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

Abstract

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-κB signaling pathway. We found that the treatment of TGR5 ligands 23(S)-mCDCA and GPBARA (3-(2-Chlorophenyl)-N-(4-chlorophenyl)-N,5-dimethylisoxazole-4-carboxamide) suppressed gene and protein expression mediated by NF-κB signaling. TGR5 overexpression with ligand treatment inhibited gene expression of interferon-inducible protein 10 (IP-10), TNF-α, and chemoattractant protein-1 (MCP-1) induced by LPS. Furthermore, we revealed that TGR5 activation antagonized NF-κB signaling pathway through suppressing its transcription activity, the phosphorylation of IκBα and p65 translocation, which suggests that TGR5 antagonizes gastric inflammation at least in part by inhibiting NF-κB 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.

Bile acids deoxycholic acid and ursodeoxycholic acid differentially regulate human β‐defensin‐1 and ‐2 secretion by colonic epithelial cells

“…However, the NF-kB-independent mechanism that underlies DCA-induced up-regulation of HbD1 in these cells remains to be determined and will be the subject of future studies in our laboratory. Our data that show that TGR5 activation in colonic epithelial cells induces activation of NF-kB are also interesting in light of previous studies that have demonstrated NF-kB inhibition by the receptor in hepatic and gastric epithelial cells (46,47). The reasons for this difference are unclear but may reflect differences in experimental conditions, as in the previous studies, TGR5 was forcibly overexpressed in gastric and hepatic cells, or could point to differences in TGR5 coupling to downstream effectors in epithelial cells of different origins.…”

TGR5, Not Only a Metabolic Regulator

“…It suggests that TGR5 antagonizes gastric cancer proliferation and migration at least in part by inhibiting STAT3 signaling. These findings identify TGR5 as an attractive therapeutic target for treatment of gastric cancer (Guo et al, 2015a,b, Figure 1). …”

“…Our group found the activation of TGR5 could inhibit inflammation in liver and stomach (Wang et al, 2011; Guo et al, 2015a). In liver, TGR5 inhibits the expression of inflammatory mediators in response to NF-κB activation induced by LPS in wild-type (WT), but not TGR5 −/− mice (Wang et al, 2011).…”

“…The activation of TGR5 by betulinic acid decreases neuroinflammation via neuron and microglia paracrine signaling during HE (McMillin et al, 2015, Table 1). Last year, our group found that TGR5 activation also suppresses gastric inflammation (Guo et al, 2015a). Chronic inflammation is connected with various diseases such as liver, colon and gastric cancer (Guo et al, 2015b).…”

Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System

“…Guo et al, 2015; Kawamata et al, 2003; Keitel et al, 2008; Pols et al, 2011; Y.-D. Wang et al, 2011; Wen et al, 2010). Gpbar1 −/− mice, like their Nr1h4 −/− counterparts, develop more severe disease than wildtype controls in several animal models of inflammatory disorder, including colitis, hepatitis and gastritis (Cipriani et al, 2011; C. Guo et al, 2015; Y.-D. Wang et al, 2011).…”