TMAO at the Crossroads of the Gut–Brain Axis: Emerging Mechanisms Linking Microbiota-Derived Metabolites to Neuroinflammation and Cognitive Dysfunction

Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite produced through the hepatic oxidation of trimethylamine. Although TMAO has been widely investigated as a therapeutic target in multiple cardiovascular and metabolic diseases, growing evidence suggests it may play a critical role in the neuroinflammation and cognitive dysfunction associated with the gut–brain axis. This narrative review summarizes the current literature to synthesize evidence on the mechanisms linking TMAO with neurological disorders; it discusses potential mechanisms contributing to this association, with particular focus on neuroinflammation, oxidative stress, and activation of inflammatory pathways. Overall, this review also suggests the potential use of TMAO and its precursors as therapeutic targets for multiple neurodegenerative disorders. However, it emphasizes the need for conducting large, adequately powered randomized clinical studies to determine its therapeutic relevance.