Chen Manyun, Peng Yilei, Hu Yuhui, Kang Zhiqiang, Chen Ting, Zhang Yulong, Chen Xiaoping, Li Qing, Yuan Zuyi, Wu Yue, Xu Heng, Zhou Gan, Liu Tao, Zhou Honghao, Yuan Chunsu, Huang Weihua, Zhang Wei
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China.
Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha 410078, China.
Acta Pharm Sin B. 2025 May;15(5):2511-2528. doi: 10.1016/j.apsb.2025.02.008. Epub 2025 Feb 11.
Metformin has been demonstrated to attenuate hyperglycaemia by modulating the gut microbiota. However, the mechanisms through which the microbiome mediates metformin monotherapy failure (MMF) are unclear. Herein, in a prospective clinical cohort study of newly diagnosed type 2 diabetes mellitus (T2DM) patients treated with metformin monotherapy, metagenomic sequencing of faecal samples revealed that abundance was approximately 12 times higher in nonresponders than in responders. rapidly hydrolysed taurine-conjugated bile acids, leading to ceramide accumulation and reversing the improvements in glucose intolerance conferred by metformin in high-fat diet-fed mice. Interestingly, C22:0 ceramide bound to mitochondrial fission factor to induce mitochondrial fragmentation and impair hepatic oxidative phosphorylation in -colonized hyperglycaemic mice, which could be exacerbated by metformin. This work suggests that metformin may be unsuitable for -rich T2DM patients and that clinicians should be aware of metformin toxicity to mitochondria. Suppressing growth with cefaclor or improving mitochondrial function using adenosylcobalamin may represent simple, safe, effective therapeutic strategies for addressing MMF.
二甲双胍已被证明可通过调节肠道微生物群来减轻高血糖。然而，微生物群介导二甲双胍单药治疗失败（MMF）的机制尚不清楚。在此，在一项对接受二甲双胍单药治疗的新诊断2型糖尿病（T2DM）患者的前瞻性临床队列研究中，粪便样本的宏基因组测序显示，无反应者中的丰度比反应者高约12倍。迅速水解牛磺酸结合的胆汁酸，导致神经酰胺积累，并逆转二甲双胍给予高脂饮食喂养小鼠的葡萄糖不耐受改善情况。有趣的是，C22:0神经酰胺与线粒体分裂因子结合，诱导线粒体碎片化，并损害定殖小鼠结肠的高血糖小鼠的肝脏氧化磷酸化，而二甲双胍可能会加剧这种情况。这项工作表明，二甲双胍可能不适合富含的T2DM患者，临床医生应意识到二甲双胍对线粒体的毒性。用头孢克洛抑制生长或使用腺苷钴胺改善线粒体功能可能是解决MMF的简单、安全、有效的治疗策略。
