Constipation-predominant Irritable Bowel Syndrome Research Articles

Methanogens, Methane and Gastrointestinal Motility

Anaerobic fermentation of the undigested polysaccharide fraction of carbohydrates produces hydrogen in the intestine which is the substrate for methane production by intestinal methanogens. Hydrogen and methane are excreted in the flatus and in breath giving the opportunity to indirectly measure their production using breath testing. Although methane is detected in 30%-50% of the healthy adult population worldwide, its production has been epidemiologically and clinically associated with constipation related diseases, like constipation predominant irritable bowel syndrome and chronic constipation. While a causative relation is not proven yet, there is strong evidence from animal studies that methane delays intestinal transit, possibly acting as a neuromuscular transmitter. This evidence is further supported by the universal finding that methane production (measured by breath test) is associated with delayed transit time in clinical studies. There is also preliminary evidence that antibiotic reduction of methanogens (as evidenced by reduced methane production) predicts the clinical response in terms of symptomatic improvement in patients with constipation predominant irritable bowel syndrome. However, we have not identified yet the mechanism of action of methane on intestinal motility, and since methane production does not account for all constipation associated cases, there is need for high quality clinical trials to examine methane as a biomarker for the diagnosis or as a biomarker that predicts antibiotic treatment response in patients with constipation related disorders.

Effect of linaclotide in irritable bowel syndrome with constipation (IBS‐C): a systematic review and meta‐analysis

Treatment options for constipation-predominant irritable bowel syndrome (IBS-C) are limited. While linaclotide improved IBS-C symptoms in randomized controlled trials (RCTs), results vary among studies and the magnitude of benefit is unclear. Two investigators independently extracted data on study participants, methods and outcomes (i.e., symptoms, quality of life, and adverse events) from eligible articles i.e., RCTs comparing linaclotide with placebo in adult patients with IBS-C with a follow-up of 12 weeks or longer. The grading of recommendations assessment, development and evaluation (GRADE) methodology was used to rate the quality of evidence. Of 182 identified citations, three RCTs enrolling 1773 patients met the inclusion criteria. Compared with placebo, fewer patients on linaclotide failed to achieve responses i.e., FDA endpoint (1604 patients, risk ratio [RR] = 0.80; 95%CI 0.76-0.85), adequate IBS symptom relief (1773 patients, RR = 0.73; 95%CI 0.65-0.82), and clinically meaningful improvement in IBS-QOL (1659 patients, RR = 0.78; 95%CI 0.72-0.86). The incidence of diarrhea leading to discontinuation of treatment was higher for linaclotide (1773 patients, RR = 14.75; 95%CI 4.04-53.81). The quality of evidence was rated as moderate for FDA endpoint and adequate relief response, high for diarrhea, and low for IBS-QOL. Generalizability may be limited by the study population (i.e., predominantly white female patients), lack of data regarding prior therapy, and availability of few RCTs. The number of patients is insufficient to identify rare adverse events. Linaclotide is moderately effective in improving symptoms of IBS-C with diarrhea being the major side effect. Further studies are needed to evaluate the long-term efficacy and safety of linaclotide for IBS-C.

Characteristics of functional bowel disorder patients: a cross‐sectional survey using the Rome III criteria

There is some evidence that, despite attempts to classify them separately, functional bowel disorders are not distinct entities and that such divisions are artificial. To examine this issue in a large cohort of secondary care patients. Consecutive, unselected adults with gastrointestinal (GI) symptoms attending out-patient clinics at two hospitals in Hamilton, Ontario were recruited. Demographic data, symptoms and presence of anxiety, depression or somatisation were collected prospectively. We used validated questionnaires, including the Rome III questionnaire, with patients categorised as having irritable bowel syndrome (IBS), functional diarrhoea or chronic idiopathic constipation (CIC). We compared data between these disorders, and measured degree of overlap between them by suspending their mutual exclusivity. Of 3656 patients providing complete lower GI symptom data, 1551 (42.4%) met criteria for a functional bowel disorder. Diarrhoea-predominant IBS (IBS-D) patients were younger, and more were female, met criteria for anxiety, and reported somatisation-type behaviour, compared with functional diarrhoea. Only loose, mushy or watery stools were more common in functional diarrhoea. When mutual exclusivity was suspended, overlap occurred in 27.6%. Constipation-predominant IBS (IBS-C) patients were younger, and more were female, had never married, reported anxiety type symptoms and exhibited somatisation-type behaviour. One in five CIC patients reported abdominal pain or discomfort. All constipation symptoms were more common in IBS-C. When the mutual exclusivity was suspended, overlap occurred in 18.1%. There were significant differences in demographics between individuals with functional bowel disorders. Despite this, the Rome III classification system falls short of describing unique entities.

