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.

Trial registration: ClinicalTrials.gov NCT02431676.

Figure 1

Change in relative abundance of gut microbiota ASVs between baseline and 6 months (top row) and baseline and 12 months (bottom row) in coach-directed weight loss arm, metformin arm, and self-directed weight loss arm. Colored ASVs are statistically significant at P < 0.05 before FDR correction. Colored dots to the left are higher in relative abundance at baseline, and colored dots to the right are higher at either 6 months or 12 months. Sample sizes by treatment arm: coach-directed baseline n = 36, 6 months n = 35, and 12 months n = 35; metformin baseline n = 40, 6 months n = 38, and 12 months n = 32; and self-directed baseline n = 38, 6 months n = 36, and 12 months n = 38.

Figure 2

Comparison of mean change in center log ratio (CLR) transformed bacterial abundances from baseline to 6 months and 12 months between treatment arms. Point estimates and 95% CIs are provided in Supplementary Table 3. Sample sizes by treatment arm: coach-directed (C) baseline n = 35, 6 months n = 35, and 12 months n = 35; metformin (M) baseline n = 38, 6 months n = 38, and 12 months n = 32; and self-directed (S) baseline n = 38, 6 months n = 36, and 12 months n = 38.

Figure 3

Comparison of mean change in log-transformed serum SCFAs from baseline to 6 months and 12 months between treatment arms (n = 118 at 6 months; n = 113 at 12 months). Point estimates and 95% CIs are provided in Supplementary Table 6. C, coach-directed; M, metformin; S, self-directed.