Here, Chen et. al. characterize the relationship between the gut microbiota and plasma metabolite changes in the context of ST-elevation myocardial infarction (STEMI), unveiling a role of butyrate-producing bacteria and their ketogenesis in post-STEMI cardiac repair, a finding validated in nonhuman primate and mouse models. They show that butyrate supplementation reduces myocardial infarction severity in mice, underscoring the significance of butyrate-producing bacteria and beta-hydroxybutyrate in improving post-MI outcomes.