Deficiency of intestinal hypoxia-inducible factor 2a reduces lactate levels to reshape the gut microbiome and increase adipose tissue thermogenesis

Accumulating evidence indicates that the gut microbiota regulates obesity through metabolite-host interactions. However, the mechanisms underlying host gene-mediated regulation of the gut microbiota are unclear. We found that intestinal HIF-2a regulates gut lactate concentration by targeting the intestinal Ldha gene. Intestine-specific HIF- 2a ablation decreased lactate levels and led to a reduction in Bacteroides vulgatus and an increase in Ruminococcus torques, which elevated the levels of taurine-conjugated cholic acid (TCA) and deoxycholic acid (DCA). These increases resulted in the activation of adipose TGR5, leading to increased cAMP level in white adipose tissue and thus upregulation of both UCP-1 and CKMT2. Together, this pathway results in elevated white adipose tissue thermogenesis. The above-described phenotypes were transferable via the fecal microbiota transplantation, while administration of TCA and DCA mirrored these phenotypes, and colonization with B. vulgatus and R. torques induced and inhibited thermogenesis, respectively. This work deepens our understanding of how host genes regulate the microbiome and provides novel strategies for alleviating obesity.