000185565 001__ 185565
000185565 005__ 20181203023049.0
000185565 022__ $$a0016-5085
000185565 02470 $$2ISI$$a000312965100035
000185565 0247_ $$2doi$$a10.1053/j.gastro.2012.09.055
000185565 037__ $$aARTICLE
000185565 245__ $$aThe Receptor TGR5 Mediates the Prokinetic Actions of Intestinal Bile Acids and Is Required for Normal Defecation in Mice
000185565 269__ $$a2013
000185565 260__ $$bW B Saunders Co-Elsevier Inc$$c2013$$aPhiladelphia
000185565 300__ $$a10
000185565 336__ $$aJournal Articles
000185565 520__ $$aBACKGROUND & 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.
000185565 6531_ $$aDigestion
000185565 6531_ $$aMouse Model
000185565 6531_ $$aIntestine
000185565 6531_ $$aDiarrhea
000185565 700__ $$uUniv Calif San Francisco, Dept Surg, San Francisco, CA 94121 USA$$aAlemi, Farzad
000185565 700__ $$uUniv Melbourne, Dept Anat & Neurosci, Parkville, Vic 3052, Australia$$aPoole, Daniel P.
000185565 700__ $$uUniv Calif San Francisco, Dept Surg, San Francisco, CA 94121 USA$$aChiu, Jonathan
000185565 700__ $$0240041$$g183105$$uEcole Polytech Fed Lausanne, Sch Life Sci, Inst Bioengn, Lab Integrat & Syst Physiol, Lausanne, Switzerland$$aSchoonjans, Kristina
000185565 700__ $$uUniv Calif San Francisco, Dept Surg, San Francisco, CA 94121 USA$$aCattaruzza, Fiore
000185565 700__ $$uVirginia Commonwealth Univ, Dept Physiol, Richmond, VA USA$$aGrider, John R.
000185565 700__ $$uMonash Inst Pharmaceut Sci, Parkville, Vic 3052, Australia$$aBunnett, Nigel W.
000185565 700__ $$aCorvera, Carlos U.$$uUniv Calif San Francisco, Dept Surg, San Francisco, CA 94121 USA
000185565 773__ $$j144$$tGastroenterology$$k1$$q145-154
000185565 909C0 $$xU12735$$0252495$$pUPSCHOONJANS
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000185565 917Z8 $$x196843
000185565 937__ $$aEPFL-ARTICLE-185565
000185565 973__ $$rREVIEWED$$sPUBLISHED$$aEPFL
000185565 980__ $$aARTICLE