Abstract
Aims/hypothesisIndividuals 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.MethodsTwenty-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/m2 and 27.5 kg/m2, HbA1c < 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.ResultsData 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/interpretationIntake 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.Trial registrationClinicaltrialsregister.eu 2015-000199-86 and ClinicalTrials.gov NCT02546050FundingThis project was funded by Danish Diabetes Association and The Novo Nordisk Foundation
Highlights
The biguanide, metformin, has been the first-line oral glucose-lowering drug of choice when treating type 2 diabetes
Twenty-four participants started the intervention with metformin and 25 participants with relevant data were included in analyses (Fig. 1b)
We show that metformin intervention has an impact on the composition of the human gut microbiota at genus and amplicon sequence variants (ASVs) levels in healthy young men, and these changes are reversed after discontinuation of metformin
Summary
The biguanide, metformin, has been the first-line oral glucose-lowering drug of choice when treating type 2 diabetes. The gut microbiota is involved in intestinal bile acid metabolism and short-chain fatty acid production, which could explain some of the glucoselowering effect of metformin, through effects on incretin secretion, hepatic glucose homeostasis and beta cell function [19, 20]. Data from 22 patients with type 2 diabetes, treated with metformin for 3 days, showed a Bacteroides fragilis-linked increase in the intestinal concentration of glycoursodeoxycholic bile acid, which in rodent studies has been associated with improvement of hyperglycaemia [15]. The faecal concentration of the short-chain fatty acid propionate was increased in 15 metformin users compared with nine non-users [21]. A hyperglycaemia-independent effect of metformin on the induced perturbation of the gut microbiota has recently been shown after 1 week of metformin intake in 18 healthy individuals [16], and elucidation hereon could further our understanding of the link between type 2 diabetes and the gut microbiota
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