Digestive and Liver Disease
Volume 39, Issue 3 , Pages 201-215, March 2007

New insights into the pathogenesis and pathophysiology of irritable bowel syndrome

  • L. Öhman
    • ,
  • M. Simrén

      Affiliations

    • Corresponding Author InformationCorresponding author at: Section of Gastroenterology & Hepatology, Department of Internal Medicine, Sahlgrenska University Hospital, S-41345 Gothenburg, Sweden. Tel.: +46 31 342 10 00; fax: +46 31 82 21 52.

Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden

Received 11 September 2006; accepted 25 October 2006.

Article Outline

Abstract 

The pathogenesis and pathophysiology of irritable bowel syndrome is complex and still incompletely known. Potential pathogenetic factors include genes, infectious events, psychological symptoms and other loosely defined environmental factors. Both alterations at the central and peripheral level are thought to contribute to the symptoms of irritable bowel syndrome, including psychosocial factors, abnormal gastrointestinal motility and secretion, and visceral hypersensitivity. Today irritable bowel syndrome is viewed upon as a disorder of dysregulation of the so-called brain–gut axis, involving abnormal function in the enteric, autonomic and/or central nervous systems, with peripheral abnormalities probably dominating in some patients and disturbed central processing of signals from the periphery in others. Lines of evidence also suggest that inflammation within the gastrointestinal tract may be of great importance in at least subgroups of irritable bowel syndrome patients. To conclude, a complex picture of the pathogenesis and pathophysiology of irritable bowel syndrome is emerging, with interactions between several different alterations resulting in the divergent symptom pattern in these patients.

Abbreviations: ANS, autonomic nervous system, CNS, central nervous system, EC, enterochromaffin, ENS, enteric nervous system, fMRI, functional magnetic resonance imaging, GI, gastrointestinal, HPA, hypothalamic-pituitary-adrenal, IBD, inflammatory bowel disease, IBS, irritable bowel syndrome, Ig, immunoglobulin, IL, interleukin, NMDA, N-methyl-d-aspartic acid, PET, positron emission tomography, SERT, serotonin reuptake transporter, TNF, tumour necrosis factor, Treg, regulatory T cells, TNBS, trinitrobenzenesulfonic acid

Keywords: Brain–gut axis, Gastrointestinal motility, Inflammation, Irritable bowel syndrome, Serotonin, Visceral hypersensitivity

 

Back to Article Outline

1. Introduction 

Irritable bowel syndrome (IBS) is characterized by abdominal pain and/or discomfort together with disturbed bowel habits [1]. It is one of the most common gastrointestinal disorders [2] and patients suffering from IBS constitute a great deal of the work load for gastroenterologists and primary care physicians [3], [4], [5], [6]. Unfortunately, the available treatment options for IBS patients are limited, which is partly due to the fact that pathogenetic and pathophysiologal factors of importance for IBS are incompletely known. However, the interest in this topic has steadily increased during the last years and this has substantially improved our current understanding of IBS. Traditionally IBS has been viewed upon as a disorder where altered gastrointestinal motility, visceral hypersensitivity and psychosocial factors are the most important pathophysiological factors. However, recent studies have provided evidence that IBS is due to a dysregulation of the brain–gut axis. This involves abnormal function and interplay between the enteric, autonomic and/or central nervous systems (ENS, ANS and CNS), with peripheral alterations probably dominating in some patients and disturbed central processing of signals from the periphery dominating in others. A major problem however is the lack of understanding about the relationship between the different pathophysiological alterations and the various symptoms experienced by the patients (Fig. 1).

This paper will focus on studies published in the last 5 years, providing evidence for altered interplay between different parts of our nervous system along the brain–gut axis in patients with IBS, as well as presence of low-grade inflammation, immunological changes, abnormal levels of gastrointestinal (GI) neuropeptides and hormones leading to disturbed GI function and the involvement of genetic factors in IBS. It will also shed light on new findings regarding ‘classical’ pathophysiological factors, such as visceral hypersensitivity, altered GI motility and psychological abnormalities. Hopefully this new knowledge will help us to understand this enigmatic disorder better in the future to be able to develop more effective treatment options.

Back to Article Outline

2. Genetic factors 

IBS patients often report that family members have similar symptoms and recent studies support that IBS clusters in families [7], [8], [9]. Twin studies to evaluate the importance of genetic versus environmental factors in the familial aggregation of IBS have been performed with somewhat discrepant results, but taken together they suggest a strong environmental basis for IBS, and if there is a genetic contribution it seems to be a modest one [10], [11], [12]. Moreover, a number of recently published investigations have examined the DNA sequences of IBS subjects directly, looking for genetic variants increasing the risk for having IBS. The strongest evidence for a link between a specific polymorphism and IBS has been found for the serotonin transporter gene. More specifically, available studies suggest that serotonin-transporter polymorphisms may be of importance for which subtype of IBS the patients belong to [13], [14], [15], as well as for the response to treatment [16]. Also polymorphisms of alpha2-adrenergic receptors have been found to be related to the bowel habit of IBS patients in one study, as well as to more severe somatic symptoms [13], whereas no association was found between polymorphisms of the beta3 subunit of the G-protein and IBS [17], contrary to what has been found in functional dyspepsia [18]. Other studies have found cytokine gene polymorphisms to be more common in IBS patients, thereby providing some evidence that genetically determined immune activity plays a role in the pathophysiology of IBS [19], [20]. However, none of the cytokine gene polymorphisms could predict the development of post-infectious IBS.

To summarize, recent investigations support a genetic susceptibility to IBS, even though it seems to be rather modest. Future studies in larger samples are needed to define clinically relevant subgroups, characterize inheritance, identify genes and to better define the environmental contributors to IBS [21].

Back to Article Outline

3. Psychological factors 

3.1. Related to IBS per se or just a consequence of symptom severity? 

Rather than being a cause of IBS, psychosocial factors have since the late eighties been looked upon largely as factors related to the severity of the disease, affecting fluctuations in the symptom pattern and determining the health care seeking behaviour of the patients. This has been based on studies supporting an association between psychosocial factors and patient status rather than with IBS per se [22], [23]. However, recent studies have challenged this view to some extent. Two population-based studies found an association between psychosocial factors and IBS, which was not explained by health care seeking, but was also seen in IBS subjects who had not sought health care for their symptoms [24], [25]. Moreover another prospective population-based study from the UK looked at factors predicting the onset of new abdominal pain over 12 months. The main findings from that study were that in subjects free of abdominal pain, psychological distress, fatigue, health anxiety and illness behaviour were predictors of future onset rather than merely a consequence of symptoms [26]. Another Australian community-based investigation demonstrated that psychological distress levels do not seem to be important in explaining GI symptom change over a 1-year period, but was linked to having persistent GI symptoms and frequently seeking health care for them over time [27]. Taken together, these results suggest that psychosocial factors may be involved in the ethiopathogenesis of IBS, contrary to the current dogma, and not just influencing the severity of the symptoms and the health care seeking behaviour of the patients.

3.2. Physical and sexual abuse 

A number of chronic physical conditions are found more often in women who report different types of physical and sexual abuse [28], and this also seems to be true for IBS according to some [29], [30] but not all recent studies [31] Psychosocial factors seem to be mediating factors linking abuse with the development of functional gastrointestinal symptoms [29], [30], [32]. Salmon et al. proposed a model in which childhood abuse is linked to IBS because it causes a tendency to dissociate, and because dissociation causes a general increase in physical symptoms [33]. However, no explanation was given as to why a generally increased level of physical symptoms specifically in some patients should lead to IBS, and to other syndromes in other patients. The association between abuse and somatisation was also supported by a study performed by Creed et al, where they demonstrated that the association between self-reported abuse and the impaired functioning in patients with severe IBS was mediated by a general tendency to report numerous bodily symptoms [34]. These findings are of great importance given the high numbers of IBS patients with simultaneous somatisation disorder, especially in referral centres [35], and the fact that the presence of somatisation also affects health-care costs in IBS [36]. However, interestingly enough, in another study no direct association between abuse and somatisation could be detected, but instead an association between ‘less extreme’ parenting variables and the presence of somatisation [37], which is in concordance with other studies underscoring the role of the parents for the future development of IBS [10], [38]. To conclude, several different explanations for the rather well established, but somewhat controversial, association between abuse and the development of IBS and other functional GI disorders exist.

3.3. Cognitive factors 

Cognitive deficits are common in patients with chronic illnesses and have also been found to be of importance for IBS patients [39], For instance, findings that IBS patients with greater depression often report more severe abdominal pain has been proposed to be partially explained by a tendency to engage in more catastrophic thinking specific to pain [40], which also relates to interpersonal problems in a complex way [41]. Moreover, the same group also demonstrated that patients with chronic pain who worry excessively engage in more catastrophic thinking and through this cognitive process experience more intensely the suffering component of pain [42]. However, when comparing patients with IBS with inflammatory bowel disease (IBD) patients and healthy controls, both IBS and IBD patients seem to rely more on passive coping strategies than controls, with no differences between the patient groups [43] Findings such as these support the role of cognitive alterations in the IBS population, and make cognitive behavioural treatment options attractive for IBS patients, and a large clinical trial has recently confirmed its effectiveness [44].

Back to Article Outline

4. Visceral hypersensitivity 

Visceral hypersensitivity is one of the most commonly found pathophysiological alterations in patients with IBS and other functional gastrointestinal disorders [45], and rectal hypersensitivity has been suggested to be a hallmark of IBS [46]. However, a drawback with many of the studies assessing visceral perception in IBS is that they are made under fasting and non-stimulated conditions, under which patients normally do not report severe symptoms. Many patients with IBS perceive that food intake, stress, the menstrual cycle and psychological factors affect the severity of their symptoms. Therefore, the effect of these factors on visceral hypersensitivity has been evaluated in several studies during the last years.

