D, Lysson A, Janssen O, Goebel MU, Schedlowski M. Are there alterations of neuroendocrine and cellular immune responses to nutrients in women with irritable bowel syndrome? Am J Gastroenterol. 2004;99:703-710. [PubMed] [DOI]|
|153.||Ng C, Malcolm A, Hansen R, Kellow J. Feeding and colonic distension provoke altered autonomic responses in irritable bowel syndrome. Scand J Gastroenterol. 2007;42:441-446. [PubMed] [DOI]|
|154.||Strobel S. Epidemiology of food sensitivity in childhood--with special reference to cow’s milk allergy in infancy. Monogr Allergy. 1993;31:119-130. [PubMed]|
|155.||Kay AB, Lessof MH. Allergy. Conventional and alternative concepts. A report of the Royal College of Physicians Committee on Clinical Immunology and Allergy. Clin Exp Allergy. 1992;22 Suppl 3:1-44. [PubMed]|
|156.||Nelis GF, Vermeeren MA, Jansen W. Role of fructose-sorbitol malabsorption in the irritable bowel syndrome. Gastroenterology. 1990;99:1016-1020. [PubMed]|
|157.||Parker TJ, Woolner JT, Prevost AT, Tuffnell Q, Shorthouse M, Hunter JO. Irritable bowel syndrome: is the search for lactose intolerance justified? Eur J Gastroenterol Hepatol. 2001;13:219-225. [PubMed]|
|158.||Zar S, Mincher L, Benson MJ, Kumar D. Food-specific IgG4 antibody-guided exclusion diet improves symptoms and rectal compliance in irritable bowel syndrome. Scand J Gastroenterol. 2005;40:800-807. [PubMed] [DOI]|
|159.||Zuo XL, Li YQ, Li WJ, Guo YT, Lu XF, Li JM, Desmond PV. Alterations of food antigen-specific serum immunoglobulins G and E antibodies in patients with irritable bowel syndrome and functional dyspepsia. Clin Exp Allergy. 2007;37:823-830. [PubMed] [DOI]|
|160.||Atkinson W, Sheldon TA, Shaath N, Whorwell PJ. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Gut. 2004;53:1459-1464. [PubMed] [DOI]|
|161.||Carroccio A, Brusca I, Mansueto P, Pirrone G, Barrale M, Di Prima L, Ambrosiano G, Iacono G, Lospalluti ML, La Chiusa SM. A cytologic assay for diagnosis of food hypersensitivity in patients with irritable bowel syndrome. Clin Gastroenterol Hepatol. 2010;8:254-260. [PubMed] [DOI]|
|162.||Carroccio A, Brusca I, Mansueto P, Soresi M, D’Alcamo A, Ambrosiano G, Pepe I, Iacono G, Lospalluti ML, La Chiusa SM. Fecal assays detect hypersensitivity to cow’s milk protein and gluten in adults with irritable bowel syndrome. Clin Gastroenterol Hepatol. 2011;9:965-971.e3. [PubMed] [DOI]|
|163.||Eswaran S, Tack J, Chey WD. Food: the forgotten factor in the irritable bowel syndrome. Gastroenterol Clin North Am. 2011;40:141-162. [PubMed] [DOI]|
|164.||Nanda R, James R, Smith H, Dudley CR, Jewell DP. Food intolerance and the irritable bowel syndrome. Gut. 1989;30:1099-1104. [PubMed]|
|165.||Zwetchkenbaum JF, Burakoff R. Food allergy and the irritable bowel syndrome. Am J Gastroenterol. 1988;83:901-904. [PubMed]|
|166.||Pearson DJ, Bentley SJ, Rix KJ, Roberts C. Food hypersensitivity and irritable bowel syndrome. Lancet. 1983;2:746-747. [PubMed]|
|167.||Niec AM, Frankum B, Talley NJ. Are adverse food reactions linked to irritable bowel syndrome? Am J Gastroenterol. 1998;93:2184-2190. [PubMed] [DOI]|
|168.||Monsbakken KW, Vandvik PO, Farup PG. Perceived food intolerance in subjects with irritable bowel syndrome-- etiology, prevalence and consequences. Eur J Clin Nutr. 2006;60:667-672. [PubMed] [DOI]|
