Dataset Information

T-type calcium channels contribute to colonic hypersensitivity in a rat model of irritable bowel syndrome.

ABSTRACT: The symptoms of irritable bowel syndrome (IBS) include significant abdominal pain and bloating. Current treatments are empirical and often poorly efficacious, and there is a need for the development of new and efficient analgesics aimed at IBS patients. T-type calcium channels have previously been validated as a potential target to treat certain neuropathic pain pathologies. Here we report that T-type calcium channels encoded by the Ca(V)3.2 isoform are expressed in colonic nociceptive primary afferent neurons and that they contribute to the exaggerated pain perception in a butyrate-mediated rodent model of IBS. Both the selective genetic inhibition of Ca(V)3.2 channels and pharmacological blockade with calcium channel antagonists attenuates IBS-like painful symptoms. Mechanistically, butyrate acts to promote the increased insertion of Ca(V)3.2 channels into primary sensory neuron membranes, likely via a posttranslational effect. The butyrate-mediated regulation can be recapitulated with recombinant Ca(V)3.2 channels expressed in HEK cells and may provide a convenient in vitro screening system for the identification of T-type channel blockers relevant to visceral pain. These results implicate T-type calcium channels in the pathophysiology of chronic visceral pain and suggest Ca(V)3.2 as a promising target for the development of efficient analgesics for the visceral discomfort and pain associated with IBS.

SUBMITTER: Marger F

PROVIDER: S-EPMC3131334 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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T-type calcium channels contribute to colonic hypersensitivity in a rat model of irritable bowel syndrome.

Marger Fabrice F Gelot Agathe A Alloui Abdelkrim A Matricon Julien J Ferrer Juan F Sanguesa JF Barrère Christian C Pizzoccaro Anne A Muller Emilie E Nargeot Joël J Snutch Terrance P TP Eschalier Alain A Bourinet Emmanuel E Ardid Denis D

Proceedings of the National Academy of Sciences of the United States of America 20110620 27

The symptoms of irritable bowel syndrome (IBS) include significant abdominal pain and bloating. Current treatments are empirical and often poorly efficacious, and there is a need for the development of new and efficient analgesics aimed at IBS patients. T-type calcium channels have previously been validated as a potential target to treat certain neuropathic pain pathologies. Here we report that T-type calcium channels encoded by the Ca(V)3.2 isoform are expressed in colonic nociceptive primary a ...[more]

PMID: 21690417

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Project description:BackgroundThe intestinal microbiota is thought to be involved in the occurrence of inflammatory bowel disease in remission with irritable bowel syndrome (IBS)-type symptoms, but the specific distinct profile of these bacteria remains unclear. This cross-sectional study aims to investigate the fecal microbiota profiling in patients with these diseases.MethodsFecal samples from 97 subjects, including Crohn's disease patients in remission with IBS-type symptoms (CDR-IBS+) or without IBS-type symptoms (CDR-IBS-), ulcerative colitis patients in remission with IBS-type symptoms (UCR-IBS+) or without IBS-type symptoms (UCR-IBS-), IBS patients and healthy controls, were collected and applied 16S ribosomal DNA (rDNA) gene sequencing. The V4 hypervariable regions of 16S rDNA gene were amplified and sequenced by the Illumina MiSeq platform. The differences in the sample diversity index in groups were analyzed with R software.ResultsThe richness of the intestinal microbiota in the CDR-IBS group was markedly lower than those in the control and IBS groups based on the analysis of observed species and the Chao index (P < 0.05). The observed species index in the CDR-IBS+ group was higher than that in the CDR-IBS- group (median index: 254.8 vs 203, P = 0.036). No difference was found in alpha diversity between UCR patients with IBS-type symptoms and those without related symptoms. At the genus level, the number of Faecalibacterium in CDR patients with IBS-type symptoms increased significantly, while Fusobacterium decreased versus those without such symptoms (mean relative abundance of Faecalibacterium: 20.35% vs 5.18%, P < 0.05; Fusobacterium: 1.51% vs 5.2%, P < 0.05). However, compared with the UCR-IBS- group, the number of Faecalibacterium in the UCR-IBS+ group decreased, while the number of Streptococcus increased, but there was no significant difference in the genus structure. The abundance and composition of the microbiota of IBS patients were not distinct from those of healthy controls.ConclusionsThe IBS-type symptoms in CD patients in remission may be related to an increase in Faecalibacterium and a decrease in Fusobacterium. The IBS-type symptoms in UC patients in remission cannot be explained by changes in the abundance and structure of the intestinal microbiota.

Project description:IntroductionIncreased intestinal permeability is a possible pathophysiological mechanism of irritable bowel syndrome (IBS). Increased colonic epithelial permeability is associated with visceral nociception in rodents and abdominal pain severity in IBS patients. Although IBS is more common in women, most studies on IBS-associated epithelial dysfunction have largely overlooked sex as a biologic variable.MethodsMen and women with Rome III- and Rome IV-positive IBS and HCs rated GI symptoms including abdominal pain severity at baseline, 24 h prior and immediately post procedure. Epithelial function was assessed ex vivo in Ussing chambers using sigmoid colon biopsies, by monitoring short-circuit current (Isc), transepithelial electrical resistance (TEER) and mucosal permeability to FITC-dextran 4 kDa (FD4). Biopsies tight junction protein mRNA expression was assessed using RNA seq. Statistical analyses included a framework of General Linear Models and linear contrast analyses performed using R software.Results44 IBS patients (66% women, 30 years) and 19 HCs (53% women, 28 years) were enrolled. The proportion of women was not different between groups. As a group, IBS patients exhibited lower TEER compared to HCs (16.9 ± 5.5 vs. 21.5 ± 6.5 Ω/cm2, p = 0.01, FDR = 0.02), but no difference in FD4 serosal concentration or Isc (basal or stimulated). Within men, IBS had lower TEER vs. HCs, but there was no disease difference within women. Independent of diagnosis, women had 1.3-fold lower TEER concentration and 1.5-fold higher FD4 serosal concentration than men. These sex differences were also seen within HCs, although within IBS, FD4 permeability only showed a trend to be higher in women vs. men. Abdominal pain ratings and IBS severity scores were not associated with TEER or FD4 concentration.DiscussionOur study confirms prior reports that IBS patients demonstrate altered sigmoid colonic epithelial function and shows for the first time that these are independent of sex. However, sex differences in sigmoid colonic epithelial function are observed independently of disease status. Further studies are needed to delineate if intestinal permeability interacts with other factors in the pathophysiology of IBS and if these interactions differ by sex.

Dataset Information

T-type calcium channels contribute to colonic hypersensitivity in a rat model of irritable bowel syndrome.

Publications

T-type calcium channels contribute to colonic hypersensitivity in a rat model of irritable bowel syndrome.

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