4.1. Effects of nutrients 

Postprandial worsening of symptoms, as well as adverse reactions to one or more foods is common in IBS patients [47]. Our group has demonstrated enhancement of the colonic sensitivity in IBS patients after duodenal lipid administration as compared with healthy controls [48], [49] (Fig. 2). This finding has thereafter also been reproduced by other groups, assessing the effect of duodenal lipid administration on rectal sensory function [50], [51], and the composition of the meal also seems to be of importance, since a fatty meal had more pronounced effects on rectal sensitivity in IBS patients than a meal rich in carbohydrates [52]. The mechanisms involved in this enhancement of colorectal sensitivity after nutrient delivery into the upper GI tract is not altogether known, but both central and peripheral factors may be involved [53], [54], and it seems to be unrelated to the bowel habit, gender and psychological factors [49].

  • View full-size image.
  • Fig. 2. 

    The proportion of patients with IBS (black bars; n=61) and healthy control subjects (white bars; n=20) reporting pain during colonic balloon distension (40mmHg) before (baseline) vs. after duodenal lipid infusion. After lipid infusion a greater proportion of patients reported pain compared with the baseline condition, but this was not the case in the controls [49].

4.2. Stress and visceral sensitivity 

Patients with IBS often describe a correlation between their symptoms and stress, and subjects who have been exposed to severe forms of stress, developing posttraumatic stress disorder, are more likely to develop several physical health problems, including IBS [55]. Several studies now exist that demonstrate an altered visceral perceptual response in IBS patients relative to control subjects after and during stress [56], [57], [58], even though differences between the results exist, which partly may be due to the different methodologies used in the different studies. Another study assessed the effect of stress after meal intake, and showed that IBS patients responded with greater negative affect to postprandial psychological stress as well as to food intake alone [59]. Severe forms of stress, such as participation in war, has also been shown to result in visceral as well as cutaneous hypersensitivity [60], further supporting a role of stress in modulating visceral perception.

4.3. Psychological symptoms and visceral sensitivity 

Even though GI symptom severity cannot reliably predict the degree of visceral hypersensitivity in IBS patients, there are data supporting an association between GI symptom severity and visceral hypersensitivity [61], [62], [63], [64], [65], [66]. Psychological factors and quality of life are also related to the GI symptom severity of IBS patients [67], [68]. Therefore, it is a logical assumption that also psychological symptom severity may influence visceral sensitivity in IBS patients. In a study of Persian Gulf war veterans cutaneous as well as visceral hypersensitivity was common, and a significant amount of the variation in the pain measures could be explained by psychological measures, indicating that psychological factors are of importance for visceral sensitivity [60]. Further support for the critical role of the mind in modulating visceral sensitivity comes from studies using hypnosis, where different emotions induced during hypnosis affected rectal sensitivity in different ways [69], and gut-directed hypnotherapy per se also affects colorectal sensitivity [53], [70]. Moreover, a study assessing the effect of psychotherapy and a selective serotonin reuptake inhibitor also included a rectal sensitivity assessment at baseline and after three months, and found that increased tolerance to rectal distension after treatment was associated with improved depression and also to reported sexual abuse [71]. On the other hand physical and sexual abuse, often causing psychological alterations, was in another study not found to be associated with rectal hypersensitivity in IBS patients [72], and an investigation assessing perceptual sensitivity and response bias during rectal distension in patients with IBS could not find evidence to support the hypothesis that increased frequency of sensations reported by IBS patients was due to psychological response bias [73]. Therefore, it is fair to say that the effect of psychological factors on visceral sensitivity in IBS patients remains somewhat unclear, even though a modulating effect of psychological factors on visceral sensitivity seems plausible.

4.4. Hormonal factors and visceral sensitivity 

The fact that IBS is more common in women and that GI symptoms fluctuate during the menstrual cycle has created a hypothesis that hormonal levels may be associated with visceral sensitivity. Indeed, some [74], but not all [75] studies suggest that gender affects the perceptual sensitivity to colorectal distensions. Moreover, the IBS symptomatology is exacerbated at menses and the rectal sensitivity changes with the menstrual cycle in IBS patients, but not in healthy volunteers, suggesting that women with IBS respond differently to fluctuations in their sex hormones [76]. There are also animal models demonstrating an effect of hormonal levels on sensitivity to colorectal distension [77]. Based on these data, a hormonal influence on visceral sensitivity in IBS patients seems to be likely.

Back to Article Outline

5. Gastrointestinal motility 

Minor GI motility alterations are commonly found in IBS at different regions of the GI tract [78], [79], [80], [81], but a clear relationship with the different symptoms of IBS patients have been hard to find [82]. However, an association between pain episodes in IBS patients and colonic high-amplitude propagating contractions has been demonstrated in two studies [83], [84]. Also of great interest, using volume-controlled rectal distension Corsetti et al. demonstrated motor hyperreactivity in the rectum in IBS patients, as well as enhanced sensitivity, further supporting a mixed picture with a combination of sensory and motor abnormalities in IBS [85]. Another interesting line of research has evaluated GI reflex activity, demonstrating alterations in IBS patients such as abnormal recto-sigmoid tone response following a low-caloric meal [86], an attenuated rectal tone response to colonic distension (‘the colorectal tonic reflex’) [87], [88], or blunted inhibition of duodenal motility and exaggerated motility of the descending colon following repeated distensions of the sigmoid colon [89].

To conclude, GI motor abnormalities are present in subgroups of IBS patients, and is probably of importance for the bowel habit of the patient [90], but its relevance for other symptoms are less clear. Recent studies suggesting rectal hyperreactvity and altered GI reflex activity are of great interest, but follow-up studies are needed to further evaluate the neuromuscular function within the gastrointestinal tract in IBS patients.

5.1. Gas handling 

In patients with IBS complaints of ‘too much gas’ causing visible abdominal distension, pain and bloating is very common [91], and during the last years our understanding of these symptoms have improved substantially. The abdominal distension can now be objectively assessed using inductance plethysmography [92], which will help to gain further understanding of this debilitating symptom. Indeed, subgroups of IBS patients seem to have a greater abdominal distension than controls [93]. Of great interest, patients with IBS complaining of bloating has been found to have impaired transit of exogenous gas loads, and the following gas retention reproduced their symptoms [94]. Importantly, this abnormality can be modulated by nutrients [95], [96], physical activity [97], body posture [98] and pharmacological agents [99], [100]. In follow-up studies the small intestine seemed to be responsible for the ineffective gas propulsion in patients complaining of bloating [101], [102], and altered gastrointestinal reflex activity in IBS patients might also be involved in the abnormal gas handling [103]. Moreover, impaired viscerosomatic reflexes and abdominal-wall dystony may also be associated with bloating, but this needs to be further studied [104]. Taken together, studies on intestinal gas dynamics have substantially improved our understanding of gas-related symptoms in IBS patients.

Back to Article Outline

6. Dysregulation of the brain–gut axis 

6.1. Brain responses to peripheral stimuli 

Despite contradicting results, several studies using different techniques such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), indicate differences between IBS patients and healthy controls in activation of different pain processing regions such as the anterior cingulate cortex, thalamus, insula and prefrontal cortex [105]. After the initial studies of pain processing in IBS patients, several brain imaging studies have been published with somewhat divergent results, with reports of increased activity in the insula, prefrontal cortex and thalamus [106], [107], as well as in the cingular cortex [106], [108], [109], but also decreased activity in the insula, amygdala and striatum [110]. Taken together the existing studies suggest that IBS patients may have increased activity during visceral distension in sensory areas [106], cortical areas involved in attention and affect, and subcortical regions associated with affect, arousal and autonomic responses [109], but also abnormal responses in areas involved in endogenous pain modulation [111], [112]. A study published this year evaluated the effect of repeated exposure to experimental aversive visceral stimuli, i.e. rectal balloon distensions, and found habituation of visceral perception and central arousal, despite stable activation of networks processing visceral pain and its anticipation [113]. This study to some extent questions the validity of visceral hypersensitivity being a valid biomarker for IBS and also shed new light on possible mechanisms underlying the enhanced sensitivity in IBS [114]. The discrepancies in some of the available studies evaluating the brain–gut axis in functional gastrointestinal disorders are probably explained by factors such as small study populations and pooling of results from heterogeneous groups, as well as the use of different methodologies [115]. It has for instance been demonstrated that male and female IBS patients show differences in activation of brain regions [116], just like the activation pattern differ between IBS subgroups based on the predominant bowel habit [112]. The psychological state of the patient is also important since emotional status has been shown to modulate brain activation patterns [117]. Interestingly, changes in some brain regions have also been associated with treatment response in IBS [118]. To conclude, there appears to be alterations along the brain–gut axis in patients with IBS. However, there are discrepancies between existing studies, and in future studies standardization of the methodology, as well as strict inclusion criteria and evaluation of larger patient groups will enhance our understanding of the interaction between the gut and different parts of our nervous system.