|169.||El-Salhy M, Ostgaard H, Gundersen D, Hatlebakk JG, Hausken T. The role of diet in the pathogenesis and management of irritable bowel syndrome (Review). Int J Mol Med. 2012;29:723-731. [PubMed] [DOI]|
|170.||Barrett JS, Gearry RB, Muir JG, Irving PM, Rose R, Rosella O, Haines ML, Shepherd SJ, Gibson PR. Dietary poorly absorbed, short-chain carbohydrates increase delivery of water and fermentable substrates to the proximal colon. Aliment Pharmacol Ther. 2010;31:874-882. [PubMed] [DOI]|
|171.||de Roest RH, Dobbs BR, Chapman BA, Batman B, O’Brien LA, Leeper JA, Hebblethwaite CR, Gearry RB. The low FODMAP diet improves gastrointestinal symptoms in patients with irritable bowel syndrome: a prospective study. Int J Clin Pract. 2013;67:895-903. [PubMed] [DOI]|
|172.||Ong DK, Mitchell SB, Barrett JS, Shepherd SJ, Irving PM, Biesiekierski JR, Smith S, Gibson PR, Muir JG. Manipulation of dietary short chain carbohydrates alters the pattern of gas production and genesis of symptoms in irritable bowel syndrome. J Gastroenterol Hepatol. 2010;25:1366-1373. [PubMed] [DOI]|
|173.||Treem WR, Ahsan N, Kastoff G, Hyams JS. Fecal short-chain fatty acids in patients with diarrhea-predominant irritable bowel syndrome: in vitro studies of carbohydrate fermentation. J Pediatr Gastroenterol Nutr. 1996;23:280-286. [PubMed]|
|174.||Fukumoto S, Tatewaki M, Yamada T, Fujimiya M, Mantyh C, Voss M, Eubanks S, Harris M, Pappas TN, Takahashi T. Short-chain fatty acids stimulate colonic transit via intraluminal 5-HT release in rats. Am J Physiol Regul Integr Comp Physiol. 2003;284:R1269-R1276. [PubMed] [DOI]|
|175.||Kamath PS, Hoepfner MT, Phillips SF. Short-chain fatty acids stimulate motility of the canine ileum. Am J Physiol. 1987;253:G427-G433. [PubMed]|
|176.||Tana C, Umesaki Y, Imaoka A, Handa T, Kanazawa M, Fukudo S. Altered profiles of intestinal microbiota and organic acids may be the origin of symptoms in irritable bowel syndrome. Neurogastroenterol Motil. 2010;22:512-519, e114-115. [PubMed] [DOI]|
|177.||Ford AC, Talley NJ, Spiegel BM, Foxx-Orenstein AE, Schiller L, Quigley EM, Moayyedi P. Effect of fibre, antispasmodics, and peppermint oil in the treatment of irritable bowel syndrome: systematic review and meta-analysis. BMJ. 2008;337:a2313. [PubMed] [DOI]|
|178.||Bijkerk CJ, de Wit NJ, Muris JW, Whorwell PJ, Knottnerus JA, Hoes AW. Soluble or insoluble fibre in irritable bowel syndrome in primary care? Randomised placebo controlled trial. BMJ. 2009;339:b3154. [PubMed] [DOI]|
|179.||Francis CY, Whorwell PJ. Bran and irritable bowel syndrome: time for reappraisal. Lancet. 1994;344:39-40. [PubMed]|
|180.||Sainsbury A, Sanders DS, Ford AC. Prevalence of irritable bowel syndrome-type symptoms in patients with celiac disease: a meta-analysis. Clin Gastroenterol Hepatol. 2013;11:359-365.e1. [PubMed] [DOI]|
|181.||El-Salhy M, Lomholt-Beck B, Gundersen D. The prevalence of celiac disease in patients with irritable bowel syndrome. Mol Med Rep. 2011;4:403-405. [PubMed] [DOI]|
|182.||Wahnschaffe U, Ullrich R, Riecken EO, Schulzke JD. Celiac disease-like abnormalities in a subgroup of patients with irritable bowel syndrome. Gastroenterology. 2001;121:1329-1338. [PubMed]|
