title: The receptor TGR5 mediates the prokinetic actions of intestinal bile acids and is required for normal defecation in mice.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Surgery, University of California, San Francisco, California, USA.
authors.forename: Farzad
authors.initials: F
authors.lastname: Alemi
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Poole
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chiu
authors.forename: Kristina
authors.initials: K
authors.lastname: Schoonjans
authors.forename: Fiore
authors.initials: F
authors.lastname: Cattaruzza
authors.forename: John R
authors.initials: JR
authors.lastname: Grider
authors.forename: Nigel W
authors.initials: NW
authors.lastname: Bunnett
authors.forename: Carlos U
authors.initials: CU
authors.lastname: Corvera
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D003672:Defecation / Q000187:drug effects* / Q000235:genetics; D003840:Deoxycholic Acid / Q000494:pharmacology; D004759:Enterochromaffin Cells / Q000187:drug effects / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D005772:Gastrointestinal Transit / Q000187:drug effects* / Q000235:genetics; D007413:Intestinal Mucosa / Q000187:drug effects; D008095:Lithocholic Acid / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism; D009828:Oleanolic Acid / Q000494:pharmacology; D010528:Peristalsis; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D014867:Water / Q000032:analysis
chemical_list: C513561:Gpbar1 protein, mouse; D043562:Receptors, G-Protein-Coupled; D003840:Deoxycholic Acid; D014867:Water; D012701:Serotonin; D008095:Lithocholic Acid; D009828:Oleanolic Acid; D015740:Calcitonin Gene-Related Peptide