Antibiotic effects on gut microbiota and metabolism are host dependent
Antibiotic effects on gut microbiota and metabolism are host dependent
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DOI：
10.1172/jci86674
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发表时间：
2016-12-01
影响因子：
15.9
通讯作者：
Kahn, C. Ronald
中科院分区：
文献类型：
--
作者：
Fujisaka, Shiho;Ussar, Siegfried;Kahn, C. Ronald
饮食、肠道菌群和宿主遗传学的相互作用在肥胖和胰岛素抵抗的发展中起着重要作用。在这里，我们研究了肠道微生物群，胰岛素抵抗和葡萄糖代谢之间的分子联系，在3个近交系小鼠品系中，使用饮食和抗生素治疗对代谢综合征具有不同的易感性。抗生素治疗改变了肠道微生物群，减少了组织炎症，改善了基础和刺激状态下的胰岛素信号传导，并改善了高脂饮食（HFD）的肥胖和糖尿病易感C57 BL/6 J小鼠的葡萄糖代谢。这些变化中的许多是通过将肠道微生物群从驱虫处理的供体转移到无菌或细菌耗尽的小鼠中来复制的。这些生理变化与血清胆汁酸和胆汁酸受体Takeda G蛋白偶联受体5（TGR 5）水平的变化密切相关，并通过TGR 5激动剂治疗部分重现。相比之下，抗生素治疗HFD喂养的耐肥胖的129 S1和易肥胖的129 S6小鼠并没有改善代谢，尽管微生物群和胆汁酸发生了变化。这些小鼠也未能显示出响应于TGR 5激动剂的炎症基因表达的减少。因此，由HFD驱动的胆汁酸和炎症信号传导、胰岛素抵抗和葡萄糖代谢的变化可以通过肠道微生物群中的禁食诱导的变化来改变;然而，这些影响取决于与宿主遗传背景和炎症潜力的重要相互作用。
Interactions of diet, gut microbiota, and host genetics play important roles in the development of obesity and insulin resistance. Here, we have investigated the molecular links between gut microbiota, insulin resistance, and glucose metabolism in 3 inbred mouse strains with differing susceptibilities to metabolic syndrome using diet and antibiotic treatment. Antibiotic treatment altered intestinal microbiota, decreased tissue inflammation, improved insulin signaling in basal and stimulated states, and improved glucose metabolism in obesity- and diabetes-prone C57BL/6J mice on a highfat diet (HFD). Many of these changes were reproduced by the transfer of gut microbiota from antibiotic-treated donors to germ-free or germ-depleted mice. These physiological changes closely correlated with changes in serum bile acids and levels of the antiinflammatory bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) and were partially recapitulated by treatment with a TGR5 agonist. In contrast, antibiotic treatment of HFD-fed, obesity-resistant 129S1 and obesity-prone 129S6 mice did not improve metabolism, despite changes in microbiota and bile acids. These mice also failed to show a reduction in inflammatory gene expression in response to the TGR5 agonist. Thus, changes in bile acid and inflammatory signaling, insulin resistance, and glucose metabolism driven by an HFD can be modified by antibiotic-induced changes in gut microbiota; however, these effects depend on important interactions with the host's genetic background and inflammatory potential.