6.2. Autonomic nervous system and the hypothalamic-pituitary adrenal axis 

Central nervous system communication with the gut is mediated through the parasympathetic and sympathetic pathways of the autonomic nervous system (ANS) by modulation of the enteric nervous system, as well as via the hypothalamic-pituitary-adrenal (HPA) axis. Several studies have reported autonomic dysfunction in IBS [119], [120]. The results are inconsistent, but increased sympathetic and decreased parasympathetic activity in IBS patients compared with healthy controls are the most frequently reported differences [121], [122], [123]. Again, the contradictory results may partly be due to varying experimental designs with differences in study populations. Anxiety and depression influences autonomic function in IBS [124], and there also seem to be discrepancies between different subgroups of IBS patients [122], [125]. Recently, Tillisch et al. [126] also showed gender differences in ANS response to visceral stimulus, with more prominent alterations in male IBS patients. Also regarding the HPA axis the results are somewhat divergent with investigations reporting attenuated [127], normal [56] and enhanced reactivity [58], [128] of the HPA-axis in IBS patients in response to various stressors, as well as an association with a proinflammatory cytokine release [128]. Again, different study designs, patient characteristics and other factors might be the explanation for the somewhat heterogeneous results [129]. However, given the well-established effects of corticotrophin releasing factor on colonic sensorimotor function and its importance in the effects of stress on GI function, pharmacological modulation of its central and peripheral effects seem to be a promising target for functional GI disorders [130], [131], [132].

Back to Article Outline

7. Neuroptides and hormones 

Today, visceral hypersensitivity, and abnormal GI motility and secretion are considered to be key factors in the pathophysiology, leading to the main symptoms of IBS. A number of different signalling molecules are involved in these functions, and alterations in several of these have been found in IBS patients. The main focus has been on serotonin, but altered levels of for instance peptide YY, neuropeptide Y [133], vasoactive intestinal peptide [134], motilin [135], cholecystokinin [136], and hormones involved in the stress response [58], [127], [128], [137] have also been demonstrated in IBS patients. However, the relevance of these findings for the symptoms remains unclear.

7.1. Altered serotonin signalling 

Serotonin is one of the key neurotransmitters within the GI tract, and affects motility, sensation and secretion. Enterochromaffin cells or EC cells synthesize and store the majority of the serotonin in the body and releases serotonin in response to different luminal stimuli. After release its effect is terminated by the serotonin reuptake transporter (SERT) [138]. Several recent studies indicate altered serotonin availability and signalling in patients with IBS, and the drug development during the last couple of years has mainly focused on drugs interacting with serotonin signalling within the gut. Taken together, when assessing serotonin levels in platelet depleted plasma these studies suggest increased release of serotonin postprandially and/or reduced serotonin reuptake in diarrhoea-predominant IBS patients [139], [140] and patients with post-infectious IBS [90], whereas impaired release seems to be a feature of patients with constipation predominant IBS [90], [139]. In a recent study, the key elements in serotonin signalling were assessed and the main findings were that IBS patients had reduced levels of serotonin in the mucosa, and of tryptophan hydroxylase, the rate limiting enzyme in the serotonin synthesis, but also reduced levels of SERT mRNA, which could increase mucosal availability of 5-HT after release [141]. The number of EC cells in the rectal mucosa was normal in this study, but when looking specifically at patients with post-infectious IBS the number of EC cells has been upregulated [142], [143] and the density of serotonin positively stained nerve fibers increased [144]. Compelling evidence for altered serotonin signalling in IBS exists, but further studies are needed to evaluate the link to genetic polymorphisms, specific symptoms other than constipation and diarrhoea, and its relevance for predicting the response to various treatment alternatives. Based on the available data on altered serotonin signalling in IBS dietary advice based on the tryptophan content in different food items might be relevant, since 1% of the tryptophan is converted into 5-HT [145].

Back to Article Outline

8. Inflammatory changes 

Evidence in the literature postulates that previous transient or chronic inflammation can lead to development of persistent gut dysfunction [146]. Firstly, the prevalence of IBS symptoms in IBD patients in long-standing remission is two to three times higher than in the normal population [147]. Secondly, approximately 15–30% of patients with IBS report onset of disease after an enteric infection [148], [149]. These observations implicate that IBS may, in at least a subpopulation, be an inflammatory disorder. During the last years a low grade inflammatory process in various compartments of the small and the large bowel has been suggested to be associated with gut symptoms in IBS patients. The inflammatory component may well be different in post-infectious IBS relative to IBS without an onset related to infection. Apart from gastroenteritis, different factors such as altered gut flora, increased permeability, genetic susceptibility and unrecognised food reactions have all been suggested as possible mediators of an inflammatory response in IBS patients (Fig. 3).

8.1. Post-infectious IBS 

The incidence of post-infectious IBS after enteric infection has been reported to vary between 3% to approximately 35% [144], [148], [149], [150], [151], [152], [153], [154], [155]. The inflammatory component of IBS has been clearly demonstrated in patients with an infectious onset of the disease. Studies have shown that patients with post-infectious IBS have an activated intestinal immune response, as defined by increased numbers of T cells in the colonic mucosa [142], [143], [156], [157]. The most commonly described feature of post-infectious IBS is augmented number of mucosal enteroendocrine cells, which is discussed in more detail below. Most interestingly, a recent study demonstrated that also non-GI infections might lead to an increased risk of developing IBS as compared to control subjects without any known infection [158]. Furthermore, in this study there was no difference in the presence of functional GI disorders between patients with gastroenteritis versus those with a non-GI infection. These data, which however needs to be confirmed in further studies, suggests that also non-GI infections may be important in the onset of gut dysfunction. Considering the many studies pointing out the relevance of gastroenteritis in the development of IBS, it is somewhat surprising to note that a trial of prednisolone treatment in patients with post infectious IBS, failed to show any effect on the symptoms [156]. The administration of prednisolone had no effect on the colonic enteroendocrine cell number, although the lamina propria T cells counts decreased. Thus, it remains to be further evaluated whether the inflammatory components of post-infectious IBS are driving the clinical symptoms of the patients.

8.2. Alterations in the gut flora 

Also the presence of specific bacterial strains or the composition of the intestinal flora may be of importance in the development of IBS symptoms [159]. The demonstration that use of antibiotics triples the likeliness to develop functional abdominal symptoms indicates the significance of the gastrointestinal microflora in IBS [160]. Several groups have during the last years reported alterations in the commensal gut flora of IBS patients. Chen and co-workers reported decreased numbers of Bifidobacterium together with increased number of Enterobacteriace in IBS patients, according to traditional culture methods [161]. However, the majority of gastrointestinal flora is believed to be strictly anaerobe and many strains are therefore difficult to sample and grow with traditional techniques. The real-time PCR based analysis of bacterial DNA from faeces allows extended and more accurate determination of the composition of the intestinal microbiota. By using this technique, the gut flora of IBS patients has been demonstrated to quantitatively differ in Clostridium coccoides and B. catenulatum from that of healthy controls [162]. Moreover, faecal sampling over a 6-month period indicated that patients with IBS have a greater instability in the composition of the intestinal microflora [163]. There are also studies suggesting increased prevalence of small intestinal bacterial overgrowth in IBS patients, as detected by the lactulose breath test [164], [165], and also a positive effect of treatment with antibiotics in these patients [166]. However, not all studies have come to the same conclusion [167]. Follow-up studies regarding the importance of the alterations in the bacterial flora in the small intestine of patients with IBS are currently being performed. Thus, it seems to be a plausible hypothesis well worth exploring further that IBS patients have increased intestinal immunological reactivity as a result of an altered gut microbiota. A thought is that bacteria are one of many irritants within the gut, leading to persistent or at least long-standing gut dysfunction [168] (Fig. 4).

  • View full-size image.
  • Fig. 4. 

    Ongoing and recently published studies imply an important role for different ‘irritants’ within the GI tract such as gut bacteria, bile acids, nutrients, allergens and various pathogens, in the evolution of IBS [168].

8.3. Defect mucosal barrier 

The epithelial cells at mucosal surfaces are connected by tight junctions. The epithelial lining is semi-permeable and does mainly permit entry of small particles. Two independent groups have recently described that patients with IBS have increased passage over the intestinal mucosa. Post-infectious IBS patients have been demonstrated to have increased small intestinal permeability by increased transport over the mucosal membrane of 51Cr-EDTA and lactulose-mannitol, respectively [153], [169]. Furthermore, non post-infectious IBS patients with diarrhoea predominance had increased small intestinal permeability compared to post-infectious IBS patients and controls [169]. These results suggest that an activated intestinal immune system in IBS patients may be due to a higher local antigen exposure, caused by an increased permeability of the intestinal epithelial layer.

8.4. Genetic predisposition to inflammatory reactions 

A few recently published articles have suggested that individuals suffering from IBS symptoms may be genetically predisposed to inflammatory reactions. Fore instance, more IBS patients are low producers of the anti-inflammatory cytokine IL-10 genotype [19], than control subjects. The combination of high producer of the proinflammatory cytokine TNF-α genotype and low producer of IL-10 genotype has also been demonstrated to be more prevalent in IBS patients than controls [20]. Furthermore, individuals who developed IBS after infectious gastroenteritis had increased expression of the proinflammatory cytokine IL-1β mRNA in rectal biopsies [144], [170]. These reports together with the fact that mutations in genes coding for receptors participating in the activation of immune system is associated with inflammatory bowel disease, implicates that genetic susceptibility may play a role in the development of IBS.

8.5. Food hypersensitivity in IBS 

It has also been suggested that food hypersensitivity may contribute to the gut immune activation in IBS, as patients may respond favourably to specific elimination diets [171], [172]. The underlying mechanisms for food hypersensitivity are currently being generally discussed. IgG and IgG4, apart from IgE, have been suggested to be the predominant antibodies produced in immune responses to specific food antigens. Traditional tests to evaluate IgE mediated reactions have limited value in non-atopic patients, which may be the case of IBS patients. However, the immunoblotting technique has revealed that the frequency IBS patients with IgE mediated food hypersensitivity may be larger than expected [173]. A study from Germany demonstrated that a subgroup of IBS patients had latent celiac disease, which consequently profited from gluten free diet. These patients could be identified by HLA-DQ2 expression and increased expression of celiac disease antibodies [174]. Moreover, recent studies have suggested that IgG and/or IgG4 mediated hypersensitivity reactions are important in the pathogenesis of IBS [171], [172], [175]. It may therefore be worthwhile to investigate the putative importance of dietary antigen specific IgG and IgE in symptom generation of IBS patients.

