Microbe‐Host Crosstalk between Short‐Chain Fatty Acids and Intestinal Epithelial HIF Provides a New Mechanism to Augment Tissue Barrier Function

Abstract

The interactions between the enteric microbiota and distal gut play important roles in regulating human health. Short chain fatty acids (i.e. butyrate) are produced by anaerobic microbes and are a major energy source for the colonic epithelium. Decreased concentrations of butyrate is strongly associated with colonic disease. Interestingly, the low oxygen conditions that enable butyrate production also place unusual metabolic demands on the colonic mucosa. However, the colonic epithelium is uniquely adapted to this austere oxygen environment through the stabilization of hypoxia‐inducible factor (HIF) and expression of HIF target genes. Because anaerobes are the major producers of butyrate, we hypothesized that microbe‐derived butyrate regulates host HIF. Studies with human intestinal epithelial cells (IECs) revealed that butyrate promotes mitochondrial‐dependent oxygen consumption and stabilizes HIF1α. Furthermore, butyrate activated HIF target genes in IECs and antibiotics decreased butyrate and HIF expression in the mouse colon. Germ free mice also showed decreased HIF1α expression in the colonic epithelium. Finally, we found that butyrate rescues physiologic hypoxia and protects the intestinal barrier via HIF. This indicates that butyrate participates in a diverse set of functions in the gut, including regulation of barrier function, and could be a potential therapeutic for mucosal protection.