TGR5-HNF4α axis contributes to bile acid-induced gastric intestinal metaplasia markers expression

Intestinal metaplasia (IM) increases the risk of gastric cancer. Our previous results indicated that bile acids (BAs) reflux promotes gastric IM development through kruppel-like factor 4 (KLF4) and caudal-type homeobox 2 (CDX2) activation. However, the underlying mechanisms remain largely elusive. Herein, we verified that secondary BAs responsive G-protein-coupled bile acid receptor 1 (GPBAR1, also known as TGR5) was increased significantly in IM specimens. Moreover, TGR5 contributed to deoxycholic acid (DCA)-induced metaplastic phenotype through positively regulating KLF4 and CDX2 at transcriptional level. Then we employed PCR array and identified hepatocyte nuclear factor 4 alpha (HNF4 alpha) as a candidate mediator. Mechanically, DCA treatment could induce HNF4 alpha expression through TGR5 and following ERK1/2 pathway activation. Furthermore, HNF4 alpha mediated the effects of DCA treatment through directly regulating KLF4 and CDX2. Finally, high TGR5 levels were correlated with high HNF4 alpha, KLF4, and CDX2 levels in IM tissues. These findings highlight the TGR5-ERK1/2-HNF4 alpha axis during IM development in patients with BAs reflux, which may help to understand the mechanism underlying IM development and provide prospective strategies for IM treatment.