Alpha-2-adrenergic receptor gene polymorphism in Turkish population with irritable bowel syndrome

Irritable bowel syndrome is a multifactorial functional gastrointestinal disorder affecting more than 10% of world population. Genetic component in pathophysiology of irritable bowel syndrome is still unknown. The aim of this study was to examine the potential impact of C-1291G polymorphism in α2-adrenergic receptor gene promoter region in the etiology of the disease. This prospective case-control study included 100 irritable bowel syndrome patients and 100 healthy controls adjusted for sex and age. The subjects were genotyped by using polymerase chain reaction amplification of the promoterregion of α2-adrenergic receptor gene. Allele and genotype frequencies were compared in patient and control groups. The study was approved by the University ethics committee. The frequency of C allele was 72% and 75%, G allele was 28% and 25% in patient and control groups, respectively (p>0.05). We found that the frequencies of C1291C, C1291G, and G1291G genotypes were 50, 44, and 6%, respectively, in the patient group and 51, 48, and 1%, respectively, in the control group (p>0.05). The subgroup analysis of patients revealed that 70 patients were constipation-predominant, 27 patients were alternating diarrhea and constipation, and 3 patients were diarrhea-predominant irritable bowel syndrome. No significant association was observed between α2-adrenergic receptor gene C-1291G polymorphism and irritable bowel syndrome in Turkish population. The high number of constipation predominant irritable bowel syndrome and very low number of diarrhea predominant irritable bowel syndrome patients might be the reason for statistical non-significance since α2-adrenergic receptor gene is found to be responsible for mediating intestinal antisecretory action and probably is involved in the pathogenesis of diarrhea predominant irritable bowel syndrome. Further investigations are needed.

Homeopathy for treatment of irritable bowel syndrome

Irritable bowel syndrome (IBS) is a common, chronic disorder that leads to decreased health-related quality of life and work productivity. Evidence-based treatment guidelines have not been able to give guidance on the effects of homeopathic treatment for IBS because no systematic reviews have been carried out to assess the effectiveness of homeopathic treatment for IBS. Two types of homeopathic treatment were evaluated in this systematic review. In clinical homeopathy a specific remedy is prescribed for a specific condition. This differs from individualised homeopathic treatment, where a homeopathic remedy based on a person's individual symptoms is prescribed after a detailed consultation. To assess the effectiveness and safety of homeopathic treatment for treating IBS. We searched MEDLINE, the Cochrane Central Register of Controlled Trials, EMBASE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Allied and Complementary Medicine Database (AMED), Cochrane IBD/FBD Group Specialised Register, Cochrane Complementary Medicine Field Specialised Register and the database of the Homeopathic Library (Hom-inform) from inception to February 2013. Randomised controlled trials (RCTs), cohort and case-control studies that compared homeopathic treatment with placebo, other control treatments, or usual care, in adults with IBS were considered for inclusion. Two authors independently assessed the risk of bias and extracted data. The primary outcome was global improvement in IBS. The overall quality of the evidence supporting this outcome was assessed using the GRADE criteria. We calculated the mean difference (MD) and 95% confidence interval (CI) for continuous outcomes and the risk ratio (RR) and 95% CI for dichotomous outcomes. Three RCTs (213 participants) were included. No cohort or case-control studies were identified. Two studies published in 1976 and 1979 compared clinical homeopathy (homeopathic remedy) to placebo for constipation-predominant IBS. One study published in 1990 compared individualised homeopathic treatment (consultation plus remedy) to usual care (defined as high doses of dicyclomine hydrochloride, faecal bulking agents and diet sheets asking the patient to take a high fibre diet) for the treatment of IBS in female patients. Due to the low quality of reporting in the included studies the risk of bias in all three studies was unclear on most criteria and high for some criteria. A meta-analysis of two small studies (129 participants with constipation-predominant IBS) found a statistically significant difference in global improvement between the homeopathic remedy asafoetida and placebo at a short-term follow-up of two weeks. Seventy-three per cent of patients in the homeopathy group improved compared to 45% of placebo patients (RR 1.61, 95% CI 1.18 to 2.18). There was no statistically significant difference in global improvement between the homeopathic remedies asafoetida plus nux vomica and placebo. Sixty-eight per cent of patients in the homeopathy group improved compared to 52% of placebo patients (1 study, N = 42, RR 1.31, 95% CI 0.80 to 2.15). GRADE analyses rated the overall quality of the evidence for the outcome global improvement as very low due to high or unknown risk of bias, short-term follow-up and sparse data. There was no statistically significant difference found between individualised homeopathic treatment and usual care (1 RCT, N = 20) for the outcome "feeling unwell", where the participant scored how "unwell" they felt before, and after treatment (MD 0.03; 95% CI -3.16 to 3.22). None of the included studies reported on adverse events. A pooled analysis of two small studies suggests a possible benefit for clinical homeopathy, using the remedy asafoetida, over placebo for people with constipation-predominant IBS. These results should be interpreted with caution due to the low quality of reporting in these trials, high or unknown risk of bias, short-term follow-up, and sparse data. One small study found no statistically difference between individualised homeopathy and usual care (defined as high doses of dicyclomine hydrochloride, faecal bulking agents and diet sheets advising a high fibre diet). No conclusions can be drawn from this study due to the low number of participants and the high risk of bias in this trial. In addition, it is likely that usual care has changed since this trial was conducted. Further high quality, adequately powered RCTs are required to assess the efficacy and safety of clinical and individualised homeopathy compared to placebo or usual care.

