Trimethylamines (TMAs) are gut-derived metabolites that undergo transformation in the liver to trimethylamine N-oxide (TMAO). While TMAO has historically been associated with cardiovascular disease risk, it’s novel interpretation as a neurological disease biomarker is gaining recognition. Both TMAO and its precursor TMA are able to readily cross the blood-brain barrier where they impact processes governing brain development, neurogenesis, and behavior. Considerable inter-individual variation exists between TMAO levels and incident health consequences largely determined by microbial profile, renal function, diet, and genetics. TMAO has been demonstrated to stimulate NF-kB, NLRP3, and MAPK, induce mitochondrial dysfunction, and regulate bile acid and cholesterol metabolism. Given TMAO’s modulation of inflammation, redox balance, and lipid metabolism, elevated levels are implicated in chronic conditions including metabolic, vascular, and neurological disease.
Firmicutes, Proteobacteria, and Actinobacteria are responsible for digesting choline, betaine, ergothioneine, and carnitine to produce TMA. TMA leaves the intestines and travels to the liver where it is oxidized by hepatic flavin monooxygenases (FMO1 and FMO3), generating TMAO. The activity of these enzymes is influenced by genetic polymorphisms, diet, sex hormones, and immune tone. Estrogen, dysbiosis, inflammation, high substrate intake, renal filtration, and genetic differences in the FMO1 and FMO3 genes will subsequently alter circulating TMAO levels. Studies have correlated an upregulation of TMAO generated by Bacteroides, Clostridium, and Faecalibacterium to exacerbated neuropathological risk. Although low levels of TMAO are purported to protect blood-brain barrier integrity, mitochondrial respiration, and cardiovascular function, a rise in TMAO levels beyond a toxic threshold may disrupt inflammatory and metabolic cascades that contribute to disease processes.
Aging is observed to elicit dysbiosis, and this change in microbial communities may provoke a shift toward amplification of TMAO production. Administration of broad spectrum antibiotics as well as the probiotic strains Lactobacillus plantarum ZDY04 and Enterobacter aerogenes ZDY01 has been shown to diminish serum TMAO concentrations. As levels climb, TMAO may activate the NLRP3 inflammasome as well as NF-kB and MAPK, triggering cytokine release and subsequent neurotoxicity. TMAO may also intensify reactive oxygen species generation by dysfunctional mitochondria in addition to lipid peroxidation. Fatty acids highly concentrate in the brain, making it especially vulnerable to oxidative stress. Microglia and astrocytes become hyperactivated in states of excess TMAO, further leading to neuronal degeneration and declines in synaptic plasticity. TMAO appears to impair endothelial function and blood-brain barrier integrity, enabling an increase in the translocation of inflammatory compounds into the brain. Collectively, these effects mechanistically support TMAO as a biomarker for neurological disruption.
As microbiome modulation remains the primary target for suppressing TMAO production, several compounds have been highlighted as therapeutic interventions owing to their role in TMAO metabolism. 3,3-dimethyl-1-butanol (DMB) is sourced from olive and grape seed oils, red wine, and balsamic vinegar and behaves as a choline analogue and TMA inhibitor. Similarly, resveratrol also derived from red grapes reduces TMAO by promoting proliferation of Lactobacillus and Bifidobacterium while repressing TMA-producing bacterial populations. Combinations of Aconitum carmichaelii, Gynostemma pentaphyllum, and Glycyrrhiza uralensis have also been observed to lower TMAO. Likewise, administration of the probiotics Lactobacillus plantarum and Akkermansia muciniphila appear to dampen TMAO concentrations.
TMAO is an interesting biomarker of neurological dysfunction for several reasons, including its noninvasive accessibility, affordability, and ability to serve as a risk factor prior to the onset of symptoms. TMAO uniquely acts as an upstream warning of altered gut-brain axis signaling compared to other widely used neurological biomarkers. However, it is important to recognize that TMAO impacts many other disease processes and thus cannot be considered as a specific biomarker of neurodegenerative disease. Considerable heterogeneity exists in studies exploring the link between TMAO concentrations and disease incidence. It is distinctly possible that other metabolic pathways more robustly affect neurological abnormalities. The influence of factors such as renal health, genetic polymorphisms, sex hormones, diet, and inflammatory status on TMAO levels indicate that it should be interpreted alongside additional diagnostics for accurate assessment of disease risk.
Arangia A, Paola RD, Cuzzocrea S, Siracusa R, D’Amico R, Impellizzeri D. The gut-brain axis and trimethylamine N-oxide: an emergent biomarker in neurological diseases. Neuroscience. 2026;607:88-99. doi:10.1016/j.neuroscience.2026.05.005