Intestinal hypoxia-inducible factor 2α regulates lactate levels to shape the gut microbiome and alter thermogenesis

Accumulating evidence suggests that the gut microbiota regulates obesity through metabolite-host interactions. However, the mechanisms underlying such interactions have been unclear. Here, we found that intestinal hypoxia-inducible factor 2 alpha(HIF-2 alpha) positively regulates gut lactate by controlling the expression of intestinal Ldha. Intestine-specific HIF-2 alpha ablation in mice resulted in lower lactate levels, and less Bacteroides vulgatus and greater Ruminococcus torques abundance, respectively. Together, these changes resulted in elevated taurine-conjugated cholic acid (TCA) and deoxycholic acid (DCA) levels and activation of the adipose G-protein-coupled bile acid receptor, GPBAR1 (TGR5). This activation upregulated expression of uncoupling protein (UCP) 1 and mitochondrial creatine kinase (CKMT) 2, resulting in elevation of white adipose tissue thermogenesis. Administration of TCA and DCA mirrored these phenotypes, and colonization with B. vulgatus and R. torques inhibited and induced thermogenesis, respectively. This work deepens our understanding of how host genes regulate the microbiome and provides novel strategies for alleviating obesity.