Hyodeoxycholic acid (HDCA) suppresses intestinal epithelial cell proliferation through FXR-PI3K/AKT pathway, accompanied by alteration of bile acids metabolism profiles induced by gut bacteria

Bile acids (BAs) have been implicated in regulation of intestinal epithelial signaling and function. This study aimed to investigate the effects of hyodeoxycholic acid (HDCA) on intestinal epithelial cell proliferation and explore the underlying mechanisms. IPEC-J2 cells and weaned piglets were treated with HDCA and the contributions of cellular signaling pathways, BAs metabolism profiles and gut bacteria were assessed. In vitro, HDCA suppressed IPEC-J2 proliferation via the BAs receptor FXR but not TGR5. In addition, HDCA inhibited the PI3K/AKT pathway, while knockdown of FXR or constitutive activation of AKT eliminated the inhibitory effects of HDCA, suggesting that FXR-dependent inhibition of PI3K/AKT pathway was involved in HDCA-suppressed IPEC-J2 proliferation. In vivo, dietary HDCA inhibited intestinal expression of proliferative markers and PI3K/AKT pathway in weaned piglets. Meanwhile, HDCA altered the BAs metabolism profiles, with decrease in primary BA and increase in total and secondary BAs in feces, and reduction of conjugated BAs in serum. Furthermore, HDCA increased abundance of the gut bacteria associated with BAs metabolism, and thereby induced BAs profiles alternation, which might indirectly contribute to HDCA-suppressed cell proliferation. Together, HDCA suppressed intestinal epithelial cell proliferation through FXR-PI3K/AKT signaling pathway, accompanied by alteration of BAs metabolism profiles induced by gut bacteria.