Autonomic functioning in irritable bowel syndrome measured by heart rate variability: A meta‐analysis

To analyze autonomic functioning which presented as the high frequency (HF) component of heart rate variability, a measurement of vagal tone, and the ratio of low frequency (LF) to HF (LF : HF), an indicator of sympathovagal balance in irritable bowel syndrome (IBS) patients. We identified relevant studies by performing a literature search of MEDLINE, EMBASE and the ISI Web of Knowledge to 31 March 2013. Pooled effect sizes with 95% confidence interval (CI) were calculated using a random effects model. Between-study heterogeneity was assessed using the Q test and I(2) statistic. In all, 11 articles including 392 IBS patients and 263 controls met the inclusion criteria of the analysis. IBS patients had lower HF band power (Hedges's g = -0.38, 95% CI -0.68 to -0.09) than the controls (I(2) = 63.6%, P = 0.003). Moreover, IBS patients showed a higher LF : HF (Hedges's g = 0.43, 95% CI 0.13-0.74), with no significant heterogeneity. A subgroup analysis of the HF index according to the recording time yielded different results for the IBS patients and controls. Additionally, constipation-predominant IBS (IBS-C) patients had decreased HF band power, whereas no significant difference was found in LF : HF. Impaired parasympathetic functioning and abnormal sympathovagal balance may be involved in the pathogenesis of IBS. Vagal dysfunction is more obvious in the IBS-C subgroup.

Pilot trial: Pregabalin on colonic sensorimotor functions in irritable bowel syndrome

In prior studies, pregabalin reduced rectal or colonic pain in patients with irritable bowel syndrome and healthy adults, suggesting reduction of afferent function. To assess effects of pregabalin on colonic compliance, sensory and motor functions in patients with constipation-predominant irritable bowel syndrome. In a pilot, double-blind, placebo-controlled, parallel-group study, we tested oral pregabalin, 200mg, in 18 patients with constipation-predominant irritable bowel syndrome. With a barostatically controlled polyethylene balloon in the left colon, we assessed sensation thresholds and colonic compliance using ascending method of limits, sensation ratings over 4 levels of distension, fasting and postprandial colonic tone and phasic motility. Analysis of covariance (adjusted for the corresponding pre-drug response) was used to compare placebo and pregabalin. After 45% participants completed studies, we conducted an interim analysis to assess the conditional power to detect pre-specified treatment effects given the observed variation and treatment group differences based on the planned sample size for the trial. Pregabalin did not significantly affect colonic compliance, sensation thresholds, sensation ratings, fasting or postprandial tone or motility index. The study was stopped for futility to detect an effect on visceral pain with the planned design and sample size. Pregabalin, 200mg, might not reduce distension-related colonic pain in constipation-predominant irritable bowel syndrome patients.

