Antibiotic Effects on Gut Microbiota, Insulin Signaling and Bile Acid Metabolism is Dependent on Host

Interactions of diet, gut microbiota and host genetics play important roles in development of obesity and insulin resistance. In obesity/diabetes-prone C57BL/6J mice, vancomycin or metronidazole treatment of high fat diet (HFD)-fed animals alters intestinal microbiota, decreases tissue inflammation, improves insulin signaling in the basal and stimulated states, and improves glucose metabolism. Many of these changes can be reproduced by transfer of gut microbiota from antibiotic-treated donors to germ-free mice or mice in which the normal gut flora had been depleted. These physiological changes closely correlate with changes in serum bile acids and levels of the anti-inflammatory bile acid receptor TGR5, and are recapitulated, in part, by treatment with a TGR5 agonist. In contrast, treatment of HFD-fed 129S6/SvEvTac or 129S1/SvImJ mice with antibiotics does not improve metabolism, despite changes in microbiota and bile acids, and these mice also fail to improve glucose tolerance in response to the TGR5 agonist. Thus, antibiotic modification of gut microbiota, acting through changes in bile acid and inflammatory signaling, can improve insulin signaling and glucose metabolism, however, these effects also depend on important interactions with host genetic background and inflammatory potential.

饮食、肠道菌群与宿主遗传的相互作用，在肥胖与胰岛素抵抗的发生发展中发挥关键作用。在易患肥胖/糖尿病的C57BL/6J小鼠模型中，对高脂饮食（High Fat Diet, HFD）喂养的动物施以万古霉素或甲硝唑干预，可改变其肠道菌群结构，减轻组织炎症，改善基础状态与刺激状态下的胰岛素信号通路功能，并优化葡萄糖代谢。将经抗生素处理的供体小鼠的肠道菌群移植到无菌小鼠（germ-free mice）或肠道正常菌群被清除的小鼠体内，可复现上述多数生理变化。这些生理改变与血清胆汁酸水平变化及抗炎性胆汁酸受体TGR5的表达水平密切相关，而给予TGR5激动剂可部分复现此类变化。与之相反，对高脂饮食喂养的129S6/SvEvTac或129S1/SvImJ小鼠施以抗生素干预，尽管其肠道菌群与胆汁酸水平发生了显著改变，但代谢状态并未得到改善；且这些小鼠也无法通过TGR5激动剂的干预提升葡萄糖耐量。由此可见，通过抗生素调控肠道菌群（其作用机制为改变胆汁酸与炎症信号通路），可改善胰岛素信号通路功能与葡萄糖代谢，但此类效应同时依赖于与宿主遗传背景及炎症潜能之间的重要相互作用。