Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, P. R. China.
Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, P. R. China.
NPJ Biofilms Microbiomes. 2023 Jul 24;9(1):51. doi: 10.1038/s41522-023-00419-y.
Vitamin B12 (VB12) deficiency, which may lead to hematologic and neurologic symptoms, has been associated with metformin use, but the underlying mechanism is unclear. Here we report the B. ovatus as an effective VB12 catcher which was enriched in the type 2 diabetes patients suffered from VB12 deficiency after 3 to 6 months of metformin treatment. Colonization of B. ovatus increased the plasma levels of methylmalonic acid and homocysteine in high-fat diet (HFD)-fed mice treated with metformin, and compromised the efficacy of metformin against the HFD-induced metabolic disorders. Mechanistically, metformin increased the intracellular accumulation of VB12 in B. ovatus via btuB upregulation and promoted ATP production for energy-dependent translocation of VB12 transporters at the inner membrane, leading to an enhanced colonization of B. ovatus to compete for VB12 with hosts and subsequently an aggravated VB12 deficiency in the host. Our findings illustrate a previously unappreciated mechanism of metformin leads to host VB12 deficiency by acting directly on gut bacteria to increase their VB12 uptake and consumption, and suggest that inter-host-microbe competition for nutrients may broadly impact human health and drug safety.
维生素 B12（VB12）缺乏可导致血液学和神经系统症状，与二甲双胍的使用有关，但潜在机制尚不清楚。在这里，我们报告卵形拟杆菌作为一种有效的 VB12 捕获物，在接受二甲双胍治疗 3 至 6 个月后，2 型糖尿病患者出现 VB12 缺乏症。二甲双胍治疗后，在高脂肪饮食（HFD）喂养的小鼠中，卵形拟杆菌的定植增加了血浆中甲基丙二酸和同型半胱氨酸的水平，并损害了二甲双胍对 HFD 诱导的代谢紊乱的疗效。在机制上，二甲双胍通过上调 btuB 增加了卵形拟杆菌细胞内 VB12 的积累，并促进了 ATP 的产生，以便能量依赖性地转运 VB12 转运蛋白穿过内膜，从而增强了卵形拟杆菌与宿主竞争 VB12 的定植能力，并随后导致宿主 VB12 缺乏加重。我们的研究结果说明了一种以前未被认识的机制，即二甲双胍通过直接作用于肠道细菌来增加其 VB12 的摄取和消耗，导致宿主 VB12 缺乏，提示宿主-微生物之间对营养物质的竞争可能广泛影响人类健康和药物安全性。