Effect of Linaclotide in Improving Quality of Life in Patients with Constipation-predominant Irritable Bowel Syndrome (IBS-C)

Purpose: Constipation-predominant irritable bowel syndrome (IBS-C) adversely affects quality of life of patients and has very few effective treatment options. Linaclotide, a new secretagogue approved for treatment of IBS-C by the Food and Drug Administration (FDA) may improve IBS-C symptoms according to recent randomized controlled trials (RCTs). We systematically reviewed the available evidence and conducted meta-analysis to evaluate the efficacy of linaclotide in improving IBS-related quality of life (IBS-QOL) in patients with IBS-C. Methods: Data sources: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, SCO-PUS, CINAHL, and gastroenterology conference proceedings and abstracts. Study eligibility criteria: RCTs comparing linaclotide with placebo in adult patients with study period of at least 12 weeks, and that measured improvement in QOL using the IBS-QOL measure. IBS-QOL is a validated, self-reported, 34-item scale that is specific to IBS and can be used assess the impact of IBS and its treatments. Clinically meaningful improvement in IBS-QOL is defined as improvement in IBS-QOL score of >14 points. Study appraisal and synthesis methods: Articles were independently assessed by two investigators. Standardized forms were used for blinded duplicate data extraction of study participants, quality, methods, and clinically meaningful improvement in quality of life (IBS-QOL) with treatment. Results: Of 110 identified citations, three RCTs enrolling 1,659 patients met the inclusion criteria. The meta-analysis revealed that in comparison to placebo, fewer patients on linaclotide failed to achieve clinically meaningful improvement in quality of life (IBS-QOL; 3 RCTs; 1,659 patients; RR=0.78; 95% CI 0.72-0.86). Limitations: Fewer studies were available at the time of this analysis. All the included studies were performed in tertiary care settings with highly selective patient cohorts and may not be generalizable. Some inconsistencies and missing data were noted. Conclusion: Linaclotide appears to be moderately effective in improving IBS-C QOL in patients with IBS-C.Figure

Effect of Linaclotide in Treatment of Constipation-predominant Irritable Bowel Syndrome (IBS-C): A Systematic Review and Meta-analysis

Purpose: Constipation-predominant irritable bowel syndrome (IBS-C) is a commonly encountered condition in clinical setting with few effective treatment options. Recent randomized controlled trials (RCTs) suggest that linaclotide may improve IBS-C symptoms. We systematically reviewed the available evidence and conducted meta-analysis to evaluate the efficacy and safety of linaclotide in treatment of IBS-C. Methods: We searched the following database resources: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, SCOPUS, CINAHL, and gastroenterology conference proceedings and abstracts. Study eligibility criteria: RCTs comparing linaclotide with placebo in adult patients with study period of at least 12 weeks. Study appraisal and synthesis methods: Articles were independently assessed by two investigators. Standardized forms were used for blinded duplicate data extraction of study participants, quality, methods, and outcomes, including adequate relief of IBS-C symptoms and adverse events from eligible articles. Results: Of 110 identified citations, 3 RCTs enrolling 1,773 patients met the inclusion criteria. The metaanalysis revealed that in comparison to placebo, fewer patients on linaclotide failed to achieve adequate IBS symptom relief (RR=0.73; 95% CI 0.65-0.82). Diarrhea was the most common side effect. Incidence of diarrhea leading to discontinuation of treatment was significantly higher in the linaclotide group (3 RCTs; 1,773 patients; RR=14.75; 95% CI 4.04-53.81). The quality of evidence was moderate for adequate relief response and high for significant diarrhea. Conclusion: Few studies were available at the time of this analysis. All the included studies involved highly selective patient population, which limits generalizability. Conclusions: Linaclotide appears to be moderately effective in providing adequate relief of IBS-C symptoms with diarrhea being the major side effect. Further studies are needed to evaluate efficacy and safety of linaclotide with longer treatment periods.Figure

Genetic variants in CDC42 and NXPH1 as susceptibility factors for constipation and diarrhoea predominant irritable bowel syndrome

ObjectiveThe complex genetic aetiology underlying irritable bowel syndrome (IBS) needs to be assessed in large-scale genetic studies. Two independent IBS cohorts were genotyped to assess whether genetic variability in immune,...

