Dietary choline + carnitine + phosphatidylcholine reach the colon partially intact, where gut microbiota produce trimethylamine (TMA) via cleavage. Portal venous TMA reaches the liver and is oxidized by FMO3 (flavin monooxygenase 3) to TMAO (trimethylamine-N-oxide). Plasma TMAO is associated with cardiovascular events in observational studies — proposed mechanism: TMAO impairs reverse cholesterol transport + promotes macrophage foam cell formation + enhances platelet hyperreactivity. The "gut microbiome → CVD" causal link is being actively investigated (Hazen lab series, mostly). FMO3 LOF variants cause trimethylaminuria ("fish odor syndrome") — exhaled + sweat-derived TMA produces a fish-like body odor.
Organ Systems
cardiovascular
digestive
Pathway Steps
choline → trimethylamine — via gut microbial choline-TMA-lyase (CutC/D) — primarily colonic Proteobacteria + Firmicutes. Gut bacteria cleave dietary choline, carnitine, and betaine to trimethylamine via CutC/D — a microbiome-dependent step, so antibiotics and microbiome composition shift TMA output. Red meat, eggs, and fish are the main precursors.
trimethylamine → trimethylamine-n-oxide — via FMO3 (hepatic) — LOF variants → trimethylaminuria; CV risk association. Hepatic FMO3 oxidizes TMA to TMAO; elevated TMAO is epidemiologically linked to atherosclerosis/CV risk (a debated diet–microbiome–host axis). FMO3 loss-of-function causes trimethylaminuria (“fish-odor syndrome”) from unoxidized, volatile TMA.