Gastroenterology

Gastroenterology

Volume 144, Issue 1, January 2013, Pages 145-154
Gastroenterology

Original Research
Basic and Translational—Alimentary Tract
The Receptor TGR5 Mediates the Prokinetic Actions of Intestinal Bile Acids and Is Required for Normal Defecation in Mice

https://doi.org/10.1053/j.gastro.2012.09.055Get rights and content

Background & Aims

Abnormal delivery of bile acids (BAs) to the colon as a result of disease or therapy causes constipation or diarrhea by unknown mechanisms. The G protein–coupled BA receptor TGR5 (or GPBAR1) is expressed by enteric neurons and endocrine cells, which regulate motility and secretion.

Methods

We analyzed gastrointestinal and colon transit, as well as defecation frequency and water content, in wild-type, knockout, and transgenic mice (trg5-wt, tgr5-ko, and tgr5-tg, respectively). We analyzed colon tissues for contractility, peristalsis, and transmitter release.

Results

Deoxycholic acid inhibited contractility of colonic longitudinal muscle from tgr5-wt but not tgr5-ko mice. Application of deoxycholic acid, lithocholic acid, or oleanolic acid (a selective agonist of TGR5) to the mucosa of tgr5-wt mice caused oral contraction and caudal relaxation, indicating peristalsis. BAs stimulated release of the peristaltic transmitters 5-hydroxytryptamine and calcitonin gene-related peptide; antagonists of these transmitters suppressed BA-induced peristalsis, consistent with localization of TGR5 to enterochromaffin cells and intrinsic primary afferent neurons. tgr5-ko mice did not undergo peristalsis or transmitter release in response to BAs. Mechanically induced peristalsis and transmitter release were not affected by deletion of tgr5. Whole-gut transit was 1.4-fold slower in tgr5-ko than tgr5-wt or tgr5-tg mice, whereas colonic transit was 2.2-fold faster in tgr5-tg mice. Defecation frequency was reduced 2.6-fold in tgr5-ko and increased 1.4-fold in tgr5-tg mice compared with tgr5-wt mice. Water content in stool was lower (37%) in tgr5-ko than tgr5-tg (58%) or tgr5-wt mice (62%).

Conclusions

The receptor TGR5 mediates the effects of BAs on colonic motility, and deficiency of TGR5 causes constipation in mice. These findings might mediate the long-known laxative properties of BAs, and TGR5 might be a therapeutic target for digestive diseases.

Section snippets

Mice

The generation of tgr5-knockout (ko), tgr5-transgenic (tg), and tgr5-wild type (wt) mice in a C57BL/6 background has been described.23 C57BL/6 mice were from Charles River (Wilmington, MA). Mice were killed by administration of sodium pentobarbital (200 mg  ·  kg−1 intraperitoneally) or co2 inhalation and bilateral thoracotomy. Institutional animal care and use committees approved all procedures.

Contractility

Full-thickness segments (1 cm) of proximal colon were mounted in organ baths in physiological saline

BAs Regulate Contractility of Colonic Muscle via TGR5

DCA is a TGR5 agonist21 that inhibits spontaneous phasic contractions of longitudinal muscle of the mouse proximal colon by a neurogenic, nitrergic mechanism.30 Consistent with this observation, DCA (100 μmol/L) inhibited spontaneous phasic contractions of longitudinal muscle of isolated proximal colon from tgr5-wt mice, inhibiting both the frequency of contractions and the muscle tension (fold basal [1.0]: frequency, 0.25 ± 0.05; tension, 0.78 ± 0.05) (Figure 1AC). In marked contrast, DCA had

Discussion

We have defined the mechanism underlying the established pathophysiological motor actions of BAs in the colon. Our results show that BAs activate TGR5, which is expressed by EC cells and IPANs, and release 5-HT and CGRP, the major transmitters of the afferent limb of the peristaltic reflex. In keeping with the prokinetic actions of BAs and TGR5, deletion of TGR5 delays gastrointestinal transit whereas overexpression of TGR5 accelerates colonic transit. Loss of TGR5 function results in excretion

Acknowledgements

The authors thank Louise Pontell and John Furness (University of Melbourne) for help with the histologic analyses.

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    Conflicts of interest: The authors disclose no conflicts.

    Funding Supported by the Northern California Institute for Research and Education, Veterans Health Administration (C.U.C.); National Health and Medical Research Council grants 63303, 103188 (to N.W.B.), and 454858 (to D.P.P.); National Institutes of Health grants DK39957, DK43207, DK57840 (to N.W.B.), and DK34153 (to J.R.G.); Monash University (N.W.B.); and Ecole Polytechnique Fédérale de Lausanne, Swiss National Science Foundation (SNF 31003A_125487) (K.S.).

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