The G-Protein-Coupled Bile Acid Receptor Gpbar1 (TGR5) Inhibits Gastric Inflammation Through Antagonizing NF-κB Signaling Pathway

Gpbar1 (TGR5), a membrane-bound bile acid receptor, is well-known for its roles in regulation of energy homeostasis and glucose metabolism. Here, we show that mice lacking TGR5 were much more susceptible to lipopolysaccharide (LPS)-induced acute gastric inflammation than wild-type (WT) mice and TGR5 is a negative regulator of gastric inflammation through antagonizing NF-KB signaling pathway. We found that the treatment of TGR5 ligands 23(S)-mCDCA and GPBARA (3 -(2 -ChlorophenyI)-N -(4-chlorophenyI)-N,5-dimethylisoxazole-4-carboxamide) suppressed gene and protein expression mediated by NF-kappa B signaling. TGR5 overexpression with ligand treatment inhibited gene expression of interferon inducible protein 10 (IP-10), INF-u, and chemoattractant protein-1 (MCP-1) induced by LPS. Furthermore, we revealed that TGR5 activation antagonized NF-KB signaling pathway through suppressing its transcription activity, the phosphorylation of IKBc.,/ and p65 translocation, which suggests that TGR5 antagonizes gastric inflammation at least in part by inhibiting NF-kappa B signaling. These findings identify TGR5 as a negative mediator of gastric inflammation that may serve as an attractive therapeutic tool for human gastric inflammation and cancer.