Metformin Affects Gut Microbiome Composition and Function and Circulating Short-Chain Fatty Acids: A Randomized Trial.

Abstract

To determine the longer-term effects of metformin treatment and behavioral weight loss on gut microbiota and short-chain fatty acids (SCFAs). 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 (<i>n</i> = 121) to either <i>1</i>) metformin (up to 2,000 mg), <i>2</i>) coach-directed behavioral weight loss, or <i>3</i>) self-directed care (control) for 12 months. We collected stool and serum at baseline (<i>n</i> = 114), 6 months (<i>n</i> = 109), and 12 months (<i>n</i> = 105). From stool, we extracted microbial DNA and conducted amplicon and metagenomic sequencing. We measured SCFAs and other biochemical parameters from fasting serum. 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 <i>Escherichia</i> (confirmed as <i>Escherichia coli</i> by metagenomic sequencing) and <i>Ruminococcus torques</i> and decreased <i>Intestinibacter bartlettii</i> at both 6 and 12 months and decreased the genus <i>Roseburia</i>, including <i>R. faecis</i> and <i>R. intestinalis,</i> 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. 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.