Bile acids promote gastric intestinal metaplasia by upregulating CDX2 and MUC2 expression via the FXR/NF-κB signalling pathway

摘要

Bile acids serve a critical role in the induction of gastric intestinal metaplasia (IM) and gastric carcinogenesis. The present study investigated the effects of bile acids on the induction of gastric IM formation. The results demonstrated that the expression levels of caudal-related homeobox transcription factor 2 (CDX2), mucin 2 (MUC2) and farnesoid X receptor (FXR) were increased in vitro and in vivo following treatment with bile acids, and CDX2 transcriptionally activated MUC2 expression. Furthermore, knockdown of FXR attenuated bile acid-enhanced CDX2 promoter activity and protein expression. Conversely, the FXR agonist GW4064 synergistically enhanced bile acid-induced CDX2 promoter activity. Bile acid treatment led to an increase in nuclear factor (NF)-κB activity and protein expression. Treatment with GW4064 or the FXR antagonist Z-guggulsterone enhanced or attenuated bile acid-induced NF-κB activity, respectively. In addition, quantitative chromatin immunoprecipitation confirmed that bile acids led to enhanced binding of p50 to the CDX2 promoter, whereas this effect was not observed for p65. Treatment with GW4064 or Z-guggulsterone enhanced and attenuated the binding activity of p50 to the CDX2 promoter, respectively. These results indicated that bile acids may activate the FXR/NF-κB signalling pathway, thereby upregulating CDX2 and MUC2 expression in normal gastric epithelial cells.