Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD
Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, MD.
Diabetes Care. 2021 Jul;44(7):1462-1471. doi: 10.2337/dc20-2257. Epub 2021 May 18.
OBJECTIVE: To determine the longer-term effects of metformin treatment and behavioral weight loss on gut microbiota and short-chain fatty acids (SCFAs). RESEARCH DESIGN AND METHODS: We conducted a 3-parallel-arm, randomized trial. We enrolled overweight/obese adults who had been treated for solid tumors but had no ongoing cancer treatment and randomized them ( = 121) to either ) metformin (up to 2,000 mg), ) coach-directed behavioral weight loss, or ) self-directed care (control) for 12 months. We collected stool and serum at baseline ( = 114), 6 months ( = 109), and 12 months ( = 105). From stool, we extracted microbial DNA and conducted amplicon and metagenomic sequencing. We measured SCFAs and other biochemical parameters from fasting serum. RESULTS: Of the 121 participants, 79% were female and 46% were Black, and the mean age was 60 years. Only metformin treatment significantly altered microbiota composition. Compared with control, metformin treatment increased amplicon sequence variants for (confirmed as by metagenomic sequencing) and and decreased at both 6 and 12 months and decreased the genus , including and at 12 months. Effects were similar in comparison of the metformin group with the behavioral weight loss group. Metformin versus control also increased butyrate, acetate, and valerate at 6 months (but not at 12 months). Behavioral weight loss versus control did not significantly alter microbiota composition but did increase acetate at 6 months (but not at 12 months). Increases in acetate were associated with decreases in fasting insulin. Additional whole-genome metagenomic sequencing of a subset of the metformin group showed that metformin altered 62 metagenomic functional pathways, including an acetate-producing pathway and three pathways in glucose metabolism. CONCLUSIONS: Metformin, but not behavioral weight loss, impacted gut microbiota composition at 6 months and 12 months. Both metformin and behavioral weight loss altered circulating SCFAs at 6 months, including increasing acetate, which correlated with lower fasting insulin. Future research is needed to elucidate whether the gut microboime mediates or modifies metformin's health effects.
目的：确定二甲双胍治疗和行为性体重减轻对肠道微生物群和短链脂肪酸（SCFA）的长期影响。
研究设计和方法：我们进行了一项 3 组平行随机试验。我们招募了接受过实体瘤治疗但无持续癌症治疗的超重/肥胖成年人，并将他们随机分为（=121））二甲双胍（高达 2000mg））教练指导的行为性体重减轻，或）自我指导的护理（对照组）治疗 12 个月。我们在基线（=114）、6 个月（=109）和 12 个月（=105）时收集粪便和血清。我们从粪便中提取微生物 DNA 并进行扩增子和宏基因组测序。我们从空腹血清中测量 SCFA 和其他生化参数。
结果：在 121 名参与者中，79%为女性，46%为黑人，平均年龄为 60 岁。只有二甲双胍治疗显著改变了微生物群落组成。与对照组相比，二甲双胍治疗增加了（通过宏基因组测序确认为）和的扩增子序列变异，并在 6 个月和 12 个月时降低了，同时在 12 个月时降低了属，包括和。在与行为性体重减轻组的比较中，二甲双胍组的效果相似。与对照组相比，二甲双胍也增加了 6 个月时的丁酸盐、乙酸盐和戊酸盐（但 12 个月时没有）。行为性体重减轻与对照组相比，微生物群落组成没有显著变化，但确实增加了 6 个月时的乙酸盐（但 12 个月时没有）。乙酸盐的增加与空腹胰岛素的降低有关。对二甲双胍组的一部分进行的全基因组宏基因组测序显示，二甲双胍改变了 62 个宏基因组功能途径，包括一个产生乙酸盐的途径和三个葡萄糖代谢途径。
结论：二甲双胍而非行为性体重减轻在 6 个月和 12 个月时影响肠道微生物群落组成。二甲双胍和行为性体重减轻都在 6 个月时改变了循环 SCFA，包括增加乙酸盐，这与空腹胰岛素降低有关。需要进一步的研究来阐明肠道微生物群是否介导或改变二甲双胍的健康效应。
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