A gut mycobiota-heart axis: fungal Talaromyces rugulosus exacerbates myocardial I/R injury via depletion of protective metabolite DMS

Ischemic heart disease remains a leading cause of global mortality. Current clinical treatment mainly relies on reperfusion techniques to restore blood supply. However, the reperfusion process itself induces additional damage, known as ischemia/reperfusion (I/R) injury. While a large number of studies have shown that gut bacteria are closely related to cardiovascular disease progression, the role of gut fungi remains unexplored. Here, we identify a previously unknown gut mycobiota-mediated mechanism that exacerbates myocardial I/R injury. Using murine I/R models and internal transcribed spacer 2 (ITS2) sequencing, we demonstrate that cardiac I/R injury selectively enriches the gut fungus Talaromyces rugulosus (T. rugulosus), and oral colonization with T. rugulosus aggravates cardiac dysfunction, inflammation, and oxidative stress. Mechanistically, T. rugulosus directly degrades N,N-dimethylsphingosine (DMS), a protective sphingolipid metabolite, as evidenced by significant reductions in both intestinal and circulating DMS levels upon fungal colonization, and in vitro assays confirming specific DMS degradation by the fungus. DMS supplementation reverses T. rugulosus exacerbated myocardial injury, attenuating inflammatory infiltration and oxidative burst. Collectively, these findings reveal a gut mycobiota-heart axis in which fungal-derived DMS depletion exacerbates cardiac I/R injury, and highlight DMS as a promising metabolic checkpoint and therapeutic target for microbiota-based cardioprotection.