Aims: Heart failure (HF) is associated with profound changes in cardiac metabolism. At present, there is still a lack of relevant research to explore the key microbiome and their metabolites affecting the progression of HF. Herein, the interaction of gut microbiota and circulating free fatty acid (FFA) in HF patients and mice is investigated. Methods and Results: In HF patients, by applying metagenomics analysis and targeted FFA metabolomics, enriched abundance of Clostridium sporogenes (C.sp) in early and late stage of HF patients, which negatively correlated to saturated free fatty acid (SFA) levels, is identified. KEGG analysis further indicates microbiota gene enrichment in FFA degradation in early HF, and decreased gene expression in FFA synthesis in late HF. In HF mice (C57BL/6J) induced by isoproterenol (ISO), impaired intestinal permeability is observed, and decreased fecal C.sp and increased SFA are further validated. At last, by supplementing C.sp to ISO‐induced HF mice, the cardiac function, fibrosis, and myocardial size are partially rescued, together with decreased circulating SFA levels. Conclusions: Clostridium abundance is increased in HF, compensating cardiac function deterioration via downregulation of circulating SFA levels. The results demonstrate that the gut microbiota–SFA axis plays an important role in HF protection, which may provide a strategic advantage for the probiotic therapy development in HF.
