The gut–brain axis and trimethylamine N-oxide: an emergent biomarker in neurological diseases

Progressive degeneration of the nervous system is a hallmark of neurological diseases. Recent research highlights gut microbiota metabolites like Trimethylamine N-oxide (TMAO)-derived from dietary betaine, carnitine, phosphatidylcholine, and choline-as key players. TMAO and its precursor TMA cross the blood-brain barrier, modulating behavior, neurogenesis, and brain development. Elevated TMAO promotes pro-inflammatory pathways, linking it to metabolic, vascular, and neurological risks. However, its role is complex with studies suggesting neuroprotective roles and variability influenced by diet, dysbiosis, renal function, and FMO3 genetics. Although preclinical and clinical data exhibit some variability, this very heterogeneity underscores our review's value in analyzing both the challenges and strengths of TMAO, providing a comprehensive overview. Therefore, this review summarizes the multifaceted role of TMAO in neurological disorders, the challenges to validation, and its promising potential as a dynamic biomarker. In conclusion, incorporating TMAO into multimarker panels places it at the forefront of precision neurology, transforming gut-brain axis research into tools for early screening, risk stratification, and intervention, before irreversible neurodegeneration.