TMAO: the pathway in the body · Biomarker & Laboratory Analysis

This page shows the biochemical pathway behind the laboratory value Trimethylamine N-oxide: which stations follow one another, which enzymes carry out each step and which cofactors they use. Every statement has a source. The page describes general textbook knowledge and says nothing about any individual person.

In brief

Trimethylamine N-oxide (TMAO) is a small, water-soluble molecule. It is formed in the liver from trimethylamine, which gut bacteria split off from choline and carnitine, and it leaves the body through the kidneys. If FMO3 cannot keep up, fishy-smelling trimethylamine remains.

The pathway step by step

Each station states what the compound does there. Three signs: ↑ supplies — builds up or makes available · ↓ depletes — inhibits, consumes or withholds · ↕ both, depending on amount. Behind it stands what the statement rests on: established physiology, observed in studies, or contested. The signs do not grade; they name the direction.

1. Choline and carnitine → Trimethylamine (TMA) CutC/D, CntA/B Certain gut bacteria split off this group with their own enzymes: from choline with choline TMA-lyase, from carnitine with an oxygenase. Human cells cannot do this. How much forms depends on which bacteria live in the gut. Source 2, 3↑ supplies Trimethylamine is the only starting material from which the liver makes TMAO. How much of it forms depends on which bacteria live in the gut and whether they carry the enzymes CutC/D or CntA/B. established physiology Source 2, 3, 1
   ⚖ When the balance tips

   too much — If trimethylamine builds up because FMO3 cannot keep up, it remains unchanged and leaves the body via urine, sweat and breath; it smells fishy as it does so.

   too little — If the gut bacteria carry few of the enzymes CutC/D or CntA/B, little trimethylamine forms, even when plenty of choline and carnitine arrive.

   established physiology · Source 1, 2, 3

2. Trimethylamine (TMA) → TMA in portal blood Uptake in the gut Trimethylamine is absorbed from the gut into the blood. The portal vein carries it to the liver first, before it reaches the rest of the circulation. There FMO3 converts most of it. Source 1↑ supplies Via the portal vein, the blood delivers trimethylamine to the liver first. There FMO3 converts most of it before it reaches the rest of the circulation. established physiology Source 1
   ⚖ When the balance tips

   too much — If more trimethylamine arrives at the liver than FMO3 can convert, part of it passes unchanged into the rest of the circulation.

   too little — If little trimethylamine arrives, the liver makes little TMAO; what is then in the blood comes mainly from ready-made TMAO in food.

   established physiology · Source 1

3. TMAO → TMAO in the blood From the liver, TMAO enters the circulation. It is a small, water-soluble molecule and is not converted any further in the body. Whether it has an effect of its own there has not been settled. Source 1↑ supplies In marine animals, TMAO keeps proteins in shape against salt and pressure. Whether it has an effect of its own in human blood is being studied in animal models and studies; the findings are inconsistent. contested Source 1
   ⚖ When the balance tips

   too much — If TMAO builds up because a lot keeps arriving or the kidneys filter more slowly, it stays in the blood longer; what this means in humans has not been settled.

   too little — If there is little TMAO in the blood, no known task is left undone; humans form it mainly as the excretion form of trimethylamine.

   contested · Source 1

4. TMAO from fish → TMAO in the blood From the liver, TMAO enters the circulation. It is a small, water-soluble molecule and is not converted any further in the body. Whether it has an effect of its own there has not been settled. Source 1↑ supplies In marine animals, TMAO keeps proteins in shape against salt and pressure. Whether it has an effect of its own in human blood is being studied in animal models and studies; the findings are inconsistent. contested Source 1
   ⚖ When the balance tips

   too much — If TMAO builds up because a lot keeps arriving or the kidneys filter more slowly, it stays in the blood longer; what this means in humans has not been settled.

   too little — If there is little TMAO in the blood, no known task is left undone; humans form it mainly as the excretion form of trimethylamine.

   contested · Source 1

5. TMAO in the blood → TMAO in the urine Filtration The kidneys filter TMAO from the blood into the urine. Most of it leaves the body within a day; the amount therefore closely follows what was eaten most recently. If the kidneys filter more slowly, it stays in the blood longer. Source 4, 1↓ depletes The kidneys remove TMAO from the blood promptly and excrete it unchanged. In this way the trimethylamine made by the bacteria also leaves the body without odour. established physiology Source 1, 4
   ⚖ When the balance tips

   too much — If a lot of TMAO is formed or eaten, the amount in the urine rises quickly with it, because the kidneys excrete it promptly.

