Intestinal hypoxia-inducible factor 2α regulates lactate levels to shape the gut microbiome and alter thermogenesis
Intestinal hypoxia-inducible factor 2α regulates lactate levels to shape the gut microbiome and alter thermogenesis
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肠道缺氧诱导因子 2a 调节乳酸水平以塑造肠道微生物群并改变生热作用
DOI：
10.1016/j.cmet.2021.07.007
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发表时间：
2021-10-05
期刊：
影响因子：
29
通讯作者：
Jiang, Changtao
中科院分区：
文献类型：
--
作者：
Wu, Qing;Liang, Xianyi;Jiang, Changtao
越来越多的证据表明，肠道微生物群通过代谢物-宿主相互作用调节肥胖。然而，这种相互作用的机制尚不清楚。在这里，我们发现，肠缺氧诱导因子2 α（HIF-2 α）积极调节肠道乳酸通过控制肠道Ldha的表达。在小鼠中，肠特异性HIF-2 α消融分别导致乳酸水平降低、普通拟杆菌减少和扭转瘤胃球菌丰度增加。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GPBAR 1（TGR 5）的激活。这种激活上调解偶联蛋白（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的给药反映了这些表型，以及B的定殖。vulgatus和R.扭矩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。
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.