Comparison of Manning, Rome I, II, and III, and Asian diagnostic criteria: Report of the Multicentric Indian Irritable Bowel Syndrome (MIIBS) study

Attempts to diagnose and subtype irritable bowel syndrome (IBS) by symptom-based criteria have limitations, as these are developed in the West and might not be applicable in other populations. This study aimed to compare different criteria for diagnosing and subtyping of IBS in India. Manning's and the Rome I, II, and III criteria as well as the Asian criteria were applied to 1,618 patients (from 17 centers in India) with chronic lower gastrointestinal (GI) symptoms with no alarm features and negative investigations. Of 1,618 patients (aged 37.5 [SD 12.6] years; 71.2% male), 1,476 (91.2%), 1,098 (67.9%), 649 (40.1%), 849 (52.5%), and 1,206 (74.5%) fulfilled Manning's, Rome I, II, and III, and the Asian criteria, respectively. The most common reason for not fulfilling the criteria was absence of the following symptoms: "more frequent stools with onset of pain," "loose stool with onset of pain," "relief of pain with passage of stool," "other abdominal discomfort/bloating," and, in a minority, not meeting the duration criterion of 3 months/12 weeks. By stool frequency, constipation-predominant IBS (<3 stools/week) was diagnosed in 319 (19.7%), diarrhea-predominant IBS (>3 stools/day) in 43 (2.7%), and unclassified in 1,256 (77.6%). By Bristol stool form, constipation, diarrhea, and unclassified were diagnosed in 655 (40.5%), 709 (43.8%), and 254 (15.7%) patients, respectively. By their own perception, 462 (28.6%), 541 (33.4%), and 452 (27.9%) patients reported constipation-predominant, diarrhea-predominant, and alternating types, respectively. By Manning's and the Asian criteria, a diagnosis of IBS was made frequently among Indian patients with chronic functional lower GI symptoms with no alarm features; the Rome II criteria gave the lowest yield. By the stool frequency criteria, a majority of patients had unclassified pattern, unlike by the stool form and patients' perception of their symptoms.

PP075-MON DIFFERENCES IN SYMPTOM SEVERITY, QUALITY OF LIFE AND BOWEL HABITS BETWEEN MALE AND FEMALE IBS PATIENTS

Rationale: Irritable bowel syndrome (IBS) is thought to be more prevalent in women than in men. We investigated the relationship between gender and symptomatology and quality of life (QoL) in patients with IBS. Methods: 174 patients who fulfilled the Rome III criteria for IBS were included. Symptom severity was scored using the IBS Symptom Severity Score (IBS-SSS). The IBS-QoL was used to assess quality of life. Stool frequency and stool consistency were determined using the Bristol stool scale. Results: Patient’s age ranged from 19 to 66 years (mean 37.4) and the male to female ratio was 1:2.6. According to the Rome-III-criteria, 31% were diagnosed as diarrheapredominant IBS (IBS-D), 12.6% as constipation-predominant (IBS-C) and 1.1% as unsubtyped (IBS-U). The most common subtype was the mixed-type (IBS-M) with 55.2%. The gender composition between the four subtypes differed significantly (p < 0.05). 16.7% of the women were classified as constipationpredominant IBS, whereas only one man had IBS-C. The severity of IBS (scored with the IBS-SSS questionnaire) did not differ between men and women. The number of days with pain was significantly higher in women than in men (p < 0.05). The overall score of the IBS-QoL as well as 7 of the 8 subscales were significantly lower in women than in men (p < 0.05), only the subscale ‘interference with activity’ showed no gender differences. Stool frequency differed significantly between men and women (p < 0.001). Men reported a stool frequency of 11.8 times a week (SD: 9.5), women 7.8 (SD: 4.9). Conclusion: There are significant gender differences in patients with IBS regarding the symptoms (e.g. IBS-C occurred almost exclusively in females) as well as in QoL. Our data showed that although women did not report higher severity of IBS, their QoL was significantly worse than the QoL of male IBS patients.