8.6. Cell populations participating in the inflammatory reactions of IBS 

Some cell populations are repeatedly described in the literature as participants of gastrointestinal inflammatory reactions in IBS patients; T lymphocytes, mast cells and enteroendocrine cells (Table 1). A number of recent publications have reported increased numbers of T cells in various lymphoid compartments of the small and/or large intestine in IBS patients. Full thickness jejunal biopsies revealed that patients with severe IBS symptoms had increased numbers of intraepithelial T cells and more T lymphocytes per ganglion in the myenteric plexus [176]. Several groups have also demonstrated increased numbers of intraepithelial T lymphocytes and lamina propria T lymphocytes, in the colonic mucosa of non post-infectious as well as IBS patients with an infectious onset [143], [157], [177], [178]. The low grade mucosal inflammation recorded in IBS patients may theoretically be due to either an unregulated mild inflammation or reflect a suppressed potent inflammatory process driven by activated T lymphocytes. CD25+ regulatory T cells (Treg), with suppressive effect on activated T lymphocytes, may play an important role in controlling intestinal inflammation. Chadwick et al. [177] have shown that IBS patients have an increased numbers of colonic lamina propria T cells expressing CD25, and it has been speculated that these cells could affect the intestinal inflammatory activity in IBS patients [179]. However, a novel study has demonstrated that IBS patients have normal frequencies of apparently functional CD25+ Treg cells in both the colonic mucosa and peripheral blood [180]. This indicates that IBS is not associated with defect regulation of activated mucosal T lymphocytes due to an altered function or frequency of CD25+ Treg cells.

Table 1. Cell populations described in the literature as participants of gastrointestinal inflammatory reactions in IBS patients
Cell populationsFeaturesIBS symptomsReferences
T cellsNumber of intraepithelial T cellsPI, D, A, C[157], [176], [177]
Number of lamina propria T cellsPI, D, A, C[143], [156], [177], [178]
T regulatory cell activityD, A, C[177], [180]

Mast cellsNumber of mast cellsPI, D, A, C[144], [181], [182], [183], [184]
Association to nervesD, A[181], [183]
Relation to sensitivityD, A[181], [184]

Enteroendocrine cellsNumber of enteroendocrine cellsPI, D[142], [143], [156], [157], [185]
Relation to sensitivityD[185]

PI; post infectious IBS, D; diarrhea IBS, A; alternating IBS, C: constipating IBS.

One of the most recognised immunological features of IBS is increased numbers of mast cells in colonic biopsies [144], [181], [182], [183], [184]. Indeed, high numbers of activated mast cells have been found in close proximity to nerves in the colonic mucosa [181], [183], with a numeric correlation to abdominal pain perception [181], and possibly also a relationship with rectal sensitivity [184]. On the other hand, an additional study found no altered gastrointestinal mast cell numbers in IBS patients relative to controls [177], although an augmented colonic mast cells numbers in patients with microscopic colitis and lymphocytic colitis was reported. The diverging results regarding colonic mast cell numbers implicates that it may be complex to include equal IBS populations at different research sites, despite the use of the Rome II criteria. All in all, the relationship between intestinal mast cell counts and gastrointestinal sensitivity of IBS patients is intriguing and needs to be further evaluated.

Increased number of EC cells is described as related to post-infectious IBS in several studies [142], [143], [156], [157]. Interestingly, post-infectious IBS patients had increased colonic EC cell numbers relative to IBS patients with a non-infectious origin and to controls. However, the number of colonic EC cells was not augmented in non post-infectious IBS patients relative to controls [143]. A novel study by Park et al. showed a relationship between the maximal tolerated intestinal pressure and the number of EC cells in the rectum of diarrhoea predominant IBS without known infectious origin [185]. The rectal sensitivity was enhanced in D-IBS patients with increased numbers of EC cells in the rectum, and the authors suggest that enteroendocrine cells might play an important role in visceral hypersensitivity.

8.7. Animal models of inflammation and IBS 

Several different animal models where a transient inflammation or infection is induced by peripheral stimuli are currently being used to study functional bowel alterations in relationship to intestinal immune activation. Novel studies of rats with resolving trinitrobenzenesulfonic acid (TNBS) induced colitis have demonstrated the presence of long-lasting visceral hyperalgesia [186] and an upregulation of colonic N-methyl-d-aspartic acid (NMDA) spinal cord receptors [187]. Furthermore, increased rate of mast cell degranulation was recorded in acetic acid induced colitis rats after being restored to health. Pre-treatment of the rats with mast cell stabiliser attenuated the rectal hypersensitivity to distension [188]. Collins and co-workers have demonstrated that an acute Trichinella spiralis infection in mice results in persistent muscle hypercontractility, gut dysmotility and hyperalgesia, which can be reversed by corticosteroid treatment [189]. The nematode infection induced increased mucosal levels of the T helper 2 cytokines interleukin-4 and interleukin-13, which are suggested to provoke the muscle hypercontractility by a direct action on smooth muscle cells [190].

Animal studies have also demonstrated that stress may increase the intestinal expression of the T helper 1 cytokine interferon-γ and amplify the colonic permeability [191]. The altered mucosal barrier function in this stress model seems to be dependent on the presence of interferon-γ producing CD4+ T cells and myosin light chain phosphorylation. Finally, the importance of intestinal commensal flora to maintain normal gut function has also been studied in mice. Antibiotic treatment resulted in increased visceral hypersensitivity, intestinal myeloperoxidas production and substance P activity. Administration of the probiotic strain Lactobacillus paracasei normalised the visceral hypersensitivity and substance P activity [192]. Taken together, animal studies support the suggestion that intestinal inflammation, alterations in gut flora and intestinal permeability resulting in an activated intestinal immune system may explain part of the gut dysfunction seen in IBS patients, and are important for better understanding of the mechanisms involved in the interaction between inflammation and gut dysfunction.

Back to Article Outline

9. Conclusion 

IBS patients present with a range of different symptoms, and typically symptoms wax and vane over time. In line with this a complex picture of the pathogenesis and pathophysiology of IBS is emerging, with interactions between several different alterations, possibly resulting in the divergent symptom pattern in these patients. In order to be able to develop better treatment alternatives for this large group of patients a better understanding of the relative importance of the different pathogenetic and pathophysiological factors is needed, as well as a more thorough knowledge about its relevance for the different symptoms in the IBS patients. This means that more research is needed!

Back to Article Outline

Practice points 


•Potential pathogenetic factors in IBS include genes, infectious events, psychological symptoms and other loosely defined environmental factors.

•Traditional pathophysiological factors in IBS include visceral hypersensitivity, altered gastrointestinal motility and secretion, as well as psychosocial factors.

•IBS can be viewed upon as a disorder of dysregulation of the brain–gut axis, involving abnormal function in the enteric, autonomic and/or central nervous systems.

•Low-grade inflammatory changes are often demonstrated in IBS patients, but its direct relevance for the symptom pattern remains to be elucidated.

Back to Article Outline

Research agenda 


•Better understand the relationship between different pathophysiological alterations and the symptom pattern in IBS patients.

•Further explore brain responses to peripheral stimuli in IBS, and also enhance the understanding of the endogenous pain modulation.

•Develop and evaluate new treatment alternatives based on the pathophysiological alterations present in IBS patients.

•Develop relevant animal models for IBS, from which the findings can be translated into humans.

Back to Article Outline

Conflict of interest statement 

None declared.

