Metformin-induced changes of the gut microbiota in healthy young men: results of a non-blinded, one-armed intervention study
Metformin-induced changes of the gut microbiota in healthy young men: results of a non-blinded, one-armed intervention study
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DOI：
10.1007/s00125-019-4848-7
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发表时间：
2019-06-01
期刊：
影响因子：
8.2
通讯作者：
Nielsen, Trine
中科院分区：
文献类型：
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作者：
Bryrup, Thomas;Thomsen, Caecilie W.;Nielsen, Trine
与非糖尿病个体相比，2型糖尿病个体的肠道微生物群的细菌组成发生了改变。然而，这些变化可能会受到药物的混淆，特别是降糖双胍，二甲双胍。我们进行了一项临床试验，在健康和以前的药物免费男子的主要目的是调查二甲双胍引起的成分变化，在非糖尿病状态。第二个目的是检查是否治疗前肠道菌群与胃肠道不良反应二甲双胍treatment.Methods 27名健康的年轻丹麦男子被列入一个为期18周的单臂交叉试验，包括干预前的时期，干预期和干预后的时期，每个时期持续6周。入选标准为18-35岁男性，BMI在18.5 kg/m2和27.5 kg/m2之间，HbA（1c）< 39 mmol/mol（5.7%），血浆肌酐在正常范围内。招募前2个月内不允许使用处方药（包括抗生素），既往无胃肠道手术、阑尾切除术或需要药物治疗的慢性疾病。在干预期间，参与者每天两次给予二甲双胍1 g。参与者在空腹状态下接受了五次检查，并采集了血液样本并记录了胃肠道症状。在干预前和干预后、干预中途和干预结束后即刻以及洗脱期后，在丹麦的弗雷德里克斯贝格医院进行检查。在9个均匀分布的时间点收集粪便样品，提取细菌DNA并进行16 S rRNA基因扩增子测序，以评估肠道微生物群组成。主观胃肠道症状在每次visit.Results完成访问1（n = 23）的参与者的数据包括在分析中。对于主要结果，11种细菌属的相对丰度在干预期间显著变化，但在治疗停止后恢复到基线水平。与以前的报告一致，我们观察到肠杆菌属的丰度降低。和梭菌属，以及大肠杆菌/志贺氏菌属的丰度增加。和巴氏双花。在基线的相对丰度12个细菌属预测自我报告的胃肠道不良反应。结论/解释二甲双胍的摄入量改变肠道菌群组成的normocellular年轻男子。二甲双胍引起的微生物群变化扩展并验证了先前在2型糖尿病患者中的报告。次要分析表明，治疗前肠道微生物群组成可能是二甲双胍摄入后胃肠道不良反应发生的决定因素。这些结果需要在更大的前瞻性研究中进一步调查和复制。
Aims/hypothesis Individuals with type 2 diabetes have an altered bacterial composition of their gut microbiota compared with non-diabetic individuals. However, these alterations may be confounded by medication, notably the blood-glucose-lowering biguanide, metformin. We undertook a clinical trial in healthy and previously drug-free men with the primary aim of investigating metformin-induced compositional changes in the non-diabetic state. A secondary aim was to examine whether the pre-treatment gut microbiota was related to gastrointestinal adverse effects during metformin treatment.Methods Twenty-seven healthy young Danish men were included in an 18-week one-armed crossover trial consisting of a pre-intervention period, an intervention period and a post-intervention period, each period lasting 6 weeks. Inclusion criteria were men of age 18-35 years, BMI between 18.5 kg/m(2) and 27.5 kg/m(2), HbA(1c) < 39 mmol/mol (5.7%) and plasma creatinine within the normal range. No prescribed medication, including antibiotics, for 2 months prior to recruitment were allowed and no previous gastrointestinal surgery, discounting appendectomy or chronic illness requiring medical treatment. During the intervention the participants were given metformin up to 1 g twice daily. Participants were examined five times in the fasting state with blood sampling and recording of gastrointestinal symptoms. Examinations took place at Frederiksberg Hospital, Denmark before and after the pre-intervention period, halfway through and immediately after the end of intervention and after the wash-out period. Faecal samples were collected at nine evenly distributed time points, and bacterial DNA was extracted and subjected to 16S rRNA gene amplicon sequencing in order to evaluate gut microbiota composition. Subjective gastrointestinal symptoms were reported at each visit.Results Data from participants who completed visit 1 (n = 23) are included in analyses. For the primary outcome the relative abundance of 11 bacterial genera significantly changed during the intervention but returned to baseline levels after treatment cessation. In line with previous reports, we observed a reduced abundance of Intestinibacter spp. and Clostridium spp., as well as an increased abundance of Escherichia/Shigella spp. and Bilophila wadsworthia. The relative abundance at baseline of 12 bacterial genera predicted self-reported gastrointestinal adverse effects.Conclusions/interpretation Intake of metformin changes the gut microbiota composition in normoglycaemic young men. The microbiota changes induced by metformin extend and validate previous reports in individuals with type 2 diabetes. Secondary analyses suggest that pre-treatment gut microbiota composition may be a determinant for development of gastrointestinal adverse effects following metformin intake. These results require further investigation and replication in larger prospective studies.