Baseline gut microbiome composition predicts metformin therapy short term efficacy in newly diagnosed type 2 diabetes patients

BackgroundThe study was conducted to investigate the effects of metformin treatment on the human gut microbiome’s taxonomic and functional profile in the Latvian population, and to evaluate the correlation of these changes with the therapeutic efficacy and tolerance.MethodsIn this longitudinal observational study, stool samples for shotgun metagenomic sequencing based analysis were collected in two cohorts. The first cohort included 35 healthy nondiabetic individuals (metformin dose 2x850mg/day) at three time-points during metformin administration. The second cohort was composed of 50 newly-diagnosed type 2 diabetes patients (metformin dose – determined by an endocrinologist) at two concordant times. Patients were defined as Responders if their HbA1c levels during three months of metformin therapy had decreased by ≥12.6 mmol/mol (1%), while in Non-responders HbA1c were decreased by <12.6 mmol/mol (1%).ResultsMetformin reduced the alpha diversity of microbiota in healthy controls (p=0.02) but not in T2D patients. Reduction in the abundance of Clostridium bartlettii overlapped between both study groups, and a large number of group-specific changes in taxonomic and functional profiles was observed. We identified an increased abundance of Prevotella copri (FDR=0.01) in Non-Responders subgroup, and enrichment of Enterococcus faecium, Lactococcus lactis, Odoribacter, and Dialister at baseline in the Responders group. Various taxonomic units were associated with the observed incidence of side effects in both cohorts.ConclusionsMetformin effects are different in T2D patients and healthy individuals. Therapy induced changes in the composition of gut microbiome revealed possible mediators of observed short-term therapeutic effects. The baseline composition of the gut microbiome may influence metformin therapy efficacy and tolerance in T2D patients and could be used as a powerful prediction tool.

研究背景
本研究旨在探究二甲双胍（metformin）治疗对拉脱维亚人群人类肠道微生物组（gut microbiome）的分类学与功能特征的影响，并评估这些变化与治疗疗效及耐受性的相关性。

研究方法
本项纵向观察性研究共纳入两个队列，用于收集粪便样本以开展基于鸟枪法宏基因组测序（shotgun metagenomic sequencing）的分析。第一队列包含35名健康非糖尿病个体，在二甲双胍给药期间的3个时间点进行采样，其给药剂量为每日2次、每次850mg。第二队列由50名新诊断的2型糖尿病患者组成，在两个匹配的时间点采样，其二甲双胍给药剂量由内分泌科医师确定。本研究将二甲双胍治疗3个月后糖化血红蛋白（HbA1c）水平降低≥12.6 mmol/mol（即1%）的患者定义为应答者，将糖化血红蛋白水平降低<12.6 mmol/mol（即1%）的患者定义为非应答者。

研究结果
二甲双胍可降低健康对照组人群的肠道菌群α多样性（p=0.02），但对2型糖尿病患者无此影响。两个研究队列均观察到巴特梭菌（Clostridium bartlettii）的丰度降低，且两组均存在大量分类学与功能特征的组特异性变化。本研究发现，非应答者亚组中普氏菌（Prevotella copri）的丰度显著升高（错误发现率FDR=0.01）；而应答者组基线时的屎肠球菌（Enterococcus faecium）、乳酸乳球菌（Lactococcus lactis）、气味杆菌属（Odoribacter）及戴氏菌属（Dialister）的丰度均显著富集。此外，两个队列中多种分类学单元均与观察到的不良反应发生率相关。

研究结论
二甲双胍对2型糖尿病患者与健康个体的作用存在差异。治疗诱导的肠道微生物组组成变化，揭示了可能介导短期治疗效应的潜在调控因子。肠道微生物组的基线组成可影响2型糖尿病患者的二甲双胍治疗疗效与耐受性，有望作为有效的预测工具。