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 2α (HIF-2α) positively regulates gut lactate by controlling the expression of intestinal Ldha. Intestine-specific HIF-2α 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.

越来越多的证据表明，肠道微生物群通过代谢物与宿主的相互作用来调节肥胖。然而，这种相互作用的潜在机制尚不清楚。在这里，我们发现肠道缺氧诱导因子 2α (HIF-2α) 通过控制肠道Ldha的表达来正向调节肠道乳酸。小鼠肠道特异性 HIF-2α 消融导致较低的乳酸水平、较少的普通拟杆菌和较大的瘤胃球菌扭矩丰度，分别。总之，这些变化导致牛磺酸结合胆酸 (TCA) 和脱氧胆酸 (DCA) 水平升高以及脂肪 G 蛋白偶联胆汁酸受体 GPBAR1 (TGR5) 的激活。这种激活上调了解偶联蛋白 (UCP) 1 和线粒体肌酸激酶 (CKMT) 2 的表达，导致白色脂肪组织产热升高。TCA 和 DCA 的施用反映了这些表型，并且B. vulgatus和R. 转矩的定植分别抑制和诱导产热。这项工作加深了我们对宿主基因如何调节微生物组的理解，并为减轻肥胖提供了新的策略。