Mingolelli et al. characterize microbiome metabolism of coumarin in ex vivo cultures from human stool. Seventeen gut species reduce coumarin to 3,4-dihydrocoumarin and melilotic acid, including E. coli, through an N-ethylmaleimide-reductase-dependent pathway. Gut metabolites demonstrate increased antioxidant activity compared to either coumarin or its host metabolite, umbelliferone.