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Metformin is the first-line treatment for type 2 diabetes, yet its mechanism of action is not fully under- stood. Recent studies suggest metformin’s interactions with gut microbiota are responsible for exerting therapeutic effects. In this study, we report that metformin targets the gut microbial enzyme agmatinase, as a competitive inhibitor, which may impair gut agmatine catabolism. The metformin inhibition constant (Ki) of E. coli agmatinase is 1 mM and relevant in the gut where the drug concentration is 1–10 mM. Met- formin analogs phenformin, buformin, and galegine are even more potent inhibitors of E. coli agmatinase (Ki = 0.6, 0.1, and 0.007 mM, respectively) suggesting a shared mechanism. Agmatine is a known effector of human host metabolism and has been reported to augment metformin’s therapeutic effects for type 2 diabetes. This gut-derived inhibition mechanism gives new insights on metformin’s action in the gut and may lead to significant discoveries in improving metformin therapy.