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

Abstract

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

An online atlas of human plasma metabolite signatures of gut microbiome composition

“…Here we identified 152 species, whose abundances were associated with metformin, of which an increased abundance of Escherichia marmotae and E. coli , and decreased abundance of Romboutsia timonensis and Intestinibacter bartlettii were the strongest associations. These top findings are in accordance with earlier studies reporting a significant enrichment of E. coli in the gut microbiota of metformin users 13,40,41 and a decreased abundance in R. timonensis and I. bartletii 13 , as well as with a recent randomized trial that showed that metformin treatment in overweight/obese individuals results in an increased abundance of E. coli and a decreased abundance of I. bartlettii at 6 and 12 months of metformin treatment 42 . Further, an increase of Ruminococcus torques was reported at both time points in that study 42 which is also supported by an earlier study 13 and our study ( p -value = 7.4 × 10 −7 ).…”

“…These top findings are in accordance with earlier studies reporting a significant enrichment of E. coli in the gut microbiota of metformin users 13,40,41 and a decreased abundance in R. timonensis and I. bartletii 13 , as well as with a recent randomized trial that showed that metformin treatment in overweight/obese individuals results in an increased abundance of E. coli and a decreased abundance of I. bartlettii at 6 and 12 months of metformin treatment 42 . Further, an increase of Ruminococcus torques was reported at both time points in that study 42 which is also supported by an earlier study 13 and our study ( p -value = 7.4 × 10 −7 ). R. timonensis is a new species that was recently isolated from the human gut 43 and has not been associated with use of metformin prior to the Mueller et al study 42 .…”

“…Further, an increase of Ruminococcus torques was reported at both time points in that study 42 which is also supported by an earlier study 13 and our study ( p -value = 7.4 × 10 −7 ). R. timonensis is a new species that was recently isolated from the human gut 43 and has not been associated with use of metformin prior to the Mueller et al study 42 . In species associated with metformin, we found an enrichment for bacterial functional modules related to sugar metabolism and sugar transport systems.…”

“…The copyright holder for this this version posted December 30, 2021. ; https://doi.org/10.1101/2021.12.23.21268179 doi: medRxiv preprint metformin prior to the Mueller et al study 42 . In species associated with metformin, we found an enrichment for bacterial functional modules related to sugar metabolism and sugar transport systems.…”

Supplementation With Chinese Medicinal Plant Extracts From Lonicera hypoglauca and Scutellaria baicalensis Mitigates Colonic Inflammation by Regulating Oxidative Stress and Gut Microbiota in a Colitis Mouse Model

“…Therefore, more research is needed to explore the protective mechanisms of Dubosiella for intestinal inflammation. The relative abundance of Ruminococcus torques group was increased after metformin treatment, which improved overweight/obese adults ( Mueller et al, 2021 ). It means that Ruminococcus torques group could alleviate obesity.…”