Gut-derived metabolites and mitochondrial homeostasis in heart failure: mechanistic links and translational perspectives.

Heart failure is a chronic cardiovascular syndrome with high morbidity and mortality worldwide, and its progression is closely linked to myocardial metabolic remodeling and disruption of mitochondrial homeostasis. Increasing evidence suggests that the gut microbiota and its metabolites represent an important interface between diet, inflammation, metabolic stress, and cardiovascular remodeling. Gut-derived metabolites, including short-chain fatty acids, trimethylamine N-oxide, tryptophan-derived metabolites, bile acids, phenylacetylglutamine, indoxyl sulfate, and urolithins, may influence myocardial mitochondrial homeostasis by affecting substrate oxidation, oxidative phosphorylation, reactive oxygen species production, inflammatory signaling, mitochondrial dynamics, mitophagy, and cell-death pathways. However, these metabolites should not be interpreted as uniformly protective or detrimental, because their biological effects may depend on concentration, exposure duration, bioavailability, protein binding, renal clearance, cellular targets, host metabotype, experimental model, and heart failure phenotype. Short-chain fatty acids and indole-3-propionic acid (IPA) have been linked to mitochondrial oxidative metabolism, nicotinamide adenine dinucleotide (NAD+)/sirtuin 3 (SIRT3)-related mitochondrial signaling, and inflammatory regulation in selected experimental settings, whereas the choline/trimethylamine N-oxide axis, indoxyl sulfate, phenylacetylglutamine, and dysregulated bile acid metabolism are associated with myocardial fibrosis, oxidative stress, mitochondrial dysfunction(definition), and adverse outcomes. Nevertheless, many clinical associations may be influenced by renal dysfunction, disease severity, and heart-to-gut reverse causality, and many mechanistic findings remain derived from animal models, <i>ex vivo</i> systems, or non-classical heart-failure models. This narrative review summarizes current evidence linking gut-derived metabolites to myocardial mitochondrial homeostasis in heart failure, with emphasis on energy metabolic remodeling, oxidative stress, inflammation, mitochondrial quality control, cell death, and fibrotic remodeling. Potential intervention strategies targeting the gut microbiota and its metabolic pathways are also discussed with attention to their translational limitations and to the need for direct mitochondrial readouts, cell-type-specific validation, and phenotype-specific clinical studies.