HDAC6/FOXP3/HNF4 alpha axis promotes bile acids induced gastric intestinal metaplasia

Bile reflux is one of the main causes of gastric intestinal metaplasia (IM) which is an important precancerous lesion. Our previous study has shown that ectopic expression of Histone deacetylase 6 (HDAC6) promotes the activation of intestinal markers in bile acids (BA) induced gastric IM cells; however, the mechanism underlying how HDAC6-mediated epigenetic modifications regulate intestinal markers is not clear. In this study, we aimed to investigate the downstream targets of HDAC6 and the underlying mechanism in the process of BA induced gastric IM. We demonstrated that deoxycholic acid (DCA) upregulated HDAC6 in gastric cells, which further inhibited the transcription of Forkhead box protein 3 (FOXP3). Then, FOXP3 transcriptionally inhibited Hepatocyte nuclear factor 4 alpha (HNF4 alpha), which further inhibits the expression of downstream intestinal markers. These molecules have been shown to be clinically relevant, as FOXP3 levels were negatively correlated with HDAC6 and HNF4 alpha in IM tissues. Transgenic mice experiments confirmed that HNF4 alpha overexpression combined with DCA treatment induced gastric mucosa to secrete intestinal mucus and caused an abnormal mucosal structure. Our findings suggest that HDAC6 reduces FOXP3 through epigenetic modification, thus forming a closed loop HDAC6/FOXP3/HNF4 alpha to promote gastric IM. Inhibition of HDAC6 may be a potential approach to prevent gastric IM in patients with bile reflux.