Identification of Critical Gut Metabolites Mediating the Protective Effects of Lacticaseibacillus paracasei on Myocardial Injury in Mice

Heart failure is a leading cause of mortality worldwide, with myocardial injury as a major pathological contributor. Probiotics have shown cardioprotective effects, but their key gut metabolites remain unclear. In this study, Lacticaseibacillus paracasei DACN528, isolated from traditional fermented yak yogurt, significantly improved body weight (13.95% increase) and heart index (18.73% increase) and reduced serum cTnI and NT-proBNP levels by 54.96 and 22.05%, respectively, in a doxorubicin-induced mouse model of myocardial injury (all p < 0.05). Electrocardiographic abnormalities were attenuated, including reductions in QT interval (29.13%), PR interval (7.98%), and ST segment elevation (28.74%). Histological analyses revealed reduced myocardial fibrosis and apoptosis, with regulation of fibrosis- and apoptosis-related genes. DACN528 also modulated mitochondrial dynamics and autophagy by altering expression of Fis1, Drp1, Mfn2, and Parkin. Moreover, it reshaped gut microbiota composition by increasing beneficial taxa such as Lactobacillus and norank_f__Muribaculaceae while decreasing harmful ones such as Allobaculum. Metabolomic and correlation analyses identified seven microbial metabolites potentially involved in cardioprotection. Among them, 5-hydroxymethylfurfural showed protective effects in H9C2 cardiomyocytes. These findings provide mechanistic insights into probiotic-mediated myocardial protection and support DACN528 as a promising candidate for cardiovascular health interventions.