Gut-Derived Metabolites and Cognitive Health: Roles of Short-Chain Fatty Acids and Trimethylamine N-oxide

The gut microbiota has emerged as an important regulator of host physiology, extending well beyond digestion and metabolism. Increasing attention has focused on the gut-brain axis, a bidirectional communication network linking the gastrointestinal tract and the central nervous system. Among the many microbial metabolites implicated in gut-brain signalling, short-chain fatty acids (SCFAs) and trimethylamine N-oxide (TMAO) have attracted particular interest because of their potential roles in neuroinflammation, vascular dysfunction, and cognitive decline. This narrative review synthesizes current evidence linking SCFAs and TMAO to cognitive health, drawing on human observational studies, experimental animal models, and mechanistic and secondary syntheses. Human data remain limited and largely observational. Altered gut microbiota composition and reduced SCFA levels have been reported in Parkinson's disease and have been associated with disease severity and neurological phenotypes. In parallel, TMAO has been detected in human cerebrospinal fluid and shown to interact with the blood-cerebrospinal fluid barrier, establishing biological plausibility for central nervous system exposure. Observational studies further link circulating TMAO levels with Alzheimer's disease biomarkers, mild cognitive impairment, and dementia-related neuroimaging features. Experimental evidence provides more direct support. TMAO supplementation promotes brain aging, cognitive impairment, and neuropathological changes in mouse and rat models. In contrast, SCFAs, particularly butyrate, exert neuroprotective effects in models of Alzheimer's disease, Parkinson's disease, and systemic inflammation, with improvements in memory and reductions in pathological markers. Mechanistic studies suggest that SCFAs may modulate immune responses, preserve blood-brain barrier integrity, and regulate microglial activity, whereas TMAO has been linked to endothelial dysfunction, oxidative stress, and neurovascular impairment. Taken together, available evidence supports biologically plausible but still preliminary roles for gut-derived metabolites in cognitive health. SCFAs appear broadly neuroprotective, while TMAO shows adverse associations, particularly in preclinical models. Human causality remains unproven, and clinical translation is premature. Well-designed longitudinal and interventional studies are required before these metabolites can be considered reliable biomarkers or therapeutic targets.