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      THE RECEPTOR TGR5 MEDIATES THE PROKINETIC ACTIONS OF INTESTINAL BILE ACIDS AND IS REQUIRED FOR NORMAL DEFECATION IN MICE

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          Abstract

          Background & Aims:

          Abnormal delivery of bile acids (BAs) to the colon, due to 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, and 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 TGR5 localization 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 t gr5-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 t gr5-tg mice, compared to 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; TGR5 deficiency causes constipation in mice. These findings might mediate the long-known laxative properties of BAs; TGR5 might be a therapeutic target for digestive diseases.

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          Author and article information

          Journal
          0374630
          3841
          Gastroenterology
          Gastroenterology
          Gastroenterology
          0016-5085
          1528-0012
          6 July 2018
          03 October 2012
          January 2013
          20 July 2018
          : 144
          : 1
          : 145-154
          Affiliations
          [1 ]Department of Surgery, University of California, San Francisco,513 Parnassus Avenue, San Francisco, CA 94143, USA
          [2 ]Department of Anatomy and Neuroscience, University of Melbourne, Parkville, VIC 3010, Australia
          [3 ]Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, School of Life Sciences, EPFL, SV, Station 15, CH-1015 Lausanne, Switzerland
          [4 ]Department of Physiology, P.O. Box 980551 Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298, USA
          [5 ]Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville,VIC 3052, Australia
          Author notes
          Correspondence: Nigel Bunnett, B.Sc., Ph.D., Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville, VIC 3052, Australia. Tel: Office - +61 3 9903 9136; Mobile - +61 407 392 619. Facsimile: +61 3 9903 9581. Nigel.Bunnett@ 123456Monash.edu ; Carlos U. Corvera, M.D., Department of Surgery, University of California, San Francisco, VA Medical Center, Surgical Service (112), 4150 Clement Street, San Francisco, CA, 94121. Tel: Office - 415 221 4180 ext. 4019. Carlos.corvera@ 123456ucsfmedctr.org .
          Article
          PMC6054127 PMC6054127 6054127 nihpa412488
          10.1053/j.gastro.2012.09.055
          6054127
          23041323
          d3edf28a-449a-403a-a675-2b9fa4b2130c
          History
          Categories
          Article

          diarrhea,intestine,mouse model,digestion
          diarrhea, intestine, mouse model, digestion

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