Prosequence switching: An effective strategy to produce biologically active E. coli heat-stable enterotoxin STh

Enterotoxigenic Escherichia coli (ETEC) infections account for the majority of cases of acute secretory diarrhea. The causative agents are enterotoxins secreted by ETEC, among them is the heat-stable enterotoxin, STh. STh is a 19-amino acid peptide containing three disulfide bonds that stimulates fluid secretion in the bowel by binding to the receptor domain of intestinal guanylyl cyclase C (GC-C). Since GC-C agonists have pharmacologic potential for diagnosis and treatment of disorders such as constipation-predominant irritable bowel syndrome (IBS-C), chronic constipation, and colorectal carcinoma, it is crucial to develop methods for the large-scale production of STh and related peptides. Here, we present a strategy for recombinant expression of STh that relies on the use of the prosequence of human uroguanylin to support proper folding and disulfide bond formation. The chimeric protein CysCys-STh consisting of the propeptide of uroguanylin as N-terminus and the STh peptide as C-terminus was expressed in E. coli, and an efficient purification protocol was developed. Trypsin digestion of this protein released the enterotoxin which could be obtained in high purity. NMR and mass spectrometry confirmed the identity and homogeneity of the toxin, and its biological activity was confirmed by a cell-based in vivo assay. The expression scheme introduced here represents a cost-efficient and scalable way of STh production.

Linaclotide: new mechanisms and new promise for treatment in constipation and irritable bowel syndrome

Chronic idiopathic constipation (CIC) and irritable bowel syndrome (IBS) are functional disorders of the lower gastrointestinal tract. Their prevalence in the general population is between 5% and 20%. Both disorders are chronic, with a relapsing and remitting natural history. The medical treatment of both conditions is unsatisfactory at present, and they represent a huge burden to the health service. Linaclotide is a first-in-class minimally adsorbed, 14-amino-acid peptide agonist of guanylate cyclase C. The drug acts on the intestinal enterocyte. As a consequence of this, intestinal fluid secretion is increased and intestinal transit is accelerated. The efficacy of linaclotide has been studied in both CIC and constipation-predominant IBS (IBS-C). Randomized controlled trials consistently demonstrate that the drug is effective in the treatment of CIC and IBS-C, across a wide range of continuous and dichotomous endpoints. The number needed to treat with linaclotide to prevent one patient with CIC or IBS-C failing to respond to therapy is between 5 and 8 in studies that have reported these data. Overall, in the majority of trials, total numbers of adverse events have been no more frequent with linaclotide, but rates of diarrhoea have been consistently higher. While the drug is clearly effective in the treatment of CIC, there are other evidence-based therapies available, and head-to-head efficacy and cost-effectiveness studies are therefore required to further delineate the role of linaclotide in the treatment of the condition. In IBS-C there are no other licensed therapies available, and linaclotide therefore represents a novel treatment with great promise.

Role of Lubiprostone on Gastrointestinal Motility

Lubiprostone is a bicyclic fatty acid derivative of prostaglandin E1 used for the treatment of chronic idiopathic constipation and constipation predominant irritable bowel syndrome.1,2 The underlying mechanism of lubiprostone is stimulation of electrogenic chloride secretion by activating chloride channel type-2 (ClC-2)3 and cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels4 in the apical membrane of the intestinal epithelial cells. Activation of ClC-2 channels or CFTR chloride channels in intestinal epithelial cells produces an active secretion of chloride ions from cells into the intestinal lumen followed by a passive secretion of electrolytes and water which increases the liquidity of the luminal contents. The luminal distension by increased intestinal fluid promotes the gastrointestinal (GI) tract motility which in turn increases the intestinal and colonic transit. Lubiprostone also has an effect on cystic fibrosis tissue by independent CFTR chloride channels.5 Lubiprostone induced chloride secretory action is mediated by direct activation of ClC-2 channels as well as stimulation of these channels through activating prostaglandin receptors. Besides, lubiprostone enhances and stimulates contraction in colonic as well as gastric muscles through prostaglandin E receptors (EP1 or EP4),6 suggesting the modulatory effects of lubiprostone on GI motility through the activation of prostaglandin receptors. In this issue of Journal of Neurogastroenterology and Motility, Chan and Mashimo7 investigated the effects of lubiprostone on intestinal smooth muscle contractions and pyloric sphincter tones from murine. They found that lubiprostone increased electrical field stimulation-induced contractions of intestinal circular smooth muscles and pyloric sphincter basal tone but not intestinal longitudinal smooth muscles. The excitatory effects of lubiprostone on intestinal circular smooth muscle and pyloric sphincter basal tone were blocked by EP1 antagonist. They speculated that lubiprostone can change the GI motility by prostaglandin receptor activation and the excitatory action of lubiprostone may be another mechanism for the increased intestinal transit and the delayed gastric emptying by lubiprostone.8 Although this study provides that lubiprostone has a role as a prokinetic agent in GI tract, the underlying mechanisms of modulating contractions were not evaluated. Many cells of GI tract express E-type prostanoid receptors including smooth muscle, neuron, macrophage and interstitial cells of Cajal that contribute to modulation of GI motility.9-11 Therefore, to evaluate the clinical effects of lubiprostone for modulating GI motility, further basic studies should be carried out to find underlying mechanisms.

