SCFAs induce autophagy in intestinal epithelial cells and relieve colitis by stabilizing HIF-1α.

Hypoxia-inducible factor-1α (HIF-1α) is a critical regulator of barrier integrity during colonic mucosal injury. Previous works have shown that the absence of autophagy is implicated in the development of inflammatory bowel disease (IBD). Additionally, changes in bacterial profiles in the gut are intimately associated with IBD. Although HIF-1α, autophagy, microbiota, and their metabolites are all involved in the pathogenesis of IBD, their roles are not known. In this study, we investigated the relationship between HIF-1α and autophagy in healthy and inflammatory states using transgenic mice, colitis models, and cell culture models. We confirmed that the absence of intestinal epithelial HIF-1α changed the composition of the intestinal microbes and increased the susceptibility of mice to dextran sodium sulfate (DSS)-induced colitis. In addition, autophagy levels in the intestinal epithelial cells (IECs) were significantly reduced in IEC-specific HIF-1α-deficient (HIF-1α∆IEC) mice. Moreover, in the cell culture models, butyrate treatment significantly increased autophagy in HT29 cells under normal conditions, whereas butyrate had little effect on autophagy after HIF-1α ablation. Furthermore, in the DSS-induced colitis model, butyrate administration relieved the colonic injury and suppressed inflammation in Cre-/HIF-1α- (HIF-1αloxP/loxP) mice. However, the butyrate-mediated protection against colonic injury was considerably diminished in the HIF-1α∆IEC mice. These results show that HIF-1α, autophagy, and intestinal microbes are essential for the maintenance of intestinal homeostasis. Butyrate can alleviate DSS-induced colitis by regulating autophagy via HIF-1α. These insights may have important implications for the development of therapeutic strategies for IBD. KEY MESSAGES: • The absence of intestinal epithelial HIF-1α leads to downregulation of autophagy in mice. • The absence of intestinal epithelial HIF-1α exacerbates DSS-induced colitis. • Short-chain fatty acids (SCFAs) can alleviate DSS-induced colitis by regulating autophagy via HIF-1α.