The Bile Acid Receptor GPBAR-1 (TGR5) Modulates Integrity of Intestinal Barrier and Immune Response to Experimental Colitis
Open Access
- 27 October 2011
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 6 (10), e25637
- https://doi.org/10.1371/journal.pone.0025637
Abstract
GP-BAR1, a member G protein coupled receptor superfamily, is a cell surface bile acid-activated receptor highly expressed in the ileum and colon. In monocytes, ligation of GP-BAR1 by secondary bile acids results in a cAMP-dependent attenuation of cytokine generation. To investigate the role GP-BAR1 in regulating intestinal homeostasis and inflammation-driven immune dysfunction in rodent models of colitis. Colitis was induced in wild type and GP-BAR1−/− mice by DSS and TNBS administration. Potential GP-BAR1 agonists were identified by in silico screening and computational docking studies. GP-BAR1−/− mice develop an abnormal morphology of colonic mucous cells and an altered molecular architecture of epithelial tight junctions with increased expression and abnormal subcellular distribution of zonulin 1 resulting in increased intestinal permeability and susceptibility to develop severe colitis in response to DSS at early stage of life. By in silico screening and docking studies we identified ciprofloxacin as a GP-BAR1 ligand. In monocytes, ciprofloxacin increases cAMP concentrations and attenuates TNFα release induced by TLR4 ligation in a GP-BAR1 dependent manner. Treating mice rendered colitic by TNBS with ciprofloxacin and oleanolic acid, a well characterized GP-BAR1 ligand, abrogates signs and symptoms of colitis. Colonic expression of GP-BAR1 mRNA increases in rodent models of colitis and tissues from Crohn's disease patients. Flow cytometry analysis demonstrates that ≈90% of CD14+ cells isolated from the lamina propria of TNBS-treated mice stained positively for GP-BAR1. GP-BAR1 regulates intestinal barrier structure. Its expression increases in rodent models of colitis and Crohn's disease. Ciprofloxacin is a GP-BAR1 ligand.Keywords
This publication has 29 references indexed in Scilit:
- Molecular mechanisms underlying bile acid‐stimulated glucagon‐like peptide‐1 secretionBritish Journal of Pharmacology, 2011
- Expression and function of the bile acid receptor GpBAR1 (TGR5) in the murine enteric nervous systemNeurogastroenterology & Motility, 2010
- AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibilityJournal of Computational Chemistry, 2009
- Expression and function of the bile acid receptor TGR5 in Kupffer cellsBiochemical and Biophysical Research Communications, 2008
- Anti-hyperglycemic activity of a TGR5 agonist isolated from Olea europaeaBiochemical and Biophysical Research Communications, 2007
- Targeted deletion of Gpbar1 protects mice from cholesterol gallstone formationBiochemical Journal, 2006
- Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1Biochemical and Biophysical Research Communications, 2005
- Identification of membrane-type receptor for bile acids (M-BAR)Biochemical and Biophysical Research Communications, 2002
- Comparative Protein Modelling by Satisfaction of Spatial RestraintsJournal of Molecular Biology, 1993
- Main-chain Bond Lengths and Bond Angles in Protein StructuresJournal of Molecular Biology, 1993