Pathogenic effect of intestinal immune dysfunction on irritable bowel syndrome in mouse model

Objective To investigate the role of intestinal immune dysfunction in the pathogenesis of irritable bowel syndrome(IBS) and to study the effects of Clostridium butylicum on the regulation of intestinal immune disorders.Methods A total of 50 male 6-week-old C57BL/6 mice were randomly divided into three groups,including the experimental group (n =20),the control group (n =20) and the Clostridium butylicum group(n =10).A mouse model of constipation-predominant IBS (C-IBS) was established by perfusing sodium butyrate solution(200 μl,concentration of 500 mmol/L) into the mouse colon twice a day for three consecutive days.The mice in control group were intrarectally perfused with normal saline enema (200 μl).Two hours before the perfusion of sodium butyrate into colon,the mice in Clostridium butylicum group were given Clostridium butylicum 500 μl(viable cell concentration of 1×109 CFU/ml) by oral gavage once a day for six days.The colorectal distention test(CRD) was carried out for evaluation of clinical parameters.HE staining of intestinal tissue section was performed for histopathological assessment of colonic mucosal inflammation.Intestinal intraepithelial lymphocytes (IELs) and lamina propria mononuclear cells (LPMCs) were isolated and analyzed by flow cytometry to evaluate the correlation between IBS and intestinal immune dysfunction/abnormal activation of intestinal immune cells in mouse model of C-IBS,and to assess the regulatory effects of Clostridium butylicum on the intestinal immune disorder.Results (1) Compared with the control group,the mice in experimental group showed a significant change in physiological parameters,histological structure of colon,inflammatory cells infiltration and low-grade inflammatory state.There was a significant increase in scores of CRD and a decrease in lowest sensory threshold (t=8.926 and t=6.103,both P＜0.001) ; (2) There was a decrease in the numbers of DC in IELs (t =2.878 and t =3.086,both P＜0.05),but an increase in the numbers of macrophage (t=3.191,P＜0.05) and the memory T cells in mice with IBS (t=3.071,P＜0.05) as compared with that in control group; (3)DCs were decreased (t=2.880 and t=2.664,both P＜0.05),but memory T cells were increased (t =3.732 and 2.682,P＜0.01 and P＜0.05) in the LPMCs of mice in experimental group; (4)There was no significant difference in the physiological index between the mice in control group and the Clostridium butylicum group.Levels of memory T cells,macrophages and DCs in the IELs were close to the normal level (6 d,t =1.103,0.0213,0.418,all P＞0.05),and levels of macrophages and DCs in the LPMCs of mice in the Clostridium butylicum group were also similar to that in the control group (6 d,t =0.782,0.347,both P＞0.05) ; (5) Compared with the mice in experimental group,the level of memory T cells in LPMCs of mice treated with Clostridium butylicum was dramatically declined (6 d,t=2.346,P=0.0470,P＜0.05),however,which was still higher than that of mice in control group (6 d,t =2.233,P =0.0476,P＜0.05).The intestinal immune function was restored to normal level with Clostridium butylicum intervention.Conclusion The pathophysiologic mechanism of IBS might be closely related to the abnormal activation of intestinal immune cellsand disordered functional state in the intestinal mucosa.Clostridium butylicum could regulate the intestinal immune homeostasis and restore the physiological function of gastrointestinal tract. Key words: C-IBS; Visceral hypersensitivity; Immune system dysfunction; Low-grade inflammatory state; Clostridium butylicum

Expression of the nociceptin/orphanin FQ receptor in the intestinal mucosa of IBS patients

