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Development and validation of a biomarker for diarrhea-predominant irritable bowel syndrome in human subjects.

ABSTRACT: Diarrhea-predominant irritable bowel syndrome (IBS) is diagnosed through clinical criteria after excluding "organic" conditions, and can be precipitated by acute gastroenteritis. Cytolethal distending toxin B (CdtB) is produced by bacteria that cause acute gastroenteritis, and a post-infectious animal model demonstrates that host antibodies to CdtB cross-react with vinculin in the host gut, producing an IBS-like phenotype. Therefore, we assessed circulating anti-CdtB and anti-vinculin antibodies as biomarkers for D-IBS in human subjects. Subjects with D-IBS based on Rome criteria (n=2375) were recruited from a large-scale multicenter clinical trial for D-IBS (TARGET 3). Subjects with inflammatory bowel disease (IBD) (n=142), subjects with celiac disease (n=121), and healthy controls (n=43) were obtained for comparison. Subjects with IBD and celiac disease were recruited based on the presence of intestinal complaints and histologic confirmation of chronic inflammatory changes in the colon or small intestine. Subjects with celiac disease were also required to have an elevated tTG and biopsy. All subjects were aged between 18 and 65 years. Plasma levels of anti-CdtB and anti-vinculin antibodies were determined by ELISA, and compared between groups. Anti-CdtB titers were significantly higher in D-IBS subjects compared to IBD, healthy controls and celiac disease (P<0.001). Anti-vinculin titers were also significantly higher in IBS (P<0.001) compared to the other groups. The area-under-the-receiver operating curves (AUCs) were 0.81 and 0.62 for diagnosis of D-IBS against IBD for anti-CdtB and anti-vinculin, respectively. Both tests were less specific in differentiating IBS from celiac disease. Optimization demonstrated that for anti-CdtB (optical density?2.80) the specificity, sensitivity and likelihood ratio were 91.6%, 43.7 and 5.2, respectively, and for anti-vinculin (OD?1.68) were 83.8%, 32.6 and 2.0, respectively. These results confirm that anti-CdtB and anti-vinculin antibodies are elevated in D-IBS compared to non-IBS subjects. These biomarkers may be especially helpful in distinguishing D-IBS from IBD in the workup of chronic diarrhea.

SUBMITTER: Pimentel M

PROVIDER: S-EPMC4430499 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Development and validation of a biomarker for diarrhea-predominant irritable bowel syndrome in human subjects.

Pimentel Mark M Morales Walter W Rezaie Ali A Marsh Emily E Lembo Anthony A Mirocha James J Leffler Daniel A DA Marsh Zachary Z Weitsman Stacy S Chua Kathleen S KS Barlow Gillian M GM Bortey Enoch E Forbes William W Yu Allen A Chang Christopher C

PloS one 20150513 5

Diarrhea-predominant irritable bowel syndrome (IBS) is diagnosed through clinical criteria after excluding "organic" conditions, and can be precipitated by acute gastroenteritis. Cytolethal distending toxin B (CdtB) is produced by bacteria that cause acute gastroenteritis, and a post-infectious animal model demonstrates that host antibodies to CdtB cross-react with vinculin in the host gut, producing an IBS-like phenotype. Therefore, we assessed circulating anti-CdtB and anti-vinculin antibodies ...[more]

PMID: 25970536

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Project description:ObjectiveFructose malabsorption is a common digestive disorder in which absorption of fructose in the small intestine is impaired. An abnormality of the main intestinal fructose transporter proteins has been proposed as a cause for fructose malabsorption. However the underlying molecular mechanism for this remains unclear. In this study, we investigated whether carbohydrate response element-binding protein (ChREBP) plays a role in intestinal fructose absorption through the regulation of genes involved in fructose transport and metabolism and ion transport.MethodsWild type (WT) and Chrebp knockout (KO) mice (6 or 8 weeks old) were fed a control diet (55% starch, 15% maltodextrin 10) or high-fructose diet (HFrD, 60% fructose, 10% starch) for 3-12 days. Body weight and food intake were measured, signs of fructose malabsorption were monitored, and the expression of genes involved in fructose transport/metabolism and ion transport was evaluated. Furthermore, transient transfection and chromatin immunoprecipitation were performed to show the direct interaction between ChREBP and carbohydrate response elements in the promoter of Slc2A5, which encodes the fructose transporter GLUT5.ResultsChrebp KO mice fed the control diet maintained a constant body weight, whereas those fed a HFrD showed significant weight loss within 3-5 days. In addition, Chrebp KO mice fed the HFrD exhibited a markedly distended cecum and proximal colon containing both fluid and gas, suggesting incomplete fructose absorption. Fructose-induced increases of genes involved in fructose transport (GLUT5), fructose metabolism (fructokinase, aldolase B, triokinase, and lactate dehydrogenase), and gluconeogenesis (glucose-6-phosphatase and fructose-1,6-bisphosphatase) were observed in the intestine of WT but not of Chrebp KO mice. Moreover the Na+/H+ exchanger NHE3, which is involved in Na+ and water absorption in the intestine, was significantly decreased in HFrD-fed Chrebp KO mice. Consistent with this finding, the high-fructose diet-fed Chrebp KO mice developed severe diarrhea. Results of chromatin immunoprecipitation assays showed a direct interaction of ChREBP with the Glut5 promoter, but not the Nhe3 promoter, in the small intestine. Ectopic co-expression of ChREBP and its heterodimer partner Max-like protein X activated the Glut5 promoter in Caco-2BBE cells.ConclusionsChREBP plays a key role in the dietary fructose transport as well as conversion into lactate and glucose through direct transcriptional control of genes involved in fructose transport, fructolysis, and gluconeogenesis. Moreover, ablation of Chrebp results in a severe diarrhea in mice fed a high-fructose diet, which is associated with the insufficient induction of GLUT5 in the intestine.

