Original ResearchBasic and Translational—Alimentary TractThe Receptor TGR5 Mediates the Prokinetic Actions of Intestinal Bile Acids and Is Required for Normal Defecation in Mice
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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 1A–C). 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.).