The Bile Acid Receptor GPBAR-1 (TGR5) Modulates Integrity of Intestinal Barrier and Immune Response to Experimental Colitis

Abstract

Background 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.AimsTo investigate the role GP-BAR1 in regulating intestinal homeostasis and inflammation-driven immune dysfunction in rodent models of colitis.MethodsColitis 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.ResultsGP-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.ConclusionsGP-BAR1 regulates intestinal barrier structure. Its expression increases in rodent models of colitis and Crohn's disease. Ciprofloxacin is a GP-BAR1 ligand.

The bile acid receptor GPBAR1 (TGR5) is expressed in human gastric cancers and promotes epithelial-mesenchymal transition in gastric cancer cell lines

“…By activating FXR, PXR and CAR, CDCA and CA elicits a series of genomic effects that have been deemed essential for regulation of lipid, cholesterol and bile acid homeostasis in intestine and liver. In addition, secondary bile acids, LCA and DCA, and their tauro-and glyco-conjugates, activate cell surface receptors, including TGR5 or M-BAR, a member of the rhodopsin-like superfamily of G protein coupled receptor (GPCR), recently christened as a GPBAR1 [10][11][12][13][14]. Similarly to other GPCRs, GPBAR1 senses molecules outside the cell and activate inside signal transduction pathways through agonist binding to an orthosteric binding site.…”

“…litocholic acid (LCA) and deoxycholic acid (DCA) and their tauro-and glyco-conjugated forms) GPBAR1 modulates multiple targets by genomic and non-genomic effects [9,10]. GPBAR1 is expressed in epithelial, endocrine [11] and neuronal cells, in the stomach and intestine, and mice harboring a disrupted GPBAR1 are more prone to develop a severe intestinal inflammation [14].…”

Bile acid activated receptors are targets for regulation of integrity of gastrointestinal mucosa

“…The receptor is expressed in macrophages, and its activation reduces macrophage-effector functions triggered by proinflammatory stimuli. In line with the immunosuppressive properties of GP-BAR1 in the immune system, GP-BAR1 serves to protect against colonic inflammation in mice by maintaining integrity of the colonic epithelial barrier [19]. GP-BAR1-deficient mice had an altered architecture of the colonic mucosa at 12 months of age that is characterized by disruption of epithelial tight junctions and a redistribution of zonulin 1 from tight junctions, which results in increased mucosal permeability, a recognized feature of intestinal inflammatory disorders.…”

“…GP-BAR1 ligands also exert immunomodulatory functions [19]. The receptor is expressed in macrophages, and its activation reduces macrophage-effector functions triggered by proinflammatory stimuli.…”

“…Previous studies have shown that bile acids increase the expression of eNOS by a GP-BAR1 and cyclic AMP (cAMP)-dependent mechanism in isolated sinusoid endothelial cells [61], a liver-specific endothelial cell subtype. Importantly, GP-BAR1 -/-mice had reduced levels of eNOS mRNA in the gastric mucosa, highlighting a functional role for GP-BAR1 in regulating eNOS gene transcription.…”