The receptor TGR5 mediates the prokinetic actions of intestinal bile acids and is required for normal defecation in mice

Gastroenterology. 2013 Jan;144(1):145-54. doi: 10.1053/j.gastro.2012.09.055. Epub 2012 Oct 3.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcitonin Gene-Related Peptide / metabolism
  • Colon / drug effects*
  • Colon / metabolism
  • Colon / physiology*
  • Defecation / drug effects*
  • Defecation / genetics
  • Deoxycholic Acid / pharmacology
  • Enterochromaffin Cells / drug effects
  • Enterochromaffin Cells / metabolism
  • Feces / chemistry
  • Gastrointestinal Transit / drug effects*
  • Gastrointestinal Transit / genetics
  • Intestinal Mucosa / drug effects
  • Lithocholic Acid / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Muscle Contraction / drug effects
  • Muscle Relaxation / drug effects
  • Neurons, Afferent / drug effects
  • Neurons, Afferent / metabolism
  • Oleanolic Acid / pharmacology
  • Peristalsis
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Serotonin / metabolism
  • Water / analysis


  • Gpbar1 protein, mouse
  • Receptors, G-Protein-Coupled
  • Deoxycholic Acid
  • Water
  • Serotonin
  • Lithocholic Acid
  • Oleanolic Acid
  • Calcitonin Gene-Related Peptide