Gut Microbiota-Derived Metabolites in Cardiovascular and Neuropsychiatric Comorbidity: From Mechanistic Insights to Therapeutic Frontiers.

The growing comorbidity between cardiovascular and neuropsychiatric disorders presents a major global health challenge. This reciprocal interaction worsens patient prognosis and hinders the diagnosis and treatment of these comorbid conditions. In recent years, the concept of the "gut-heart-brain axis" has highlighted the central pathogenic and therapeutic role of the gut microbiota in linking these distal systems. This review therefore aims to clarify this axis and to explore how specific gut microbiota metabolites modulate this bidirectional physiological interaction. We have integrated recent research to elucidate how gut microbiota dysbiosis regulates cardiovascular-neuropsychiatric comorbidities through the following convergent pathways: gut barrier disruption leading to metabolic endotoxemia; NLRP3 inflammasome activation; adaptive immunity shifting towards Th17 cell dominance and suppressing regulatory T cells; hypothalamic-pituitary-adrenal axis overactivation; and autonomic nervous system dysfunction. We critically reviewed microbiome-targeted interventions, noting that although the existing literature provides reliable epidemiological associations and proof of concept in animal models, definitive causal relationships in human populations remain insufficiently confirmed. Establishing such causal relationships between specific microbial metabolites and the outcomes of chronic cardiovascular or neuropsychiatric diseases will require rigorous longitudinal and interventional studies.