Trimethylamine N-oxide (TMAO) has a molecular mass of 75.1 daltons and belongs to the family of amine oxides. It is commonly found in the tissues of a wide range of marine creatures, particularly marine elasmobranchs, where TMAO is known to protect against the negative effects of temperature, salinity, high urea, and hydrostatic pressure. Urea, for example, destabilizes various macromolecular structures and hinders cellular activities, including ligand binding, which TMAO counteracts. In the marine environment, TMAO may be broken down into small methylated amines such as tri-, di-, and monomethylamine, which are precursors of marine aerosols. TMAO has long been known to marine biologists, but its link with cardiovascular disorders in humans has recently brought it to the forefront.
TMAO has been proven to rebuild proteins to its native structure and allow them to recover enzymatic activity that was lost due to the presence of urea. Although it is commonly accepted that TMAO stabilizes protein folding, the mechanism by which TMAO interacts with proteins is unknown. One theory presupposes that TMAO’s amphiphilic structural arrangement allows it to form H-bonds with water and selectively exclude or interact with particular protein functional groups.
Synthesis of TMAO
TMAO is synthesized from trimethylamine (TMA), which is produced by gut microbiota from dietary choline and phosphatidylcholine (lecithin). Another mechanism identified by Koeth et al. involves the degradation of l-carnitine via two successive microbial processes. Consistent with this, L-carnitine is metabolized into the intermediate metabolite γ-butyrobetaine, which is ultimately turned into TMA, which is then transformed into TMAO with the aid of host hepatic flavin-monooxygenases-3 (FMO3).
Red meat, eggs, dairy products, and salt-water fish are high in choline, lecithin, and carnitine and hence a potential source of TMAO. TMA is a gas that is oxidized within live creatures to generate TMAO by flavin monooxygenases (FMO1 and FMO3). TMAO is then either delivered to the tissues for accumulation as an osmolyte or, more typically, removed by the kidney. In humans, a mutation in the FMO3 gene produces trimethylaminuria, a disease in which people excrete TMA rather than TMAO. The illness known as fish odor syndrome is characterized by a fishy body odor in urine, perspiration, breath, and other bodily excretions.
TMAO and Cholesterol Metabolism
TMAO is an important regulator of lipid metabolism. TMAO, choline, and carnitine supplementation reduced reverse cholesterol transfer (RCT), a process that counterbalances elevated cholesterol accumulation within peripheral tissues by moving excess cholesterol to the liver and small intestine. Furthermore, TMAO supplementation decreased the expression of the enteral cholesterol transporters Niemann-Pick C1-like1 (Npc1L1), that transports cholesterol from the intestinal lumen into enterocytes, which transports cholesterol out of enterocytes into the gut lumen. However, it is unclear whether these transporter modifications are responsible for the observed systemic drop in RCT caused by TMAO.
Clinical Laboratory Analysis of TMAO
Elevated levels of TMAO have been linked to increased incidence of cardiac diseases. The TMAO test can be used to assess the risk of cardiovascular disease independently of existing risk factors. TMAO can also be used to determine changes in gut microbiota in patients who may benefit from intensive intervention, and to monitor medication targeted at lowering TMAO concentrations.
The preferable material is freshly drawn serum collected in ordinary red-top tubes or LipoTubes. EDTA plasma can also be used as a test specimen. However, serum specimens in serum separator gel tubes are ineligible for analysis. Fasting for 10-12 hours before to blood collection is suggested.
For a few days before the blood sample, the patient should avoid eating fish and seafood since it may temporarily raise TMAO.
The TMAO is stable for 14 days when stored at room temperature and in the refrigerator.
TMAO medical decision limits
- Low: <6.2 µM
- Moderate: 6.2 -9.9 µM
- High: ≥ 10.0 µM
- Velasquez MT, Ramezani A, Manal A, Raj DS. Trimethylamine N-Oxide: The Good, the Bad and the Unknown. Toxins (Basel). 2016;8(11):326. Published 2016 Nov 8. doi:10.3390/toxins8110326
- Yang S, Li X, Yang F, Zhao R, Pan X, Liang J, Tian L, Li X, Liu L, Xing Y, Wu M. Gut Microbiota-Dependent Marker TMAO in Promoting Cardiovascular Disease: Inflammation Mechanism, Clinical Prognostic, and Potential as a Therapeutic Target. Front Pharmacol. 2019 Nov 19;10:1360. doi: 10.3389/fphar.2019.01360. PMID: 31803054; PMCID: PMC6877687.
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