   too little — If the kidneys filter more slowly, TMAO stays in the blood longer and less of it appears in the urine.

   established physiology · Source 1, 4

Further stations

• Choline and carnitine — from food Choline is found mainly in eggs, liver and pulses, carnitine mainly in red meat. Both molecules carry a group of three methyl groups on a nitrogen atom. They supply the starting material for trimethylamine. Source 1↑ supplies Choline and carnitine supply the group of three methyl groups on a nitrogen from which gut bacteria split off trimethylamine. Whatever reaches the gut is available to the bacteria as starting material. established physiology Source 1, 2, 3
  ⚖ When the balance tips

  too much — If more choline or carnitine reaches the bacteria in the gut, they have more starting material, and more trimethylamine forms.

  too little — If little of it reaches the bacteria, little trimethylamine forms; TMAO in the body then comes mainly from ready-made TMAO in food.

  established physiology · Source 1, 4

• TMAO — trimethylamine N-oxide In the liver cell, the enzyme FMO3 attaches an oxygen atom to the nitrogen atom of trimethylamine. This requires FAD and NADPH. Unlike TMA, the product, TMAO, is odourless. In this way TMA leaves the body without odour. Source 1↓ depletes Forming TMAO uses up trimethylamine: FMO3 turns the volatile, fishy-smelling substance into an odourless, readily water-soluble molecule that the kidneys excrete easily. established physiology Source 1
  ⚖ When the balance tips

  too much — If a lot of trimethylamine arrives, FMO3 makes correspondingly more TMAO as long as its capacity lasts; the amount then mainly follows what the gut bacteria supply.

  too little — If FMO3 activity is low, for example due to variants in the FMO3 gene, little TMAO forms and trimethylamine is left over.

  established physiology · Source 1

• TMAO from fish — sea fish and prawns Sea fish, prawns and mussels already contain ready-made TMAO; in these animals it keeps proteins stable in salt water. It is absorbed unchanged from food. It adds directly to the amount in the blood. Source 4, 1↑ supplies Ready-made TMAO from sea fish and seafood supplies TMAO without the detour via gut bacteria and FMO3 and adds directly to the amount in the blood. established physiology Source 4, 1
  ⚖ When the balance tips

  too much — After a meal with a lot of sea fish, TMAO in blood and urine rises quickly and falls back within about a day.

  too little — If no ready-made TMAO comes with food, TMAO comes solely from the route via gut bacteria and liver.

  established physiology · Source 4, 1

Cofactors in this pathway

• Choline — Starting material from which the bacterial choline TMA lyase splits off trimethylamine; the more arrives, the more TMA Source 2, 1
• Carnitine — Starting material from which the bacterial enzyme CntA/B splits off trimethylamine; the more arrives, the more TMA Source 3, 1In the ORY catalogue as a laboratory value: Carnitin
• Vitamin B2 (FAD) — Flavin cofactor of FMO3, which makes TMAO from trimethylamine in the liver; without FAD, TMA stays unchanged Source 1
• NADPH — Electron donor of FMO3 when converting TMA to TMAO Source 1
• Oxygen — Provides the oxygen atom that FMO3 attaches to the nitrogen; this makes TMA odourless Source 1
• Iron — Sits in the Rieske centre of the bacterial enzyme CntA; without iron, CntA releases no TMA Source 3

Sources

1. Fennema D, Phillips IR, Shephard EA. Trimethylamine and Trimethylamine N-Oxide, a Flavin-Containing Monooxygenase 3 (FMO3)-Mediated Host-Microbiome Metabolic Axis Implicated in Health and Disease. Drug Metab Dispos 2016 · PubMed 27190056
2. Craciun S, Balskus EP. Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme. Proc Natl Acad Sci U S A 2012 · PubMed 23151509
3. Zhu Y, Jameson E, Crosatti M et al. Carnitine metabolism to trimethylamine by an unusual Rieske-type oxygenase from human microbiota. Proc Natl Acad Sci U S A 2014 · PubMed 24591617
4. Krüger R, Merz B, Rist MJ et al. Associations of current diet with plasma and urine TMAO in the KarMeN study: direct and indirect contributions. Mol Nutr Food Res 2017 · PubMed 28755411

As of 2026-09-16. Draft written by Claude to schema v2; sources checked in PubMed; expert approval pending
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