Alosetron retards small bowel and overall colonic transit in diarrhea-predominant irritable bowel syndrome (D-IBS)

Genetic variations in metabolism of endocannabinoids and in CNR1 (gene for cannabinoid 1 receptor) are associated with symptom phenotype, colonic transit, and left colon motility in irritable bowel syndrome (IBS). Our aim was to evaluate associations between two variations in CNR1 genotype (rs806378 and [AAT]n triplets) with symptom phenotype, small bowel and colonic transit, and rectal sensations in 455 patients with IBS and 228 healthy controls. Small bowel and colonic transit were measured by scintigraphy, rectal sensation by isobaric distensions. Associations with genotype were assessed by χ2 test (symptom phenotype) and ANCOVA (quantitative traits) based on a dominant genetic model. Significant association of CNR1 rs806378 (but not CNR1 [AAT]n) genotype and symptom phenotype was observed (χ2 P = 0.028). There was significant association of CNR1 rs806378 ( P = 0.014; CC vs. CT/TT) with colonic transit in IBS-diarrhea (IBS-D) group; the TT group had the fastest colonic transit at 24 and 48 h. There was significant overall association of CNR1 rs806378 with sensation rating of gas ( P = 0.025), but not pain; the strongest associations for gas ratings were in IBS-D ( P = 0.002) and IBS-alternating ( P = 0.025) subgroups. For CNR1 (AAT)n, gene-by-phenotype interactions were observed for colonic transit at 24 ( P = 0.06) and 48 h ( P = 0.002) and gas ( P = 0.046, highest for IBS-D, P = 0.034), but not pain sensation; the strongest association with transit was in controls, not in IBS. These data support the hypothesis that cannabinoid receptors may play a role in control of colonic transit and sensation in humans and deserve further study as potential mediators or therapeutic targets in lower functional gastrointestinal disorders.

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Genetic Susceptibility to Inflammation is Associated With Colonic Transit and Other Intermediate Phenotypes in Irritable Bowel Syndrome

Gastroenterology ◽

10.1016/s0016-5085(11)60618-5 ◽

2011 ◽

Vol 140 (5) ◽

pp. S-152 ◽

Cited By ~ 2

Author(s):

Michael Camilleri ◽

Paula Carlson ◽

Sanna McKinzie ◽

Marco Zucchelli ◽

Mauro D'Amato ◽

...

Keyword(s):

Irritable Bowel Syndrome ◽

Genetic Susceptibility ◽

Colonic Transit ◽

Intermediate Phenotypes ◽

Irritable Bowel

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2103 Fecal bile acids, fecal short-chain fatty acids, and the intestinal microbiota in patients with irritable bowel syndrome (IBS) and control volunteers

Journal of Clinical and Translational Science ◽

10.1017/cts.2018.75 ◽

2018 ◽

Vol 2 (S1) ◽

pp. 12-13

Author(s):

Andrea Shin ◽

David Nelson ◽

John Wo ◽

Michael Camilleri ◽

Toyia James-Stevenson ◽

...

Keyword(s):

