Heart failure (HF) affects over 55 million individuals globally, with prevalence projected to exceed 11 million in the United States by 2050 and is increasingly recognized as a systemic disorder extending beyond hemodynamic dysfunction to encompass profound alterations in neural and gut physiology. Cognitive impairment affects nearly half of HF patients and represents a major determinant of morbidity, self-care capacity, and mortality. Recent advances suggest that the gut microbiome serves as a pivotal intermediary in the heart–brain crosstalk, influencing neurocognitive outcomes through inflammatory, metabolic, and neurohumoral pathways. Dysbiosis in HF disrupts intestinal barrier integrity, facilitating translocation of endotoxins and microbial metabolites such as trimethylamine-N-oxide (TMAO), short-chain fatty acids (SCFAs), and bile acids, which in turn modulate neuroinflammation, cerebral perfusion, and neuronal signaling. The gut–heart–brain axis provides an integrative framework linking HF and cognitive impairment pathophysiology through dysbiosis-driven systemic inflammation and metabolite dysregulation. Gut-derived biomarkers and microbiome-targeted interventions represent promising strategies for detection of early alterations and precision treatment, highlighting the urge for prospective, multi-omics studies to establish causality and therapeutic efficacy. This review synthesizes current evidence connecting gut microbiome dysbiosis and metabolite alterations to both HF and cognitive impairment pathophysiology and proposes translational strategies for integrating microbiome-targeted therapies in HF patients with cognitive dysfunction.

Heart failure (HF) affects over 55 million individuals globally, with prevalence projected to exceed 11 million in the United States by 2050 and is increasingly recognized as a systemic disorder extending beyond hemodynamic dysfunction to encompass profound alterations in neural and gut physiology. Cognitive impairment affects nearly half of HF patients and represents a major determinant of morbidity, self-care capacity, and mortality. Recent advances suggest that the gut microbiome serves as a pivotal intermediary in the heart–brain crosstalk, influencing neurocognitive outcomes through inflammatory, metabolic, and neurohumoral pathways. Dysbiosis in HF disrupts intestinal barrier integrity, facilitating translocation of endotoxins and microbial metabolites such as trimethylamine-N-oxide (TMAO), short-chain fatty acids (SCFAs), and bile acids, which in turn modulate neuroinflammation, cerebral perfusion, and neuronal signaling. The gut-heart-brain axis provides an integrative framework linking HF and cognitive impairment pathophysiology through dysbiosis-driven systemic inflammation and metabolite dysregulation. Gut-derived biomarkers and microbiome-targeted interventions represent promising strategies for detection of early alterations and precision treatment, highlighting the urge for prospective, multi-omics studies to establish causality and therapeutic efficacy. This review synthesizes current evidence connecting gut microbiome dysbiosis and metabolite alterations to both HF and cognitive impairment pathophysiology and proposes translational strategies for integrating microbiome-targeted therapies in HF patients with cognitive dysfunction.