Gut microbiota-derived trimethylamine N-oxide (TMAO) and its association with neuroinflammation in migraine

Background and objectives Migraine is a common primary headache disorder associated with neuroinflammation, with evidence implicating gut microbiota and metabolites in neurological mechanisms pathways. Since trimethylamine-N-oxide (TMAO), derived from dietary precursors by gut microbial metabolism, is associated with cardiovascular and neurodegenerative conditions, and its role in migraines is unclear, we aimed to evaluate whether serum TMAO level and related metabolites in migraine patients can be biomarkers. Methods A total of 106 participants were enrolled, consisting of healthy controls (n=46; mean age ± SD=39±8 yr old) and migraine patients (n=60). The migraine cohort was divided into migraine with aura (n=18; mean age±SD=33±11 yr old) and migraine without aura (n=42; mean age±SD=37±10 yr old), according to the International Classification of Headache Disorders, 3rd edition (ICHD-3). Blood samples were centrifuged, stored at -80°C, and analysed for TMAO, carnitine, betaine, and choline levels using liquid chromatography-mass spectrometry (LC-MS/MS). Results There were no significant differences between the groups for age, smoking, or body mass index (BMI). Serum TMAO levels were significantly higher in patients with migraine with aura [2.75 (1.98-3.91) ng/mL] and migraine without aura [2.85 (2.08-5.53) ng/mL] compared to controls [1.40 (1.00-3.01) ng/mL] (P<0.001). Serum choline, betaine, and carnitine levels were significantly higher in the migraine groups (all P < 0.01). Interpretation and conclusions These findings indicate elevated TMAO levels in patients with migraine, suggesting a possible involvement of TMAO in migraine-associated neuroinflammatory processes. Targeted studies and cohort-based investigations are needed to clarify its role in migraine and evaluate its potential as a biomarker.