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Metformin is widely used in the treatment of type 2 diabetes (T2D), but its mechanism of action is poorly defined. Recent evidence implicates the gut microbiota as a site of metformin action. In a double-blind study, we randomized individuals with treatment-naive T2D to placebo or metformin for 4 months and showed that metformin had strong effects on the gut microbiome. These results were verified in a subset of the placebo group that switched to metformin 6 months after the start of the trial. Transfer of fecal samples (obtained before and 4 months after treatment) from metformin-treated donors to germ-free mice showed that glucose tolerance was improved in mice that received metformin-altered microbiota. By directly investigating metformin-microbiota interactions in a gut simulator, we showed that metformin affected pathways with common biological functions in species from two different phyla, and many of the metformin-regulated genes in these species encoded metalloproteins or metal transporters. Our findings provide support for the notion that altered gut microbiota mediates some of metformin's antidiabetic effects.
Hao Wu,Eduardo Esteve
José Manuel Fernández-Real,Fredrik Bäckhed
Hao Wu,Eduardo Esteve,Valentina Tremaroli,Muhammad Tanweer Khan,Robert Caesar,Louise Mannerås-Holm,Marcus Ståhlman,Lisa M Olsson,Matteo Serino,Mercè Planas-Fèlix,Gemma Xifra,Josep M Mercader,David Torrents,Rémy Burcelin,Wifredo Ricart,Rosie Perkins,José Manuel Fernández-Real,Fredrik Bäckhed