Bacteroides acidifaciens exacerbates cardiac ischemia/reperfusion injury via the microbial-host isozyme DPP4

Ischemia/reperfusion (I/R) injury is a key driver in cardiomyocyte loss and cardiac dysfunction in ischemic heart disease. Here, we uncover a previously unrecognized gut microbiota-mediated mechanism that contributes to myocardial I/R injury. Using murine I/R models and fecal microbiota transplantation, we demonstrate that the gut microbiota mediates cardiac damage through selective enrichment of Bacteroides acidifaciens (B. acidifaciens) following I/R-induced intestinal hypoxia and elevated luminal lactate levels. B. acidifaciens produces dipeptidyl peptidase 4 (BaDPP4), which degrades cardioprotective peptides (e.g., glucagon-like peptide-1 [GLP-1]) in the plasma, amplifying myocardial injury. Pharmacological inhibition of BaDPP4 with daurisoline, a microbial DPP4-specific inhibitor, mitigates cardiac dysfunction. In acute myocardial infarction patients with I/R injury, B. acidifaciens abundance and BaDPP4 levels correlate with clinical markers of cardiac damage. Together, these findings reveal a gut-heart axis whereby microbial-derived DPP4 exacerbates cardiac I/R injury and highlight the hypoxia-lactate-BaDPP4 axis as a promising target for microbiota-based cardioprotection.