Project description:Altered gut microbiota are assumed to be involved in the pathogenesis of irritable bowel syndrome (IBS). However, gut microbiota alterations reported in different studies are divergent and sometimes even contradictory. To better elucidate the relationship between altered gut microbiota and IBS, we characterized fecal microbiota of diarrhea-predominant IBS (IBS-D) patients and further explored the effect of rifaximin on gut microbiota using bacterial 16S rRNA gene-targeted pyrosequencing. In our study, IBS-D patients defined by Rome III criteria and age-and-gender matched healthy controls (HC) were enrolled to investigate the fecal microbiota alterations. These IBS-D patients were then treated with rifaximin for 2 weeks and followed up for 10 weeks. Fecal microbiota alterations, small intestine bacterial overgrowth (SIBO) and gastrointestinal (GI) symptoms of IBS-D patients were analyzed before and after treatment. Our results showed fecal microbiota richness but not diversity was decreased in IBS-D patients as compared to HC and there were alterations of fecal microbiota at different taxonomy levels. The abundant phyla Firmicutes was significantly decreased and Bacteroidetes was increased in IBS-D patients. Moreover, the alterations of predominant fermenting bacteria such as Bacteroidales and Clostridiales might be involved in the pathophysiology of IBS-D. In addition, rifaximin was effective in terms of SIBO eradication and even GI symptoms of IBS-D patients achieved at least 10-week improvement after treatment. Furthermore, rifaximin induced alterations of some special bacteria rather than affected the overall composition of microbiota in IBS-D patients. Meanwhile, a potential decrease in propanoate and butanoate metabolism was found in these IBS-D patients after rifaximin treatment. Taken together, there were alterations of gut microbiota in IBS-D patients as compared to HC. Rifaximin could relieve GI symptoms, modify gut microbiota in IBS-D patients and eradicate SIBO in those patients with SIBO, suggesting an additional therapeutic mechanism of rifaximin in the treatment of IBS-D. Our findings of compositional gut microbiota alterations in IBS-D and the effect of rifaximin on the gut microbiota implied that altered gut microbiota were associated with the pathogenesis of IBS.

Project description:OBJECTIVES: Despite a documented clinical need, no patient reported outcome (PRO) symptom measure meeting current regulatory requirements for clinically relevant end points is available for the evaluation of treatment benefit in diarrhea-predominant IBS (IBS-D). METHODS: Patients (N=113) with IBS-D participated in five study phases: (1) eight concept elicitation focus groups (N=34), from which a 17-item IBS-D Daily Symptom Diary and four-item IBS-D Symptom Event Log (Diary and Event Log) were developed; (2) one-on-one cognitive interviews (N=11) to assess the instrument's comprehensiveness, understandability, appropriateness, and readability; (3) four data triangulation focus groups (N=32) to confirm the concepts elicited; (4) two hybrid (concept elicitation and cognitive interview) focus groups (N=16); and (5) two iterative sets of one-on-one cognitive interviews (N=20) to further clarify the symptoms of IBS-D and debrief a revised seven-item Diary and four-item Event Log. RESULTS: Of thirty-six concepts initially identified, 22 were excluded because they were not saturated, not clinically relevant, not critical symptoms of IBS-D, considered upper GI symptoms, or too broad or vaguely defined. The remaining concepts were diarrhea, immediate need (urgency), bloating/pressure, frequency of bowel movements, cramps, abdominal/stomach pain, gas, completely emptied bowels/incomplete evacuation, accidents, bubbling in intestines (bowel sounds), rectal burning, stool consistency, rectal spasm, and pain while wiping. The final instrument included a daily diary with separate items for abdominal and stomach pain and an event log with four items completed after each bowel movement as follows: (1) a record of the bowel movement/event and an assessment of (2) severity of immediacy of need/bowel urgency, (3) incomplete evacuation, and (4) stool consistency (evaluated using the newly developed Astellas Stool Form Scale). Based on rounds of interviews and clinical input, items considered secondary or nonspecific to IBS-D (rectal burning, bubbling in intestines, spasms, and pain while wiping) were excluded. CONCLUSIONS: The IBS-D Symptom Diary and Event Log represent a rigorously developed PRO instrument for the measurement of the IBS-D symptom experience from the perspective of the patient. Its content validity has been supported, and future work should evaluate the instrument's psychometric properties.