|183.||Wahnschaffe U, Schulzke JD, Zeitz M, Ullrich R. Predictors of clinical response to gluten-free diet in patients diagnosed with diarrhea-predominant irritable bowel syndrome. Clin Gastroenterol Hepatol. 2007;5:844-50; quiz 769. [PubMed] [DOI]|
|184.||Vazquez-Roque MI, Camilleri M, Smyrk T, Murray JA, Marietta E, O’Neill J, Carlson P, Lamsam J, Janzow D, Eckert D. A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function. Gastroenterology. 2013;144:903-911.e3. [PubMed] [DOI]|
|185.||Biesiekierski JR, Peters SL, Newnham ED, Rosella O, Muir JG, Gibson PR. No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates. Gastroenterology. 2013;145:320-8.e1-320-8.e3. [PubMed] [DOI]|
|186.||El-Salhy M, Vaali K, Dizdar V, Hausken T. Abnormal small-intestinal endocrine cells in patients with irritable bowel syndrome. Dig Dis Sci. 2010;55:3508-3513. [PubMed] [DOI]|
|187.||Kidd M, Modlin IM, Gustafsson BI, Drozdov I, Hauso O, Pfragner R. Luminal regulation of normal and neoplastic human EC cell serotonin release is mediated by bile salts, amines, tastants, and olfactants. Am J Physiol Gastrointest Liver Physiol. 2008;295:G260-G272. [PubMed] [DOI]|
|188.||De Ponti F, Tonini M. Irritable bowel syndrome: new agents targeting serotonin receptor subtypes. Drugs. 2001;61:317-332. [PubMed]|
|189.||Mawe GM, Coates MD, Moses PL. Review article: intestinal serotonin signalling in irritable bowel syndrome. Aliment Pharmacol Ther. 2006;23:1067-1076. [PubMed] [DOI]|
|190.||Houghton LA, Atkinson W, Whitaker RP, Whorwell PJ, Rimmer MJ. Increased platelet depleted plasma 5-hydroxytryptamine concentration following meal ingestion in symptomatic female subjects with diarrhoea predominant irritable bowel syndrome. Gut. 2003;52:663-670. [PubMed]|
|191.||Dunlop SP, Coleman NS, Blackshaw E, Perkins AC, Singh G, Marsden CA, Spiller RC. Abnormalities of 5-hydroxytryptamine metabolism in irritable bowel syndrome. Clin Gastroenterol Hepatol. 2005;3:349-357. [PubMed]|
|192.||Atkinson W, Lockhart S, Whorwell PJ, Keevil B, Houghton LA. Altered 5-hydroxytryptamine signaling in patients with constipation- and diarrhea-predominant irritable bowel syndrome. Gastroenterology. 2006;130:34-43. [PubMed] [DOI]|
|193.||El-Salhy M, Lomholt-Beck B, Hausken T. Chromogranin A as a possible tool in the diagnosis of irritable bowel syndrome. Scand J Gastroenterol. 2010;45:1435-1439. [PubMed] [DOI]|
|194.||El-Salhy M, Mazzawi T, Gundersen D, Hausken T. Chromogranin A cell density in the rectum of patients with irritable bowel syndrome. Mol Med Rep. 2012;6:1223-1225. [PubMed] [DOI]|
|195.||El-Salhy M, Wendelbo IH, Gundersen D. Reduced chromogranin A cell density in the ileum of patients with irritable bowel syndrome. Mol Med Rep. 2013;7:1241-1244. [PubMed] [DOI]|
|196.||Sidhu R, Drew K, McAlindon ME, Lobo AJ, Sanders DS. Elevated serum chromogranin A in irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD): a shared model for pathogenesis? Inflamm Bowel Dis. 2010;16:361. [PubMed] [DOI]|
|197.||Sidhu R, McAlindon ME, Leeds JS, Skilling J, Sanders DS. The role of serum chromogranin A in diarrhoea predominant irritable bowel syndrome. J Gastrointestin Liver Dis. 2009;18:23-26. [PubMed]|