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

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posted on 2021-05-18, 14:16 authored by Noel T. Mueller, Moira K. Differding, Mingyu Zhang, Nisa Maruthar, Stephen P Juraschek, Edgar R. Miller III, Lawrence J. Appel, Hsin-Chieh Yeh
Objective: To determine the longer-term effects of metformin and behavioral weight loss on gut microbiota and SCFAs.

Methods: We conducted a 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: 1) metformin (up to 2000mg), 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, 46% were black, and the mean age was 60y. Only metformin intervention significantly altered microbiota composition. Compared to control, metformin increased E. Coli and Ruminococcus torques and decreased Intestinibacter Bartletti at both 6 and 12 months, and decreased the genus Roseburia (genus), including R. faecis and R. intestinalis, at 12 months. Effects were similar when comparing metformin to the behavioral weight loss group. Metformin also altered 62 metagenomic functional pathways and increased butyrate, acetate, and valerate at 6 months. Behavioral weight loss vs. control did not significantly alter microbiota composition, but did increase acetate at 6 months. Increases in acetate were associated with decreases in fasting insulin.

Conclusions: Metformin, but not behavioral weight loss, impacted gut microbiota composition and function at 6 months and 12 months. Both metformin and behavioral weight loss altered 6-month SCFAs, including increasing acetate which correlated with improved insulin sensitivity.


The SPIRIT study was funded by the Maryland Cigarette Restitution Fund. N.T.M. was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health (K01HL141589). HCY was supported in part by the National Cancer Institute’s Cancer Centers Support Grant to the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (5P30CA006973)


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