Background: Circulating SCFAs, produced by gut microbiota, have been associated with lower cardiometabolic disease risk factors. Evidence suggests metformin and behavioral weight loss alter gut microbiota, but no trials have examined their effects on circulating SCFAs.

Objective: To determine the effects of metformin and behavioral weight loss on serum SCFAs.

Methods: We conducted a parallel-arm, randomized trial, called SPIRIT. We enrolled overweight/obese adults who were previously treated for malignant tumors, but had no ongoing cancer treatment. We randomized 121 participants to 12 months of: 1) coach-directed behavioral weight loss, 2) metformin, or 3) self-directed weight loss (control). Targeted SCFAs were measured in serum by LC-MS/MS. We used ANCOVA to compare group differences in SCFA change from baseline to 6 months and 12 months.

Results: Groups did not differ by sex (79% female), race (45% black) or age (mean 60 years). At 6 months, mean weight loss was 3.9%, 2.7%, and 0.9% in coach-directed, metformin, and self-directed, respectively (both Ps<0.05 compared to self-directed). Compared to self-directed, metformin and coach-directed interventions increased acetate at 6 months (not 12 months); metformin increased butyrate and valerate at 6 months (not 12 months); and coach-directed decreased methylbutyrate at 12 months (Figure).

Conclusion: Metformin and behavioral weight loss affect serum SCFAs.


N.T. Mueller: None. M. Zhang: None. S.P. Juraschek: None. E. Miller: None. N.M. Maruthur: Other Relationship; Self; Johns Hopkins HealthCare Solutions. L.J. Appel: None.


Maryland Department of Health and Mental Hygiene; National Institutes of Health (to N.T.M.)

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