Irritable Bowel Syndrome ◽

Bile Acid ◽

Organic Acids ◽

Gastrointestinal Transit ◽

Fecal Microbiota ◽

Colonic Transit ◽

Short Chain ◽

Fecal Excretion ◽

Acid Excretion ◽

Irritable Bowel

OBJECTIVES/SPECIFIC AIMS: Objectives and goals of this study will be to: (1) compare fecal microbiota and fecal organic acids in irritable bowel syndrome (IBS) patients and controls and (2) investigate the association between colonic transit and fecal microbiota in IBS patients and controls. METHODS/STUDY POPULATION: We propose an investigation of fecal organic acids, colonic transit and fecal microbiota in 36 IBS patients and 18 healthy controls. The target population will be adults ages 18–65 years meeting Rome IV criteria for IBS (both diarrhea- and constipation-predominant, IBS-D and IBS-C) and asymptomatic controls. Exclusion criteria are: (a) history of microscopic colitis, inflammatory bowel disease, celiac disease, visceral cancer, chronic infectious disease, immunodeficiency, uncontrolled thyroid disease, liver disease, or elevated AST/ALT>2.0× the upper limit of normal, (b) prior radiation therapy of the abdomen or abdominal surgeries with the exception of appendectomy or cholecystectomy >6 months before study initiation, (c) ingestion of prescription, over the counter, or herbal medications affecting gastrointestinal transit or study interpretation within 6 months of study initiation for controls or within 2 days before study initiation for IBS patients, (d) pregnant females, (e) antibiotic usage within 3 months before study participation, (f) prebiotic or probiotic usage within the 2 weeks before study initiation, (g) tobacco users. Primary outcomes will be fecal bile acid excretion and profile, short-chain fatty acid excretion and profile, colonic transit, and fecal microbiota. Secondary outcomes will be stool characteristics based on responses to validated bowel diaries. Stool samples will be collected from participants during the last 2 days of a 4-day 100 g fat diet and split into 3 samples for fecal microbiota, SCFA, and bile acid analysis and frozen. Frozen aliquots will be shipped to the Metabolite Profiling Facility at Purdue University and the Mayo Clinic Department of Laboratory Medicine and Pathology for SCFA and bile acid measurements, respectively. Analysis of fecal microbiota will be performed in the research laboratory of Dr David Nelson in collaboration with bioinformatics expertise affiliated with the Nelson lab. Colonic transit time will be measured with the previously validated method using radio-opaque markers. Generalized linear models will be used as the analysis framework for comparing study endpoints among groups. RESULTS/ANTICIPATED RESULTS: This study seeks to examine the innovative concept that specific microbial signatures are associated with increased fecal excretion of organic acids to provide unique insights on a potential mechanistic link between altered intraluminal organic acids and fecal microbiota. DISCUSSION/SIGNIFICANCE OF IMPACT: Results may lead to development of targets for novel therapies and diagnostic biomarkers for IBS, emphasizing the role of the fecal metabolome.

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Uncoordinated colonic transit in patients with irritable bowel syndrome

Gastroenterology ◽

10.1016/0016-5085(95)26777-8 ◽

1995 ◽

Vol 108 (4) ◽

pp. A616

Author(s):

Y. Horikawa ◽

H. Mieno ◽

T. Ishida ◽

T. Shimatani ◽

M. Inoue ◽

...

Keyword(s):

Irritable Bowel Syndrome ◽

Colonic Transit ◽

Irritable Bowel

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Association of HLA-DQ gene with bowel transit, barrier function, and inflammation in irritable bowel syndrome with diarrhea

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00294.2012 ◽

2012 ◽

Vol 303 (11) ◽

pp. G1262-G1269 ◽

Cited By ~ 39

Author(s):

Maria I. Vazquez-Roque ◽

Michael Camilleri ◽

Thomas Smyrk ◽

Joseph A. Murray ◽

Jessica O'Neill ◽

...

Keyword(s):

Irritable Bowel Syndrome ◽

Protein Expression ◽

Mrna Expression ◽

Barrier Function ◽

Intraepithelial Lymphocytes ◽

Colonic Transit ◽

Mucosal Inflammation ◽

Hla Dq ◽

Irritable Bowel ◽

Hla Dq2

Patients with irritable bowel syndrome (IBS) with diarrhea (IBS-D) carrying human leukocyte antigen (HLA)-DQ2/8 genotypes benefit from gluten withdrawal. Our objective was to compare gastrointestinal barrier function, mucosal inflammation, and transit in nonceliac IBS-D patients and assess association with HLA-DQ2/8 status. In 45 IBS-D patients who were naive to prior exclusion of dietary gluten, we measured small bowel (SB) and colonic mucosal permeability by cumulative urinary lactulose and mannitol excretion (0–2 h for SB and 8–24 h for colon), inflammation on duodenal and rectosigmoid mucosal biopsies (obtained in 28 of 45 patients), tight junction (TJ) protein mRNA and protein expression in SB and rectosigmoid mucosa, and gastrointestinal and colonic transit by validated scintigraphy. SB mucosal biopsies were stained with hematoxylin-eosin to assess villi and intraepithelial lymphocytes, and immunohistochemistry was used to assess CD3, CD8, tryptase, and zonula occludens 1 (ZO-1); colonic biopsy intraepithelial lymphocytes were quantitated. Associations of HLA-DQ were assessed using Wilcoxon's rank-sum test. Relative to healthy control data, we observed a significant increase in SB permeability ( P < 0.001), a borderline increase in colonic permeability ( P = 0.10), and a decrease in TJ mRNA expression in rectosigmoid mucosa in IBS-D. In HLA-DQ2/8-positive patients, ZO-1 protein expression in the rectosigmoid mucosa was reduced compared with that in HLA-DQ2/8-negative patients and colonic transit was slower than in HLA-DQ2/8-negative patients. No other associations with HLA genotype were identified. There is abnormal barrier function (increased SB permeability and reduced mRNA expression of TJ proteins) in IBS-D relative to health that may be, in part, related to immunogenotype, given reduced ZO-1 protein expression in rectosigmoid mucosa in HLA-DQ2/8-positive relative to HLA-DQ2/8-negative patients.

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