Project description:BackgroundOral serum-derived bovine immunoglobulin (SBI)/protein isolate is a medical food intended to manage chronic diarrhea. It has been shown to improve pain and diarrhea in adults with diarrhea-predominant irritable bowel syndrome (d-IBS).AimTo determine if SBI can improve symptoms in children with d-IBS.MethodsWe performed a randomized, double-blind, placebo-controlled, pilot study (NCT02609529) to evaluate the effectiveness of SBI in children 8-18 years with d-IBS. We recorded stool number, abdominal pain, and stool form in all patients for 1 week and then assigned the patients at a ratio of 2:1 to treatment with SBI 5 g BID or placebo for 3 weeks. The patients and their parents completed the Pediatric Quality of Life Inventory™ for Gastrointestinal Symptoms (PedsQOL) and the Pediatric Functional Disability Index (FDI). In addition, complete blood counts and serum chemistries were recorded at the start and end of treatment to evaluate safety.ResultsFifteen patients (nine SBI, six placebo) completed the study. Both SBI and placebo groups reported nonstatistical reductions in stool frequency per week. The SBI group showed a significant reduction in stool frequency at weeks 1 and 2 but not at the end of treatment. The SBI group also demonstrated statistical improvements in abdominal pain and stool form by 3 weeks. The placebo group did not achieve similar improvements. The overall FDI and PedsQOL scores, as well as PedsQOL subscale scores for pain, discomfort when eating, diarrhea, worry about stomach aches, and communication, improved significantly in the SBI group, but not in the placebo group. No serious adverse events occurred. Serum chemistries and hemograms were normal at baseline and at the end of study in all patients.ConclusionIn this single-center, exploratory pilot study, we demonstrated that 10 g SBI per day was safe in children with d-IBS and improved symptoms. Larger studies, with longer treatment duration, seem warranted based on these initial positive results.

Project description:In this study, we aim to evaluate the efficacy and safety of acupoint catgut embedding for the treatment of diarrhea-predominant irritable bowel syndrome and constipation-predominant irritable bowel syndrome. We searched seven online databases to collect studies published up to Feb 29th, 2020. Study quality of each included article was evaluated by the Cochrane Collaboration Risk of Bias Tool. Systematic reviews and meta-analyses were conducted based on the Cochrane systematic review method by using RevMan 5.3 software. Among the included trials, acupoint catgut embedding alone or plus oral western medicine or plus other acupoint-based therapies, or plus oral traditional Chinese medicine were the main therapies in the experimental groups. Interventions in control groups mainly include oral western medicine alone, other acupoint-based therapies alone, or other acupoint-based therapies alone. Primary outcomes in this study include recovery rate, accumulative marked effective rate, accumulative effective rate, and recurrence rate. Finally, 30 trials involving 1889 participants were included. The results of systematic reviews and meta-analyses show that acupoint catgut embedding alone or plus oral western medicine or plus other acupoint-based therapy or plus oral traditional Chinese medicine was significantly better compared with using oral western medicine alone in terms of efficacy for IBS-C and IBS-D. In addition, acupoint catgut embedding alone or plus oral western medicine or plus other acupoint-based therapy or plus oral traditional Chinese medicine could improve the effective rate and decrease the recurrence rate for IBS-D compared with using oral western medicine, other acupoint-based therapies, or oral traditional Chinese medicine alone. Adverse events of acupoint catgut embedding include local induration, redness, swelling, and itchiness, but they were all mild and disappeared swiftly with ordinary local interventions. There is an urgent need for RCTs of high quality and large sample size and with longer treatment duration and follow-up periods of acupoint catgut embedding for IBS.

Dataset Information

Development and validation of a biomarker for diarrhea-predominant irritable bowel syndrome in human subjects.

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Development and validation of a biomarker for diarrhea-predominant irritable bowel syndrome in human subjects.

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