Microbial aldehyde-alcohol dehydrogenase degrades metformin to limit therapeutic response in type 2 diabetes.

Metformin is a first-line therapy for type 2 diabetes, yet therapeutic responses vary widely. Whether gut microbes directly inactivate metformin and limit its efficacy remains unclear. Here, we identify a gut microbial aldehyde-alcohol dehydrogenase, AdhE, from Eubacterium species enriched in individuals with a low response to metformin. AdhE converts metformin to pharmacologically inactive products, lowering intestinal and systemic drug exposure. Genetic deletion of AdhE or phage-mediated depletion of AdhE-producing Eubacterium hallii MD1 restores metformin exposure and glycemic control in mice. An artificial intelligence-guided structure-based screen identifies the dietary phytochemical daidzein as a microbial AdhE inhibitor that blocks metformin degradation and improves metformin responsiveness. These findings establish gut microbial drug inactivation as a modifiable determinant of therapeutic response and provide a framework for microbial enzyme-guided strategies to improve established therapies.