Multi-Omics Causal Inference Identifies <i>Phocaeicola vulgatus</i> –Mediated 5’-Methylthioadenosine Clearance Contributing to Mitochondrial Protection in Heart Failure

Abstract Background Heart failure (HF) is a multifactorial metabolic disorder. While gut microbial dysbiosis is increasingly implicated in HF, the specific causal microbes and their molecular mediators linking intestinal perturbations to cardiac dysfunction remain undefined. Methods We performed integrated fecal 16S rRNA and serum metabolomic profiling in a clinical HF cohort comprising 149 HF patients and 50 healthy controls. We systematically assessed the multidimensional alterations and diagnostic potential of the gut microbiome and serum metabolome. Key microbe-metabolite interactions were identified through causal inference and experimentally validated using i n vitro bacterial cultures, in vivo mouse models of HF, and assays of mitochondrial function. Results HF patients exhibited significant alterations in the gut microbiome and serum metabolome related to energy homeostasis, vascular tone regulation, and inflammatory balance. These differential microbial and metabolic signatures demonstrated superior diagnostic potential for HF. A key finding was depletion of the commensal bacterium Phocaeicola vulgatus led to the accumulation of serum 5’-methylthioadenosine (MTA), which in turn induced mitochondrial dysfunction and aggravated cardiac injury. Restoring P. vulgatus mitigated these effects by metabolizing MTA, whereas direct MTA administration recapitulated mitochondrial dysfunction and exacerbated HF pathology. Conclusions This study provides an integrative multi-omics perspective on the gut microbiome-serum metabolome interplay in HF, revealing both diagnostic biomarkers and mechanistic insights. Through a causal inference framework, we identify the P. vulgatus –MTA axis as a causal pathway through which gut microbes influence HF progression.