Metformin is widely used to surmount insulin resistance (IR) and type 2 diabetes. Evidence indicates that metformin improves insulin resistance associated with gut microbiota, but the underlying mechanism remains unclear. In the present study, metformin effectively improved insulin sensitivity and alleviated liver inflammation and oxidative stress in high-fat diet (HFD)-fed mice. Metabolomics analysis showed that metformin increased tauroursodeoxycholic acid (TUDCA) levels both in intestinal content and liver by reducing the production and activity of bile salt hydrolase (BSH). We further found that TUDCA was able to antagonize with KEAP1 to prevent its binding to Nrf2 and activate Nrf2/ARE pathway, thereby reducing intracellular ROS and improving insulin signaling. Moreover, metformin increased the proportion of Akkermanisia muciniphlia in the HFD-fed mice, while in vitro growth curve test confirmed that it’s TUDCA, not metformin, promoted the proliferation of A. muciniphlia. Subsequently, TUDCA administration could effectively ameliorate insulin resistance, activate hepatic Nrf2/ARE pathways, and increase the abundance of intestinal A. muciniphlia in ob/ob mice. These findings reveal that metformin remodels the gut microbiota, reduces oxidative stress and enhances insulin sensitivity partly due to increasing the production of TUDCA. This provides a novel mechanism by which metformin alleviates diet-induced insulin resistance and improves metabolism.

中文翻译：

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二甲双胍增加牛磺熊去氧胆酸水平以改善饮食诱导的肥胖小鼠的胰岛素抵抗

二甲双胍被广泛用于克服胰岛素抵抗 (IR) 和 2 型糖尿病。有证据表明二甲双胍可改善与肠道微生物群相关的胰岛素抵抗，但其潜在机制尚不清楚。在本研究中，二甲双胍可有效改善高脂饮食 (HFD) 喂养小鼠的胰岛素敏感性并减轻肝脏炎症和氧化应激。代谢组学分析表明，二甲双胍通过降低胆盐水解酶 (BSH) 的产生和活性，增加肠道内容物和肝脏中的牛磺熊去氧胆酸 (TUDCA) 水平。我们进一步发现 TUDCA 能够与 KEAP1 拮抗，阻止其与 Nrf2 结合并激活 Nrf2/ARE 通路，从而减少细胞内 ROS 并改善胰岛素信号传导。此外，二甲双胍增加了Akkermanisia muciniphlia在HFD 喂养的小鼠中，而体外生长曲线测试证实它是TUDCA，而不是二甲双胍，促进了A. muciniphlia的增殖。随后，TUDCA管理能有效地改善胰岛素抵抗，激活Nrf2的肝/ ARE途径，增加肠道的丰度A. muciniphlia中的ob / ob小鼠。这些发现表明，二甲双胍可重塑肠道微生物群，减少氧化应激并增强胰岛素敏感性，部分原因是增加了 TUDCA 的产生。这提供了一种新的机制，通过该机制二甲双胍减轻饮食诱导的胰岛素抵抗并改善新陈代谢。