Back to Article Outline

References 

  1. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology. 2006;130:1480–1491
  2. Quigley EM, Bytzer P, Jones R, Mearin F. Irritable bowel syndrome: The burden and unmet needs in Europe. Dig Liver Dis. 2006;38:717–723
  3. Harvey RF, Salih SY, Read AE. Organic and functional disorders in 2000 gastroenterology outpatients. Lancet. 1983;1:632–634
  4. Thompson WG, Heaton KW, Smyth GT, Smyth C. Irritable bowel syndrome in general practice: prevalence, characteristics, and referral. Gut. 2000;46:78–82
  5. Bellini M, Tosetti C, Costa F, Biagi S, Stasi C, Del Punta A, et al. The general practitioner's approach to irritable bowel syndrome: from intention to practice. Dig Liver Dis. 2005;37:934–939
  6. Dapoigny M. Irritable bowel syndrome and the general practitioners. Dig Liver Dis. 2005;37:907–908
  7. Kalantar JS, Locke GR, Zinsmeister AR, Beighley CM, Talley NJ. Familial aggregation of irritable bowel syndrome: a prospective study. Gut. 2003;52:1703–1707
  8. Locke GR, Zinsmeister AR, Talley NJ, Fett SL, Melton LJ. Familial association in adults with functional gastrointestinal disorders. Mayo Clin Proc. 2000;75:907–912
  9. Kanazawa M, Endo Y, Whitehead WE, Kano M, Hongo M, Fukudo S. Patients and nonconsulters with irritable bowel syndrome reporting a parental history of bowel problems have more impaired psychological distress. Dig Dis Sci. 2004;49:1046–1053
  10. Levy RL, Jones KR, Whitehead WE, Feld SI, Talley NJ, Corey LA. Irritable bowel syndrome in twins: heredity and social learning both contribute to etiology. Gastroenterology. 2001;121:799–804
  11. Mohammed I, Cherkas LF, Riley SA, Spector TD, Trudgill NJ. Genetic influences in irritable bowel syndrome: a twin study. Am J Gastroenterol. 2005;100:1340–1344
  12. Morris-Yates A, Talley NJ, Boyce PM, Nandurkar S, Andrews G. Evidence of a genetic contribution to functional bowel disorder. Am J Gastroenterol. 1998;93:1311–1317
  13. Kim HJ, Camilleri M, Carlson PJ, Cremonini F, Ferber I, Stephens D, et al. Association of distinct alpha(2) adrenoceptor and serotonin transporter polymorphisms with constipation and somatic symptoms in functional gastrointestinal disorders. Gut. 2004 Jun;53:829–837
  14. Pata C, Erdal ME, Derici E, Yazar A, Kanik A, Ulu O. Serotonin transporter gene polymorphism in irritable bowel syndrome. Am J Gastroenterol. 2002;97:1780–1784
  15. Yeo A, Boyd P, Lumsden S, Saunders T, Handley A, Stubbins M, et al. Association between a functional polymorphism in the serotonin transporter gene and diarrhoea predominant irritable bowel syndrome in women. Gut. 2004;53:1452–1458
  16. Camilleri M, Atanasova E, Carlson PJ, Ahmad U, Kim HJ, Viramontes BE, et al. Serotonin-transporter polymorphism pharmacogenetics in diarrhoea- predominant irritable bowel syndrome. Gastroenterology. 2002;123:425–432
  17. Andresen V, Camilleri M, Kim HJ, Stephens DA, Carlson PJ, Talley NJ, et al. Is there an association between GNbeta3-C825T genotype and lower functional gastrointestinal disorders?. Gastroenterology. 2006;130:1985–1994
  18. Holtmann G, Siffert W, Haag S, Mueller N, Langkafel M, Senf W, et al. G-protein beta 3 subunit 825 CC genotype is associated with unexplained (functional) dyspepsia. Gastroenterology. 2004;126:971–979
  19. 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
  20. van der Veek PP, van den Berg M, de Kroon YE, Verspaget HW, Masclee AA. Role of tumour necrosis factor-alpha and interleukin-10 gene polymorphisms in irritable bowel syndrome. Am J Gastroenterol. 2005;100:2510–2516
  21. Saito YA, Petersen GM, Locke GR, Talley NJ. The genetics of irritable bowel syndrome. Clin Gastroenterol Hepatol. 2005;3:1057–1065
  22. Drossman DA, McKee DC, Sandler RS, Mitchell CM, Cramer EM, Lowman BC, et al. Psychosocial factors in the irritable bowel syndrome. A multivariate study of patients and nonpatients with irritable bowel syndrome. Gastroenterology. 1988;95:701–708
  23. Whitehead WE, Bosmajian L, Zonderman AB, Costa PT, Schuster MM. Symptoms of psychologic distress associated with irritable bowel syndrome. Comparison of community and medical clinic samples. Gastroenterology. 1988;95:709–714
  24. Locke GR, Weaver AL, Melton LJ, Talley NJ. Psychosocial factors are linked to functional gastrointestinal disorders: a population based nested case-control study. Am J Gastroenterol. 2004;99:350–357
  25. Weinryb RM, Osterberg E, Blomquist L, Hultcrantz R, Krakau I, Asberg M. Psychological factors in irritable bowel syndrome: a population-based study of patients, non-patients and controls. Scand J Gastroenterol. 2003;38:503–510
  26. Halder SL, McBeth J, Silman AJ, Thompson DG, Macfarlane GJ. Psychosocial risk factors for the onset of abdominal pain. Results from a large prospective population-based study. Int J Epidemiol. 2002;31:1219–1225discussion 25–6
  27. Koloski NA, Talley NJ, Boyce PM. Does psychological distress modulate functional gastrointestinal symptoms and health care seeking? A prospective, community Cohort study. Am J Gastroenterol. 2003;98:789–797
  28. Romans S, Belaise C, Martin J, Morris E, Raffi A. Childhood abuse and later medical disorders in women. An epidemiological study. Psychother Psychosom. 2002;71:141–150
  29. Koloski NA, Talley NJ, Boyce PM. A history of abuse in community subjects with irritable bowel syndrome and functional dyspepsia: the role of other psychosocial variables. Digestion. 2005;72:86–96
  30. Perona M, Benasayag R, Perello A, Santos J, Zarate N, Zarate P, et al. Prevalence of functional gastrointestinal disorders in women who report domestic violence to the police. Clin Gastroenterol Hepatol. 2005;3:436–441
  31. Hobbis IC, Turpin G, Read NW. A re-examination of the relationship between abuse experience and functional bowel disorders. Scand J Gastroenterol. 2002;37:423–430
  32. Blanchard EB, Keefer L, Lackner JM, Galovski TE, Krasner S, Sykes MA. The role of childhood abuse in Axis I and Axis II psychiatric disorders and medical disorders of unknown origin among irritable bowel syndrome patients. J Psychosom Res. 2004;56:431–436
  33. Salmon P, Skaife K, Rhodes J. Abuse, dissociation, and somatisation in irritable bowel syndrome: towards an explanatory model. J Behav Med. 2003;26:1–18
  34. Creed F, Guthrie E, Ratcliffe J, Fernandes L, Rigby C, Tomenson B, et al. Reported sexual abuse predicts impaired functioning but a good response to psychological treatments in patients with severe irritable bowel syndrome. Psychosom Med. 2005;67:490–499
  35. North CS, Downs D, Clouse RE, Alrakawi A, Dokucu ME, Cox J, et al. The presentation of irritable bowel syndrome in the context of somatisation disorder. Clin Gastroenterol Hepatol. 2004;2:787–795
  36. Spiegel BM, Kanwal F, Naliboff B, Mayer E. The impact of somatisation on the use of gastrointestinal health-care resources in patients with irritable bowel syndrome. Am J Gastroenterol. 2005;100:2262–2273
  37. Lackner JM, Gudleski GD, Blanchard EB. Beyond abuse: the association among parenting style, abdominal pain, and somatisation in IBS patients. Behav Res Ther. 2004;42:41–56
  38. Levy RL, Whitehead WE, Von Korff MR, Feld AD. Intergenerational transmission of gastrointestinal illness behaviour. Am J Gastroenterol. 2000;95:451–456
  39. Attree EA, Dancey CP, Keeling D, Wilson C. Cognitive function in people with chronic illness: inflammatory bowel disease and irritable bowel syndrome. Appl Neuropsychol. 2003;10:96–104
  40. Lackner JM, Quigley BM, Blanchard EB. Depression and abdominal pain in IBS patients: the mediating role of catastrophizing. Psychosom Med. 2004;66:435–441
  41. Lackner JM, Gurtman MB. Pain catastrophizing and interpersonal problems: a circumplex analysis of the communal coping model. Pain. 2004;110:597–604
  42. Lackner JM, Quigley BM. Pain catastrophizing mediates the relationship between worry and pain suffering in patients with irritable bowel syndrome. Behav Res Ther. 2005;43:943–957
  43. Jones MP, Wessinger S, Crowell MD. Coping strategies and interpersonal support in patients with irritable bowel syndrome and inflammatory bowel disease. Clin Gastroenterol Hepatol. 2006;4:474–481
  44. Drossman DA, Toner BB, Whitehead WE, Diamant NE, Dalton CB, Duncan S, et al. Cognitive-behavioural therapy versus education and desipramine versus placebo for moderate to severe functional bowel disorders. Gastroenterology. 2003;125:19–31
  45. Camilleri M, Coulie B, Tack JF. Visceral hypersensitivity: facts, speculations, and challenges. Gut. 2001;48:125–131
  46. Bouin M, Plourde V, Boivin M, Riberdy M, Lupien F, Laganiere M, et al. Rectal distention testing in patients with irritable bowel syndrome: sensitivity, specificity, and predictive values of pain sensory thresholds. Gastroenterology. 2002;122:1771–1777
  47. Simrén M, Månsson A, Langkilde AM, Svedlund J, Abrahamsson H, Bengtsson U, et al. Food-related gastrointestinal symptoms in the irritable bowel syndrome. Digestion. 2001;63:108–115
