Trimethylamine N-oxide (TMAO) has emerged as a key link between the gut microbiome and cardiovascular health. Elevated TMAO is associated with a higher risk of heart attack, stroke, and mortality—even in individuals with no other major risk factors. In functional medicine, it serves as a valuable biomarker at the intersection of diet, microbial balance, and metabolic disease.

What Is TMAO and How Is It Formed?

TMAO is produced when gut bacteria metabolize nutrients like choline, L-carnitine, and betaine—primarily found in red meat, eggs, and dairy. These microbes release trimethylamine (TMA), which is then oxidized by the liver enzyme FMO3 into TMAO. Even low-choline diets can result in TMAO formation, as choline is also recycled in bile and processed by the gut microbiome.

Each person’s microbiota influences how much TMAO is produced—making this a highly individualized, yet modifiable, risk factor.

How TMAO Contributes to Cardiovascular Disease

TMAO impacts the cardiovascular system in several ways:

• Endothelial dysfunction: TMAO activates inflammatory signals that impair blood vessel function.

• Cholesterol transport impairment: It reduces reverse cholesterol transport, allowing LDL to accumulate.

• Plaque formation: TMAO encourages foam cell development, fueling atherosclerosis.

• Increased clotting risk: It enhances platelet aggregation, raising the risk of thrombotic events.

These effects make TMAO a direct mediator of the gut-heart connection.

TMAO as a Predictive Biomarker

Clinical research confirms that high TMAO levels predict major adverse cardiac events (MACE). Cleveland Clinic studies show a 2.5x increase in MACE risk in those with the highest TMAO levels. A 2024 meta-analysis found nearly double the risk of both cardiovascular events and mortality in people with elevated TMAO.

Importantly, this risk holds true even when adjusting for cholesterol, blood pressure, and diabetes—making TMAO an independent and actionable marker.

Best Practices for TMAO Testing

TMAO can be measured via plasma or serum through specialty labs. Testing is most accurate when:

• Patients fast for at least 8 hours

• Fish and seafood are avoided the day before (due to naturally high TMAO content)

Interpretation ranges:

• <6 µmol/L: Low risk

• 6.2–9.9 µmol/L: Moderate risk

• ≥10 µmol/L: High risk

High values may reflect both microbial imbalance and dietary patterns, and should prompt intervention.

Functional Medicine Strategies to Lower TMAO

1. Diet and Lifestyle

Reducing TMAO starts with dietary change:

• Limit red meat, egg yolks, and high-fat dairy

• Increase fiber, vegetables, legumes, and whole grains

• Embrace a Mediterranean-style or plant-rich diet

These shifts not only lower precursor intake but also promote a gut microbiome less likely to produce TMA.

2. Gut Microbiome Modulation

The goal is to reduce TMA-producing bacteria and support a healthier microbial profile:

• Eat diverse, fiber-rich foods that act as prebiotics

• Supplement with probiotics such as Lactobacillus and Bifidobacterium

• Avoid unnecessary antibiotics and gut-disrupting drugs

Polyphenols like resveratrol have been shown to shift microbiota composition and reduce TMAO in both animals and humans.

3. Nutraceuticals and Supplements

• Berberine: Inhibits microbial TMA production and supports lipid metabolism

• Garlic (allicin): Antimicrobial effects that reduce TMA-producing strains

• Polyphenols: Found in green tea, grapes, cranberries, and cocoa—support microbial balance and antioxidant activity

• Others: Psyllium (binds precursors), DIM, and emerging therapies like DMB (a microbial enzyme inhibitor)

These tools can be layered with dietary changes to enhance TMAO reduction and cardiovascular protection.

Additional Considerations

Kidney Function

Since TMAO is cleared by the kidneys, levels can rise in chronic kidney disease (CKD). In these patients, elevated TMAO may reflect impaired excretion rather than overproduction—and signals the need for kidney support alongside cardiometabolic care.

Individual Variability

TMAO production is shaped by microbiome composition, diet, and genetics (particularly FMO3 activity). Omnivores tend to produce more TMAO than vegetarians, even with the same nutrient intake—highlighting the need for personalized treatment plans.

Conclusion

TMAO offers a powerful lens into the gut-heart connection. For functional medicine practitioners, it’s a practical and modifiable marker that reveals hidden cardiometabolic risk. Through diet, targeted microbiome support, and evidence-based supplementation, we can reduce TMAO and support better long-term outcomes.

As research continues, TMAO may become a routine part of cardiovascular risk assessment—reminding us that heart health often starts in the gut.

-Carey Kunz, ND, IFMCP

Director of Education at FMP Essentials

References

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