Metformin-induced changes of the gut microbiota in patients with type 2 diabetes mellitus: Results from a prospective cohort study

Abstract

Abstract Background The microbiota's impact on hypoglycemic agents is increasingly evident. However, the influence of metformin, a primary anti-diabetes drug, on gut microbiota remains unclear. Research design and methods This prospective cohort study aimed to investigate the longitudinal effects of metformin on the gut microbiota in 25 newly diagnosed, treatment-naïve diabetes patients receiving 1500 mg daily doses. Microbiota compositions were analyzed at baseline, 1, 3, and 6 months using 16S rRNA gene se-quencing. Results Metformin showed clinical improvements, but no significant dissimilarity in microbiome composition structure (Adonis: P = 0.077). Species richness and intestinal flora diversity declined, and α diversity significantly decreased after 3 months. The Firmicutes to Bacteroidetes ratio (ANOVA: P = 0.037) markedly decreased. Metformin treatment consistently increased Escherichia-Shigella and decreased Romboutsia, while Pseudomonas decreased at 3 months. Fuzzy c-means clustering identified three longitudinal trajectory clusters for microbial fluctuations: (i) genera temporarily changing, (ii) genera continuing to decrease (Bacteroides), and (iii) genera continuing to increase(Lachnospiraceae ND3007 group, [Eubacterium] xylanophilum group, Romboutsia, Faecalibacterium and Ruminococcaceae UCG-014). The correlation matrix revealed associations between specific fecal taxa and metformin-related clinical parameters hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), Uric Acid (UA), high-density lipoproteincholesterol (HDL-C), alanine aminotransferase (ALT), C-reactive protein(CRP), triglyceride(TG) (p < 0.05). Metacyc database showed that metformin significantly altered 17 functional pathways. Amino acid metabolism pathways such as isoleucine biosynthesis predominated in the post-treatment group. Conclusions Metformin's role in glucose metabolism regulation may primarily involve specific alterations in certain gut microbial species rather than an overall increase in microbial species diversity. This may suggest gut microbiota targets in future studies on metabolic abnormalities caused by metformin.