  48. 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
  49. Simrén M, Abrahamsson H, Björnsson ES. Lipid-induced colonic hypersensitivity in the irritable bowel syndrome (IBS): The role of bowel habit, gender and psychological factors. Clin Gastroenterol Hepatol 2007; in press.
  50. Caldarella MP, Milano A, Laterza F, Sacco F, Balatsinou C, Lapenna D, et al. Visceral sensitivity and symptoms in patients with constipation- or diarrhea-predominant irritable bowel syndrome (IBS): effect of a low-fat intraduodenal infusion. Am J Gastroenterol. 2005;100:383–389
  51. Distrutti E, Hauer SK, Fiorucci S, Pensi MO, Morelli A. Intraduodenal lipids increase perception of rectal distension in IBS patients. Gastroenterology. 2000;118(Suppl 2):A138
  52. Simrén M, Agerforz P, Björnsson ES, Abrahamsson H. Nutrient-dependent enhancement of rectal sensitivity in irritable bowel syndrome (IBS). Neurogastroenterol Motil 2007; in press.
  53. Simrén M, Ringström G, Björnsson ES, Abrahamsson H. Treatment with hypnotherapy reduces the sensory and motor component of the gastrocolonic response in irritable bowel syndrome. Psychosom Med. 2004;66:233–238
  54. Simrén M, Simms L, D'Souza D, Abrahamsson H, Björnsson ES. Lipid-induced colonic hypersensitivity in irritable bowel syndrome: the role of 5HT3-receptors. Aliment Pharmacol Ther. 2003;17:279–287
  55. Dobie DJ, Kivlahan DR, Maynard C, Bush KR, Davis TM, Bradley KA. Posttraumatic stress disorder in female veterans: association with self-reported health problems and functional impairment. Arch Intern Med. 2004;164:394–400
  56. Dickhaus B, Mayer EA, Firooz N, Stains J, Conde F, Olivas TI, et al. Irritable bowel syndrome patients show enhanced modulation of visceral perception by auditory stress. Am J Gastroenterol. 2003;98:135–143
  57. 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
  58. Posserud I, Agerforz P, Ekman R, Bjornsson ES, Abrahamsson H, Simren M. Altered visceral perceptual and neuroendocrine response in patients with irritable bowel syndrome during mental stress. Gut. 2004;53:1102–1108
  59. Elsenbruch S, Lovallo WR, Orr WC. Psychological and physiological responses to postprandial mental stress in women with the irritable bowel syndrome. Psychosom Med. 2001;63:805–813
  60. Dunphy RC, Bridgewater L, Price DD, Robinson ME, Zeilman CJ, Verne GN. Visceral and cutaneous hypersensitivity in Persian Gulf war veterans with chronic gastrointestinal symptoms. Pain. 2003;102:79–85
  61. Awad RA, Camacho S, Martin J, Rios N. Rectal sensation, pelvic floor function and symptom severity in Hispanic population with irritable bowel syndrome with constipation. Colorectal Dis. 2006;8:488–493
  62. Kuiken SD, Lindeboom R, Tytgat GN, Boeckxstaens GE. Relationship between symptoms and hypersensitivity to rectal distension in patients with irritable bowel syndrome. Aliment Pharmacol Ther. 2005;22:157–164
  63. Lee KJ, Kim JH, Cho SW. Relationship of underlying abnormalities in rectal sensitivity and compliance to distension with symptoms in irritable bowel syndrome. Digestion. 2006;73:133–141
  64. Verne GN, Sen A, Price DD. Intrarectal lidocaine is an effective treatment for abdominal pain associated with diarrhea-predominant irritable bowel syndrome. J Pain. 2005;6:493–496
  65. Zar S, Benson MJ, Kumar D. Rectal afferent hypersensitivity and compliance in irritable bowel syndrome: differences between diarrhoea-predominant and constipation- predominant subgroups. Eur J Gastroenterol Hepatol. 2006;18:151–158
  66. Zuo XL, Li YQ, Shi L, Lv GP, Kuang RG, Lu XF, et al. Visceral hypersensitivity following cold water intake in subjects with irritable bowel syndrome. J Gastroenterol. 2006;41:311–317
  67. Simrén M, Abrahamsson H, Svedlund J, Björnsson ES. Quality of life in patients with irritable bowel syndrome seen in referral centers versus primary care: the impact of gender and predominant bowel pattern. Scand J Gastroenterol. 2001;36:545–552
  68. Simrén M, Svedlund J, Posserud I, Bjornsson ES, Abrahamsson H. Health- related quality of life in patients attending a gastroenterology outpatient clinic: functional disorders versus organic diseases. Clin Gastroenterol Hepatol. 2006;4:187–195
  69. Houghton LA, Calvert EL, Jackson NA, Cooper P, Whorwell P. Visceral sensation and emotion: a study using hypnosis. Gut. 2002;51:701–704
  70. Lea R, Houghton LA, Calvert EL, Larder S, Gonsalkorale WM, Whelan V, et al. Gut-focused hypnotherapy normalizes disordered rectal sensitivity in patients with irritable bowel syndrome. Aliment Pharmacol Ther. 2003;17:635–642
  71. Guthrie E, Barlow J, Fernandes L, Ratcliffe J, Read N, Thompson DG, et al. Changes in tolerance to rectal distension correlate with changes in psychological state in patients with severe irritable bowel syndrome. Psychosom Med. 2004;66:578–582
  72. Ringel Y, Whitehead WE, Toner BB, Diamant NE, Hu Y, Jia H, et al. Sexual and physical abuse are not associated with rectal hypersensitivity in patients with irritable bowel syndrome. Gut. 2004;53:838–842
  73. Corsetti M, Ogliari C, Marino B, Basilisco G. Perceptual sensitivity and response bias during rectal distension in patients with irritable bowel syndrome. Neurogastroenterol Motil. 2005;17:541–547
  74. Chang L, Mayer EA, Labus JS, Schmulson M, Lee OY, Olivas TI, et al. Effect of sex on perception of rectosigmoid stimuli in irritable bowel syndrome. Am J Physiol Regul Integr Comp Physiol. 2006;291:R277–R284
  75. Kim HS, Rhee PL, Park J, Lee JH, Kim YH, Kim JJ, et al. Gender-related differences in visceral perception in health and irritable bowel syndrome. J Gastroenterol Hepatol. 2006;21:468–473
  76. Houghton LA, Lea R, Jackson N, Whorwell PJ. The menstrual cycle affects rectal sensitivity in patients with irritable bowel syndrome but not healthy volunteers. Gut. 2002;50:471–474
  77. Ji Y, Murphy AZ, Traub RJ. Estrogen modulates the visceromotor reflex and responses of spinal dorsal horn neurons to colorectal stimulation in the rat. J Neurosci. 2003;23:3908–3915
  78. Bassotti G, Sietchiping-Nzepa F, De Roberto G, Chistolini F, Morelli A. Colonic regular contractile frequency patterns in irritable bowel syndrome: the ‘spastic colon’ revisited. Eur J Gastroenterol Hepatol. 2004;16:613–617
  79. Clemens CH, Samsom M, Van Berge Henegouwen GP, Smout AJ. Abnormalities of left colonic motility in ambulant nonconstipated patients with irritable bowel syndrome. Dig Dis Sci. 2003;48:74–82
  80. Portincasa P, Moschetta A, Baldassarre G, Altomare DF, Palasciano G. Pan-enteric dysmotility, impaired quality of life and alexithymia in a large group of patients meeting ROME II criteria for irritable bowel syndrome. World J Gastroenterol. 2003;9:2293–2299
  81. Kwan CL, Davis KD, Mikula K, Diamant NE. Abnormal rectal motor physiology in patients with irritable bowel syndrome. Neurogastroenterol Motil. 2004;16:251–263
  82. Posserud I, Ersryd A, Simrén M. Functional findings in irritable bowel syndrome. World J Gastroenterol. 2006;12:2814–2822
  83. 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
  84. Clemens CH, Samsom M, Roelofs JM, van Berge Henegouwen GP, Smout AJ. Association between pain episodes and high amplitude propagated pressure waves in patients with irritable bowel syndrome. Am J Gastroenterol. 2003;98:1838–1843
  85. Corsetti M, Cesana B, Bhoori S, Basilisco G. Rectal hyperreactivity to distention in patients with irritable bowel syndrome: role of distention rate. Clin Gastroenterol Hepatol. 2004;2:49–56
  86. Di Stefano M, Miceli E, Missanelli A, Mazzocchi S, Corazza G. Meal-induced recto-sigmoid tone modification: a low-caloric meal accurately separates functional and organic gastrointestinal disease patients. Gut. 2006;55:1409–1414
  87. Ng C, Danta M, Prott G, Badcock CA, Kellow J, Malcolm A. Modulatory influences on antegrade and retrograde tonic reflexes in the colon and rectum. Am J Physiol Gastrointest Liver Physiol. 2004;287:G962–G966
  88. Ng C, Danta M, Kellow J, Badcock CA, Hansen R, Malcolm A. Attenuation of the colorectal tonic reflex in female patients with irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol. 2005;289:G489–G494
  89. Fukudo S, Kanazawa M, Kano M, Sagami Y, Endo Y, Utsumi A, et al. Exaggerated motility of the descending colon with repetitive distention of the sigmoid colon in patients with irritable bowel syndrome. J Gastroenterol. 2002;37(Suppl 14):145–150
  90. Dunlop SP, Coleman NS, Blackshaw E, Perkins AC, Singh G, Marsden CA, et al. Abnormalities of 5-hydroxytryptamine metabolism in irritable bowel syndrome. Clin Gastroenterol Hepatol. 2005;3:349–357
  91. Chang L, Lee OY, Naliboff B, Schmulson M, Mayer EA. Sensation of bloating and visible abdominal distension in patients with irritable bowel syndrome. Am J Gastroenterol. 2001;96:3341–3347
  92. Lewis MJ, Reilly B, Houghton LA, Whorwell PJ. Ambulatory abdominal inductance plethysmography: towards objective assessment of abdominal distension in irritable bowel syndrome. Gut. 2001;48:216–220
