Gut microbiota and intestinal FXR mediate the clinical benefits of metformin.
Gut microbiota and intestinal FXR mediate the clinical benefits of metformin.
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肠道微生物群和肠道 FXR 介导二甲双胍的临床益处。
DOI：
10.1038/s41591-018-0222-4
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发表时间：
2018-12
期刊：
影响因子：
82.9
通讯作者：
Jiang C
中科院分区：
文献类型：
--
作者：
Sun L;Xie C;Wang G;Wu Y;Wu Q;Wang X;Liu J;Deng Y;Xia J;Chen B;Zhang S;Yun C;Lian G;Zhang X;Zhang H;Bisson WH;Shi J;Gao X;Ge P;Liu C;Krausz KW;Nichols RG;Cai J;Rimal B;Patterson AD;Wang X;Gonzalez FJ;Jiang C
二甲双胍的抗高血糖作用被认为是由其对肝细胞中信号传导过程的直接作用引起的，导致肝细胞增生降低。最近，据报道二甲双胍改变了人类的肠道微生物群，这表明该药物的降血糖作用可能是调节肠道微生物群的结果。然而，与二甲双胍代谢获益相关的关键微生物信号代谢物和宿主靶点仍然难以捉摸。在这里，我们对新诊断的2型糖尿病（T2 D）患者接受二甲双胍治疗3 d的样本进行了宏基因组学和代谢组学分析，结果显示肠道中脆弱类杆菌减少，胆汁酸甘氨熊去氧胆酸（GUDCA）增加。这些变化伴随着肠道法尼醇X受体（FXR）信号传导的抑制。我们进一步发现，高脂饮食（HFD）喂养的小鼠定植有B。脆弱的易患更严重的葡萄糖耐受不良，二甲双胍治疗对葡萄糖耐受不良的代谢益处被取消。GUDCA被进一步确定为一种肠道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aB发挥作用。fragilis-GUDCA-肠道FXR轴可改善代谢功能障碍，包括高血糖症。
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 thatBacteroides fragiliswas 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 withB. fragiliswere 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 aB. fragilis–GUDCA–intestinal FXR axis to improve metabolic dysfunction, including hyperglycemia.
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影响因子：
82.9
作者：
Friedman SL;Neuschwander-Tetri BA;Rinella M;Sanyal AJ
通讯作者：
Sanyal AJ
影响因子：
13.5
作者：
Kong, Bo;Wang, Li;Guo, Grace L.
通讯作者：
Guo, Grace L.
肠道选择性法尼醇 X 受体抑制可改善肥胖相关的代谢功能障碍。
影响因子：
16.6
作者：
Jiang C;Xie C;Lv Y;Li J;Krausz KW;Shi J;Brocker CN;Desai D;Amin SG;Bisson WH;Liu Y;Gavrilova O;Patterson AD;Gonzalez FJ
通讯作者：
Gonzalez FJ
影响因子：
25.7
作者：
Mueller, Michaela;Thorell, Anders;Trauner, Michael
通讯作者：
Trauner, Michael
影响因子：
24.5
作者：
Parséus A;Sommer N;Sommer F;Caesar R;Molinaro A;Ståhlman M;Greiner TU;Perkins R;Bäckhed F
通讯作者：
Bäckhed F