Managing Cardiac Risks Associated with TMAO
The evidence regarding TMAO and cardiovascular risk is conflicting and context-dependent, but the most prudent approach is to reduce dietary sources of TMAO precursors (red meat, processed meat, high-fat dairy, eggs) while maintaining consumption of fish 1-2 times weekly, as the cardiovascular benefits of seafood outweigh theoretical TMAO concerns. 1
Understanding the TMAO Paradox
The relationship between TMAO and cardiovascular disease is more nuanced than initially suggested:
TMAO is produced when gut microbiota convert L-carnitine and phosphatidylcholine (abundant in red meat, processed meat, eggs, and dairy) into trimethylamine, which is then oxidized by hepatic enzymes to TMAO 1
Observational studies show strong positive correlations between elevated TMAO levels and cardiovascular disease risk, particularly in patients with chronic kidney disease (1.18-4.32 fold increased mortality), peripheral artery disease (1.38-2.06 fold), type 2 diabetes (2.07-2.7 fold), and heart failure (1.18-1.79 fold) 2
However, the TMAO paradigm does not align with epidemiological findings showing that fatty fish—which is rich in TMAO and its precursors—is associated with beneficial cardiometabolic outcomes 1
The American Heart Association acknowledges this paradox, noting that concerns about TMAO from fish are not supported by the large body of evidence showing cardiovascular benefits from seafood consumption 1
Dietary Modification Strategy
Foods to Limit or Reduce
Prioritize reducing red and processed meats, which produce the most harmful TMAO-related metabolites:
Red meat and processed meats should be limited because proteolytic fermentation produces not only TMAO but also other detrimental metabolites including ammonia, p-cresol, and hydrogen sulfide 1
Processed meats contain additional compounds (nitrates, nitrites, saturated fats) that amplify microbiome-mediated detrimental effects, including production of carcinogenic N-nitroso compounds and secondary bile acids 1
High-fat dairy, eggs, and foods rich in L-carnitine and phosphatidylcholine should be consumed in moderation 1
Foods to Maintain or Increase
Continue regular fish consumption despite TMAO content:
The American Heart Association recommends consuming nonfried seafood, especially species higher in omega-3 fatty acids, 1-2 times per week for cardiovascular benefits, including reduced risk of cardiac death, coronary heart disease, and ischemic stroke 1
The benefits of seafood consumption outweigh theoretical TMAO concerns, as controlled feeding trials of sufficient duration assessing validated cardiovascular markers are still needed to elucidate causal contributions of TMAO from fish 1
Increase plant-based foods with beneficial effects:
Cruciferous vegetables can inhibit FMO3 activity (the enzyme that converts trimethylamine to TMAO), potentially reducing TMAO production 1
Polyphenol-rich foods (fruits, whole grains, vegetables, legumes, seeds, nuts) have anti-inflammatory and antioxidant properties that may counteract TMAO-related cardiovascular effects 1
Risk Stratification and Monitoring
TMAO's cardiovascular risk appears modified by renal function:
In patients with impaired renal function (eGFR <60 mL/min per 1.73 m²), high TMAO levels are associated with 1.56-fold higher risk of incident atherosclerotic cardiovascular disease 3
In patients with normal or mildly reduced renal function (eGFR ≥60 mL/min per 1.73 m²), TMAO does not significantly associate with incident cardiovascular disease 3
For patients with renal dysfunction, monitoring TMAO levels is recommended, as betaine and choline metabolism may contribute to this uremic toxin 4
The prognostic effect of TMAO is enhanced in patients with heart failure and preserved ejection fraction who have comorbid malnutrition 5
Special Considerations
Betaine and choline supplementation requires caution:
Enteral administration of betaine may be converted into methylamine-N-oxide by gut microflora and subsequently metabolized into TMAO, potentially having negative long-term cardiovascular impact 4
The upper limit for betaine in adults is 3.5 g/day, and for choline supplementation during pregnancy is also 3.5 g/day 4, 6
Betaine is used as adjunct treatment for homocystinuria (CBS deficiency) and may be beneficial when methylation processes are impaired, such as in MTHFR 677TT genotype 4
Common Pitfalls to Avoid
Do not eliminate fish from the diet based on TMAO concerns alone—the cardiovascular benefits are well-established and outweigh theoretical risks 1
Do not assume all TMAO sources are equally harmful—the metabolic context matters, with red meat producing additional harmful metabolites beyond TMAO 1
Do not ignore renal function when assessing TMAO-related cardiovascular risk—the association is strongest in patients with impaired kidney function 3
Recognize that TMAO levels may be confounded by reduced kidney function rather than being purely causal for cardiovascular disease 1