  93. Houghton LA, Whorwell PJ. Towards a better understanding of abdominal bloating and distension in functional gastrointestinal disorders. Neurogastroenterol Motil. 2005;17:500–511
  94. Serra J, Azpiroz F, Malagelada JR. Impaired transit and tolerance of intestinal gas in the irritable bowel syndrome. Gut. 2001;48:14–19
  95. Serra J, Azpiroz F, Malagelada JR. Gastric distension and duodenal lipid infusion modulate intestinal gas transit and tolerance in humans. Am J Gastroenterol. 2002;97:2225–2230
  96. Serra J, Salvioli B, Azpiroz F, Malagelada JR. Lipid-induced intestinal gas retention in irritable bowel syndrome. Gastroenterology. 2002;123:700–706
  97. Dainese R, Serra J, Azpiroz F, Malagelada JR. Effects of physical activity on intestinal gas transit and evacuation in healthy subjects. Am J Med. 2004;116:536–539
  98. Dainese R, Serra J, Azpiroz F, Malagelada JR. Influence of body posture on intestinal transit of gas. Gut. 2003;52:971–974
  99. Caldarella MP, Serra J, Azpiroz F, Malagelada JR. Prokinetic effects in patients with intestinal gas retention. Gastroenterology. 2002;122:1748–1755
  100. Coleski R, Owyang C, Hasler WL. Modulation of Intestinal Gas Dynamics in Healthy Human Volunteers by the 5-HT Receptor Agonist Tegaserod. Am J Gastroenterol. 2006;101:1858–1865
  101. Salvioli B, Serra J, Azpiroz F, Lorenzo C, Aguade S, Castell J, et al. Origin of gas retention and symptoms in patients with bloating. Gastroenterology. 2005;128:574–579
  102. 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
  103. Passos MC, Serra J, Azpiroz F, Tremolaterra F, Malagelada JR. Impaired reflex control of intestinal gas transit in patients with abdominal bloating. Gut. 2005;54:344–348
  104. Tremolaterra F, Villoria A, Azpiroz F, Serra J, Aguade S, Malagelada JR. Impaired viscerosomatic reflexes and abdominal-wall dystony associated with bloating. Gastroenterology. 2006;130:1062–1068
  105. Hobson AR, Aziz Q. Brain imaging and functional gastrointestinal disorders: has it helped our understanding?. Gut. 2004;53:1198–1206
  106. Verne GN, Himes NC, Robinson ME, Gopinath KS, Briggs RW, Crosson B, et al. Central representation of visceral and cutaneous hypersensitivity in the irritable bowel syndrome. Pain. 2003;103:99–110
  107. Yuan YZ, Tao RJ, Xu B, Sun J, Chen KM, Miao F, et al. Functional brain imaging in irritable bowel syndrome with rectal balloon-distention by using fMRI. World J Gastroenterol. 2003;9:1356–1360
  108. Chang L, Berman S, Mayer EA, Suyenobu B, Derbyshire S, Naliboff B, et al. Brain responses to visceral and somatic stimuli in patients with irritable bowel syndrome with and without fibromyalgia. Am J Gastroenterol. 2003;98:1354–1361
  109. Naliboff BD, Derbyshire SW, Munakata J, Berman S, Mandelkern M, Chang L. Cerebral activation in patients with irritable bowel syndrome and control subjects during rectosigmoid stimulation. Psychosom Med. 2001;63:365–375
  110. Bonaz B, Baciu M, Papillon E, Bost R, Gueddah N, Le Bas JF, et al. Central processing of rectal pain in patients with irritable bowel syndrome: an fMRI study. Am J Gastroenterol. 2002;97:654–661
  111. Mayer EA, Berman S, Suyenobu B, Labus J, Mandelkern MA, Naliboff BD, et al. Differences in brain responses to visceral pain between patients with irritable bowel syndrome and ulcerative colitis. Pain. 2005;115:398–409
  112. Wilder-Smith CH, Schindler D, Lovblad K, Redmond SM, Nirkko A. Brain functional magnetic resonance imaging of rectal pain and activation of endogenous inhibitory mechanisms in irritable bowel syndrome patient subgroups and healthy controls. Gut. 2004;53:1595–1601
  113. Naliboff BD, Berman S, Suyenobu B, Labus JS, Chang L, Stains J, et al. Longitudinal change in perceptual and brain activation response to visceral stimuli in irritable bowel syndrome patients. Gastroenterology. 2006;131:352–365
  114. Aziz Q. Visceral hypersensitivity: fact or fiction. Gastroenterology. 2006;131:661–664
  115. Drossman DA. Brain imaging and its implications for studying centrally targeted treatments in irritable bowel syndrome: a primer for gastroenterologists. Gut. 2005;54:569–573
  116. Naliboff BD, Berman S, Chang L, Derbyshire SW, Suyenobu B, Vogt BA, et al. Sex-related differences in IBS patients: central processing of visceral stimuli. Gastroenterology. 2003;124:1738–1747
  117. Drossman DA, Ringel Y, Vogt BA, Leserman J, Lin W, Smith JK, et al. Alterations of brain activity associated with resolution of emotional distress and pain in a case of severe irritable bowel syndrome. Gastroenterology. 2003;124:754–761
  118. Morgan V, Pickens D, Gautam S, Kessler R, Mertz H. Amitriptyline reduces rectal pain related activation of the anterior cingulate cortex in patients with irritable bowel syndrome. Gut. 2005;54:601–607
  119. van Orshoven NP, Andriesse GI, van Schelven LJ, Smout AJ, Akkermans LM, Oey PL. Subtle involvement of the parasympathetic nervous system in patients with irritable bowel syndrome. Clin Auton Res. 2006;16:33–39
  120. Gupta V, Sheffield D, Verne GN. Evidence for autonomic dysregulation in the irritable bowel syndrome. Dig Dis Sci. 2002;47:1716–1722
  121. Heitkemper M, Jarrett M, Cain KC, Burr R, Levy RL, Feld A, et al. Autonomic nervous system function in women with irritable bowel syndrome. Dig Dis Sci. 2001;46:1276–1284
  122. Thompson JJ, Elsenbruch S, Harnish MJ, Orr WC. Autonomic functioning during REM sleep differentiates IBS symptom subgroups. Am J Gastroenterol. 2002;97:3147–3153
  123. Waring WS, Chui M, Japp A, Nicol EF, Ford MJ. Autonomic cardiovascular responses are impaired in women with irritable bowel syndrome. J Clin Gastroenterol. 2004;38:658–663
  124. Jarrett ME, Burr RL, Cain KC, Hertig V, Weisman P, Heitkemper MM. Anxiety and depression are related to autonomic nervous system function in women with irritable bowel syndrome. Dig Dis Sci. 2003;48:386–394
  125. Elsenbruch S, Orr WC. Diarrhea- and constipation-predominant IBS patients differ in postprandial autonomic and cortisol responses. Am J Gastroenterol. 2001;96:460–466
  126. Tillisch K, Mayer EA, Labus JS, Stains J, Chang L, Naliboff BD. Sex specific alterations in autonomic function among patients with irritable bowel syndrome. Gut. 2005;54:1396–1401
  127. Bohmelt AH, Nater UM, Franke S, Hellhammer DH, Ehlert U. Basal and stimulated hypothalamic-pituitary-adrenal axis activity in patients with functional gastrointestinal disorders and healthy controls. Psychosom Med. 2005;67:288–294
  128. Dinan TG, Quigley EM, Ahmed SM, Scully P, O’Brien S, O’Mahony L, et al. Hypothalamic-pituitary-gut axis dysregulation in irritable bowel syndrome: plasma cytokines as a potential biomarker?. Gastroenterology. 2006;130:304–311
  129. Chang L, Neuroendocrine . Neuroimmune Markers in IBS: Pathophysiological Role or Epiphenomenon?. Gastroenterology. 2006;130:596–600
  130. Sagami Y, Shimada Y, Tayama J, Nomura T, Satake M, Endo Y, et al. 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
  131. Tache Y. Corticotropin releasing factor receptor antagonists: potential future therapy in gastroenterology?. Gut. 2004;53:919–921
  132. Tache Y, Million M, Nelson AG, Lamy C, Wang L. Role of corticotropin- releasing factor pathways in stress-related alterations of colonic motor function and viscerosensibility in female rodents. Gend Med. 2005;2:146–154
  133. Simrén M, Stotzer PO, Sjovall H, Abrahamsson H, Bjornsson ES. Abnormal levels of neuropeptide Y and peptide YY in the colon in irritable bowel syndrome. Eur J Gastroenterol Hepatol. 2003;15:55–62
  134. Palsson OS, Morteau O, Bozymski EM, Woosley JT, Sartor RB, Davies MJ, et al. Elevated vasoactive intestinal peptide concentrations in patients with irritable bowel syndrome. Dig Dis Sci. 2004;49:1236–1243
  135. Simrén M, Björnsson ES, Abrahamsson H. High interdigestive and postprandial motilin levels in patients with the irritable bowel syndrome. Neurogastroenterol Motil. 2005;17:51–57
  136. Van Der Veek PP, Biemond I, Masclee AA. Proximal and distal gut hormone secretion in irritable bowel syndrome. Scand J Gastroenterol. 2006;41:170–177
  137. Ehlert U, Nater UM, Bohmelt A. High and low unstimulated salivary cortisol levels correspond to different symptoms of functional gastrointestinal disorders. J Psychosom Res. 2005;59:7–10
  138. Mawe GM, Coates MD, Moses PL. Review article: intestinal serotonin signalling in irritable bowel syndrome. Aliment Pharmacol Ther. 2006;23:1067–1076
  139. Atkinson W, Lockhart S, Whorwell PJ, Keevil B, Houghton LA. Altered 5-hydroxytryptamine signalling in patients with constipation- and diarrhea-predominant irritable bowel syndrome. Gastroenterology. 2006;130:34–43
  140. 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
  141. Coates MD, Mahoney CR, Linden DR, Sampson JE, Chen J, Blaszyk H, et al. Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome. Gastroenterology. 2004;126:1657–1664
  142. 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
