The anti-hyperglycemic effect of metformin is believed to be caused by its direct action on signaling processes in hepatocytes, leading to lower hepatic gluconeogenesis. Recently, metformin was reported to alter the gut microbiota community in humans, suggesting that the hyperglycemia-lowering action of the drug could be the result of modulating the population of gut microbiota. However, the critical microbial signaling metabolites and the host targets associated with the metabolic benefits of metformin remained elusive. Here, we performed metagenomic and metabolomic analysis of samples from individuals with newly diagnosed type 2 diabetes (T2D) naively treated with metformin for 3 d, which revealed that Bacteroides fragilis was decreased and the bile acid glycoursodeoxycholic acid (GUDCA) was increased in the gut. These changes were accompanied by inhibition of intestinal farnesoid X receptor (FXR) signaling. We further found that high-fat-diet (HFD)-fed mice colonized with B. fragilis were predisposed to more severe glucose intolerance, and the metabolic benefits of metformin treatment on glucose intolerance were abrogated. GUDCA was further identified as an intestinal FXR antagonist that improved various metabolic endpoints in mice with established obesity. Thus, we conclude that metformin acts in part through a B. fragilis-GUDCA-intestinal FXR axis to improve metabolic dysfunction, including hyperglycemia.

中文翻译：

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肠道菌群和肠道FXR介导二甲双胍的临床益处。

据信，二甲双胍的抗高血糖作用是由其对肝细胞信号传导过程的直接作用引起的，从而导致较低的肝糖异生。最近，据报道，二甲双胍改变了人类肠道菌群的群落，这表明该药降低血糖的作用可能是调节肠道菌群的结果。但是，关键的微生物信号代谢物和与二甲双胍代谢益处相关的宿主靶标仍然难以捉摸。在这里，我们对初次接受二甲双胍治疗3天的新诊断为2型糖尿病（T2D）的个体进行了宏基因组学和代谢组学分析，结果表明脆弱的拟杆菌减少了，肠道中的胆汁酸糖去糖去氧胆酸（GUDCA）增加了。这些变化伴随着肠道法呢素X受体（FXR）信号的抑制。我们进一步发现，定植有易碎芽孢杆菌的高脂饮食（HFD）喂养的小鼠易患更严重的葡萄糖耐受不良，而二甲双胍治疗对葡萄糖耐受不良的代谢益处则被废除。GUDCA被进一步鉴定为肠道FXR拮抗剂，可改善肥胖小鼠的各种代谢终点。因此，我们得出结论，二甲双胍部分通过脆弱的芽孢杆菌-GUDCA-肠FXR轴起作用，以改善代谢功能障碍，包括高血糖症。并取消了二甲双胍治疗对葡萄糖耐受不良的代谢益处。GUDCA被进一步鉴定为肠道FXR拮抗剂，可改善肥胖小鼠的各种代谢终点。因此，我们得出结论，二甲双胍部分通过脆弱的芽孢杆菌-GUDCA-肠FXR轴起作用，以改善代谢功能障碍，包括高血糖症。并取消了二甲双胍治疗对葡萄糖耐受不良的代谢益处。GUDCA被进一步鉴定为肠道FXR拮抗剂，可改善肥胖小鼠的各种代谢终点。因此，我们得出结论，二甲双胍部分通过脆弱的芽孢杆菌-GUDCA-肠FXR轴起作用，以改善代谢功能障碍，包括高血糖症。