Lactococcus lactis subsp. Cremoris reprograms systemic metabolism and protects against myocardial injury.

Therapeutic microbes are increasingly recognized as potent modulators of host physiology, yet their influence beyond the gut remains underexplored. While Lactococcus lactis subsp. Cremoris (LLC) has been shown to preserve gut epithelial integrity and counteract Western diet-induced metabolic syndrome in murine models, its effects on extraintestinal systems such as the gut-cardiovascular axis, are not well defined. In this study, we employed a multimodal experimental approach to investigate whether LLC confers cardioprotective benefits. We showed that LLC supplementation significantly preserved cardiac function and reduced myocardial scarring following ischemia-reperfusion injury. Untargeted metabolomic profiling of cardiac tissue revealed distinct shifts in the cardiac metabolome, with pathway enrichment analyses highlighting alterations in glutathione metabolism, fatty acid degradation, and other key cardiometabolic pathways. Furthermore, we employed weighted gene coexpression network analysis of our cardiac metabolomics dataset to capture the system-level changes induced by LLC. These findings position LLC as a promising probiotic capable of promoting systemic metabolic reprogramming and mitigating adverse cardiovascular outcomes. Our data support a model in which LLC exerts cardioprotective effects through the modulation of lipid metabolism and enhancement of anti-inflammatory signaling along the gut‒heart axis.