  143. Dunlop SP, Jenkins D, Spiller RC. Distinctive clinical, psychological, and histological features of postinfective irritable bowel syndrome. Am J Gastroenterol. 2003;98:1578–1583
  144. Wang LH, Fang XC, Pan GZ. Bacillary dysentery as a causative factor of irritable bowel syndrome and its pathogenesis. Gut. 2004;53:1096–1101
  145. Agazzi A, De Ponti F, De Giorgio R, Candura SM, Anselmi L, Cervio E, et al. Review of the implications of dietary tryptophan intake in patients with irritable bowel syndrome and psychiatric disorders. Dig Liver Dis. 2003;35:590–595
  146. Tornblom H, Abrahamsson H, Barbara G, Hellstrom PM, Lindberg G, Nyhlin H, et al. Inflammation as a cause of functional bowel disorders. Scand J Gastroenterol. 2005;40:1140–1148
  147. Simrén M, Axelsson J, Gillberg R, Abrahamsson H, Svedlund J, Björnsson E. Quality of life in inflammatory bowel disease in remission: The impact of IBS-like symptoms and associated psychological factors. Am J Gastroenterol. 2002;97:389–396
  148. Parry SD, Stansfield R, Jelley D, Gregory W, Phillips E, Barton JR, et al. Is irritable bowel syndrome more common in patients presenting with bacterial gastroenteritis? A community-based, case-control study. Am J Gastroenterol. 2003;98:327–331
  149. Parry SD, Stansfield R, Jelley D, Gregory W, Phillips E, Barton JR, et al. Does bacterial gastroenteritis predispose people to functional gastrointestinal disorders? A prospective, community-based, case-control study. Am J Gastroenterol. 2003;98:1970–1975
  150. Borgaonkar MR, Ford DC, Marshall JK, Churchill E, Collins SM. The incidence of irritable bowel syndrome among community subjects with previous acute enteric infection. Dig Dis Sci. 2006;51:1026–1032
  151. Ji S, Park H, Lee D, Song YK, Choi JP, Lee SI. Post-infectious irritable bowel syndrome in patients with Shigella infection. J Gastroenterol Hepatol. 2005;20:381–386
  152. Kim HS, Kim MS, Ji SW, Park H. The development of irritable bowel syndrome after Shigella infection: 3 year follow-up study. Korean J Gastroenterol. 2006;47:300–305
  153. Marshall JK, Thabane M, Garg AX, Clark W, Meddings J, Collins SM. Intestinal permeability in patients with irritable bowel syndrome after a waterborne outbreak of acute gastroenteritis in Walkerton, Ontario. Aliment Pharmacol Ther. 2004;20:1317–1322
  154. Marshall JK, Thabane M, Garg AX, Clark WF, Salvadori M, Collins SM. Incidence and epidemiology of irritable bowel syndrome after a large waterborne outbreak of bacterial dysentery. Gastroenterology. 2006;131:445–450
  155. Mearin F, Perez-Oliveras M, Perello A, Vinyet J, Ibanez A, Coderch J, et al. Dyspepsia and irritable bowel syndrome after a Salmonella gastroenteritis outbreak: one-year follow-up cohort study. Gastroenterology. 2005;129:98–104
  156. Dunlop SP, Jenkins D, Neal KR, Naesdal J, Borgaonker M, Collins SM, et al. Randomized, double-blind, placebo-controlled trial of prednisolone in post-infectious irritable bowel syndrome. Aliment Pharmacol Ther. 2003;18:77–84
  157. Spiller RC, Jenkins D, Thornley JP, Hebden JM, Wright T, Skinner M, et al. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut. 2000;47:804–811
  158. 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
  159. Bazzocchi G, Gionchetti P, Almerigi PF, Amadini C, Campieri M. Intestinal microflora and oral bacteriotherapy in irritable bowel syndrome. Dig Liver Dis. 2002;34(Suppl 2):S48–S53
  160. Maxwell PR, Rink E, Kumar D, Mendall MA. Antibiotics increase functional abdominal symptoms. Am J Gastroenterol. 2002;97:104–108
  161. 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
  162. Malinen E, Rinttila T, Kajander K, Matto J, Kassinen A, Krogius L, et al. Analysis of the fecal microbiota of irritable bowel syndrome patients and healthy controls with real-time PCR. Am J Gastroenterol. 2005;100:373–382
  163. Matto J, Maunuksela L, Kajander K, Palva A, Korpela R, Kassinen A, et al. Composition and temporal stability of gastrointestinal microbiota in irritable bowel syndrome—a longitudinal study in IBS and control subjects. FEMS Immunol Med Microbiol. 2005;43:213–222
  164. 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
  165. Pimentel M, Wallace D, Hallegua D, Chow E, Kong Y, Park S, et al. A link between irritable bowel syndrome and fibromyalgia may be related to findings on lactulose breath testing. Ann Rheum Dis. 2004;63:450–452
  166. 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
  167. Walters B, Vanner SJ. Detection of Bacterial Overgrowth in IBS Using the Lactulose H Breath Test: Comparison with C-d-Xylose and Healthy Controls. Am J Gastroenterol. 2005;100:1566–1570
  168. Camilleri M. Mechanisms in IBS: something old, something new, something borrowed. Neurogastroenterol Motil. 2005;17:311–316
  169. Dunlop SP, Hebden J, Campbell E, Naesdal J, Olbe L, Perkins AC, et al. Abnormal intestinal permeability in subgroups of diarrhea-predominant irritable bowel syndromes. Am J Gastroenterol. 2006;101:1288–1294
  170. Gwee KA, Collins SM, Read NW, Rajnakova A, Deng Y, Graham JC, et al. Increased rectal mucosal expression of interleukin 1beta in recently acquired post-infectious irritable bowel syndrome. Gut. 2003;52:523–526
  171. 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
  172. 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
  173. Simonato B, De Lazzari F, Pasini G, Polato F, Giannattasio M, Gemignani C, et al. IgE binding to soluble and insoluble wheat flour proteins in atopic and non-atopic patients suffering from gastrointestinal symptoms after wheat ingestion. Clin Exp Allergy. 2001;31:1771–1778
  174. 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
  175. Zar S, Benson MJ, Kumar D. Food-Specific Serum IgG4 and IgE Titers to Common Food Antigens in Irritable Bowel Syndrome. Am J Gastroenterol. 2005;100:1550–1557
  176. Tornblom 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
  177. Chadwick VS, Chen W, Shu D, Paulus B, Bethwaite P, Tie A, et al. Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology. 2002;122:1778–1783
  178. Ohman L, Isaksson S, Lundgren A, Simren M, Sjovall 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
  179. Collins SM. A case for an immunological basis for irritable bowel syndrome. Gastroenterology. 2002;122:2078–2080
  180. Holmén N, Isaksson S, Simrén M, Sjövall H, Öhman L. CD24+CD25+ Regulatory T cells in irritable bowel syndrome patients. Neurogastroenterol Motil 2007; in press.
  181. Barbara G, Stanghellini V, De Giorgio R, Cremon C, Cottrell GS, Santini D, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology. 2004;126:693–702
  182. O'Sullivan M, Clayton N, Breslin NP, Harman I, Bountra C, McLaren A, et al. Increased mast cells in the irritable bowel syndrome. Neurogastroenterol Motil. 2000;12:449–457
  183. Park CH, Joo YE, Choi SK, Rew JS, Kim SJ, Lee MC. Activated mast cells infiltrate in close proximity to enteric nerves in diarrhea-predominant irritable bowel syndrome. J Korean Med Sci. 2003;18:204–210
  184. Park JH, Rhee PL, Kim HS, Lee JH, Kim YH, Kim JJ, et al. Mucosal mast cell counts correlate with visceral hypersensitivity in patients with diarrhea predominant irritable bowel syndrome. J Gastroenterol Hepatol. 2006;21(Pt 1):71–78
  185. Park JH, Rhee PL, Kim G, Lee JH, Kim YH, Kim JJ, et al. Enteroendocrine cell counts correlate with visceral hypersensitivity in patients with diarrhoea-predominant irritable bowel syndrome. Neurogastroenterol Motil. 2006;18:539–546
  186. Adam B, Liebregts T, Gschossmann JM, Krippner C, Scholl F, Ruwe M, et al. Severity of mucosal inflammation as a predictor for alterations of visceral sensory function in a rat model. Pain. 2006;123:179–186
  187. Zhou Q, Caudle RM, Price DD, Del Valle-Pinero AY, Verne GN. Selective up-regulation of NMDA-NRI receptor expression in myenteric plexus after TNBS induced colitis in rats. Mol Pain. 2006;2:3
  188. La JH, Kim TW, Sung TS, Kim HJ, Kim JY, Yang IS. Role of mucosal mast cells in visceral hypersensitivity in a rat model of irritable bowel syndrome. J Vet Sci. 2004;5:319–324
  189. Bercik P, Wang L, Verdu EF, Mao YK, Blennerhassett P, Khan WI, et al. Visceral hyperalgesia and intestinal dysmotility in a mouse model of postinfective gut dysfunction. Gastroenterology. 2004;127:179–187
  190. 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
  191. Ferrier L, Mazelin L, Cenac N, Desreumaux P, Janin A, Emilie D, et al. Stress- induced disruption of colonic epithelial barrier: role of interferon-gamma and myosin light chain kinase in mice. Gastroenterology. 2003;125:795–804
  192. Verdu EF, Bercik P, Verma-Gandhu M, Huang XX, Blennerhassett P, Jackson W, et al. Specific probiotic therapy attenuates antibiotic induced visceral hypersensitivity in mice. Gut. 2006;55:182–190

PII: S1590-8658(06)00581-0

doi:10.1016/j.dld.2006.10.014

Digestive and Liver Disease
Volume 39, Issue 3 , Pages 201-215, March 2007

Article Tools

* Image Usage & Resolution