TMAO

Trimethylamine N-oxide (TMAO) is a small organic molecule produced in humans through a two-step process involving gut microbiota and the liver. Microbes metabolize dietary choline, carnitine, and betaine to trimethylamine (TMA), which is absorbed and oxidized in the liver by the enzyme flavin-containing monooxygenase 3 (FMO3) to form TMAO. Some TMAO can also come directly from dietary preformed TMAO found in certain seafood, which can contribute to circulating levels.

In humans, the precise physiological role of TMAO is not fully understood. It is known to act as an osmolyte and to influence protein stability in some contexts, but its core function in human biology remains the subject of ongoing research. TMAO is generally regarded as a metabolic end product of gut microbial metabolism and hepatic oxidation rather than a essential nutrient with a defined, beneficial role.

Health associations and interpretation: Numerous observational studies have linked higher plasma TMAO levels with increased risk of cardiovascular disease and mortality, though causality has not been established. TMAO levels are influenced by diet (notably red meat, eggs, and certain fish), the composition of the gut microbiome, hepatic FMO3 activity, and kidney function, with reduced renal clearance elevating circulating TMAO. It is also considered a potential biomarker of microbial metabolism and renal clearance rather than a proven causal agent in disease; experimental data in animals suggest possible pro-atherogenic effects, but human evidence remains inconclusive.

Genetics and clinical relevance: Deficiency of the hepatic enzyme FMO3 causes trimethylaminuria (fish odor syndrome), illustrating the metabolic pathway from TMA to TMAO. Because TMAO biology is influenced by multiple factors, strategies to modulate its levels (diet, microbiome interventions, or pharmacology) are of research interest but lack established clinical guidelines.