Nociceptin/orphanin FQ (N/OFQ) and the N/OFQ peptide (NOP) receptor play important roles in regulating gastrointestinal function. To assess whether the NOP receptor is implicated in the etiopathogenesis of irritable bowel syndrome (IBS), we measured the levels of NOP receptor mRNA and protein in the jejunal and colonic tissues of healthy subjects and patients with diarrhea-predominant IBS (D-IBS) and constipation-predominant IBS (C-IBS). Mucosal biopsies were obtained from the jejunum and colon of patients diagnosed with D-IBS and C-IBS by the Rome III criteria and from healthy control subjects. The expression of NOP receptor mRNA was measured quantitatively using quantitative PCR (qPCR) and NOP protein expression was assayed immunohistochemically using a rabbit monoclonal antibody to OFQ. NOP receptor mRNA was detected in the jejunum and colon of healthy subjects and was more highly expressed in the jejunum than in the colon. Expression was lower in the jejunum and colon of patients with D-IBS; however, it was similar in patients with C-IBS and healthy subjects. The numbers of OFQ-positive cells in the jejunum and colon were similar among the three groups. The NOP receptor may be involved in the regulation of intestinal movement in healthy individuals. Its involvement in the pathophysiology of IBS may depend on whether the IBS is constipation- or diarrhea-predominant.

A Case of Esophageal Pseudomembranes

290 Question: A 36-year-old woman presented for evaluation of chronic retrosternal burning. She continued to have daily symptoms despite using omeprazole twice daily. She rarely had liquid regurgitation. Otherwise, she denied dysphagia, odynophagia, and weight loss. Her medical history was notable for migraine headaches and constipationpredominant irritable bowel syndrome. Aside from omeprazole, the only other medication used was an oral contraceptive. Because of the persistence of her symptoms despite high-dose proton pump inhibitor treatment, she underwent testing. Esophageal manometry demonstrated frequent failed peristalsis, but normal basal lower esophageal sphincter pressure and normal relaxation. A subsequent barium esophagram demonstrated normal esophageal peristalsis. An esophagogastroduodenoscopy revealed large white membranes adjacent to normal appearing mucosa in both the mid and distal esophagus (Figure A). Esophageal biopsies were obtained (Figure B). What is the most likely diagnosis? Look on page 489 for the answer and see the GASTROENTEROLOGY web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI.

PTU-134 Prevalance and Investigational Pathways of Patients with Constipation Predominant Irritable Bowel Syndrome

IntroductionOur group has previously described investigational pathways that occur in patients with diarrhoea predominant irritable bowel syndrome (IBS-D). Currently, there is a paucity of work undertaken in either primary or...

Effects of electroacupuncture on plasma CGRP and SP expression in rats of constipation-predominant irritable bowel syndrome

Objective To observe effects of electro-acupuncture on the expression of calcitonin gene-related peptide (CGRP) and substance P (SP) in constipation-predominant IBS rats,and to discuss the mechanism of IBS's acupuncture treatment.Methods To set WISTAR adult rats as the object and to establish models of irritable bowel syndrome rats.The experiment rats were randomly divided into a normal group,a model group,a EA Shangjuxu group and a EA Dachangshu group.The Shangjuxu group and Dachangshu group were bounded and given EA,once daily,for a total of seven times.Model group was bounded but not treatedwith EA,the normal group was done nothing.After the treatment,5ml of inferior vena blood was got inanesthesia state.The value of plasma CGRP and SP in rats' plasma were measued with Elisa.Results Compared with the normal control group,CGRP and SP content[(52.62± 15.05)pg/ml,(27.10±5.03) pg/ml] in IBS model group was obviously increased,the difference was statistically significant (P＜ 0.01,P＜ 0.01) ; the changes of plasma CGRP content [(37.82± 15.34)pg/ml,(38.93± 12.05)pg/ml] and SP content[(19.62± 5.68) pg/ml,(18.90± 5.07)pg/ml] were not obvious in EA Shangjuxu group and EA Dachangshu group (P＞0.05,P＞0.05).Compared with IBS model group,the content of plasma CGRP and SP was significantly descend in EA Shangjuxu group and EA Dachangshu group (P＜0.05,P＜0.05,P＜0.01,P＜0.01).The concentration of CGRP and SP in EA Shangjuxu group and EA Dachangshu group had no significant difference(P＞0.05,P＞0.05).Conclusion Electroacupuncture could treat IBS through regulating CGRP and SP in IBS rats. Key words: Electro-acupuncture; Irritable bowel syndrome; Calcitonin gene-related peptide; Substance P