TMAO: The Gut-Heart Connection Your Cardiologist May Not Be Measuring - Body of Harmony

TMAO: The Gut-Heart Connection Your Cardiologist May Not Be Measuring

by: Payam Hakimi
October 2026
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By Payam Hakimi, D.O., Medical Director, Body of Harmony Institute of Health & Healing

For decades, the conversation about heart health has centered on cholesterol. Yet many people suffer heart attacks and strokes with perfectly "normal" lipid panels. That gap has pushed researchers to look elsewhere, and one of the most compelling places they have looked is the gut.

Enter TMAO (trimethylamine N-oxide), a small molecule produced through a partnership between what you eat, the bacteria living in your intestines, and your liver. Over the past fifteen years, TMAO has emerged as one of the clearest examples of how the gut microbiome can influence cardiovascular, metabolic, and kidney health. Understanding it offers a powerful lesson in root-cause medicine: the heart does not exist in isolation from the gut.

What TMAO Is and How Your Body Makes It

TMAO is made in three steps, and only one of them happens inside human cells.

The food. Certain nutrients carry a "trimethylamine" chemical group. The most important are choline and phosphatidylcholine (abundant in egg yolks, liver, and organ meats) and L-carnitine (concentrated in red meat and many sports supplements).
The microbes. Specific gut bacteria possess enzymes that cleave these nutrients and release a gas called trimethylamine (TMA). Without these microbes, very little TMA is formed.
The liver. TMA is absorbed into the portal circulation, where a liver enzyme called flavin-containing monooxygenase 3 (FMO3) converts it into TMAO. The kidneys then clear TMAO from the blood.

The role of the microbiome was demonstrated elegantly at the Cleveland Clinic. When healthy volunteers ate two hard-boiled eggs plus labeled phosphatidylcholine, their TMAO levels rose. After a course of broad-spectrum antibiotics, the rise nearly disappeared, then returned once the antibiotics were stopped (Tang et al., 2013).

This is a crucial insight. Two people can eat the same meal and produce very different amounts of TMAO, depending on the bacteria they host.

What the Research Shows

People with the highest TMAO levels consistently show higher rates of heart attack, stroke, and death in large studies, though whether TMAO directly causes that risk is still being worked out.

The landmark findings. In 2011, a metabolomics study in Nature identified TMAO as a predictor of cardiovascular disease and showed that feeding TMAO or choline to mice accelerated atherosclerosis (Wang et al., 2011). Two years later, in more than 4,000 patients undergoing cardiac evaluation, those in the highest TMAO quartile had about 2.5 times the three-year risk of heart attack, stroke, or death compared with the lowest quartile, even after adjusting for traditional risk factors (Tang et al., 2013).

The pooled evidence. Meta-analyses have since confirmed the pattern across populations:

Population	Studies (participants)	Higher vs. lower TMAO	Source
General and at-risk adults	17 studies (26,167)	1.91× all-cause mortality; 1.67× major cardiac and cerebrovascular events	Schiattarella et al., 2017
Coronary heart disease	9 cohorts (10,301)	1.58× major adverse cardiac events	Yao et al., 2020
Heart failure	12 studies (13,425)	1.35× all-cause mortality	Li et al., 2022
After coronary stenting (PCI)	13 cohorts (11,279)	1.99× major adverse cardiac events	Zhang et al., 2025

How it may cause harm. Laboratory and animal research points to several mechanisms:

Platelet hyperreactivity. TMAO increases calcium release inside platelets, making them more prone to clot. In over 4,000 subjects, TMAO independently predicted heart attack and stroke risk (Zhu et al., 2016).
Impaired cholesterol clearance. In mice, TMAO reduced reverse cholesterol transport, the process that removes cholesterol from artery walls (Koeth et al., 2013).
Foam cell formation. TMAO promoted cholesterol accumulation in macrophages, an early step in plaque formation (Wang et al., 2011).
Inflammation and endothelial dysfunction, both supported by a growing body of experimental work (Canyelles et al., 2023).

An honest note on causation. Good medicine requires intellectual honesty. TMAO is cleared by the kidneys, and when studies adjust for kidney function, the association with cardiovascular outcomes often weakens. One Mendelian randomization study found no causal link between genetically higher TMAO and cardiometabolic disease, while another linked TMAO to higher systolic blood pressure (Canyelles et al., 2023). TMAO may be partly a driver and partly a signal of deeper dysfunction. Either way, it is a meaningful window into the health of the gut-heart-kidney axis.

It's Not Just What You Eat

TMAO levels reflect four interacting factors, which is why a simple "avoid eggs and steak" message misses the point.

1. Diet, especially red meat. In a tightly controlled crossover trial of 113 adults, four weeks of red meat more than doubled plasma TMAO compared with white meat or non-meat protein. Red meat also reduced the kidneys' ability to excrete TMAO, and levels fell within four weeks of stopping it (Wang et al., 2019). Notably, saturated fat itself did not change TMAO.

2. Your microbiome. After an L-carnitine challenge, omnivores produced far more TMAO than vegans or vegetarians, and specific bacterial groups tracked with TMAO levels (Koeth et al., 2013). Long-term dietary patterns shape the very microbes that make TMA.

3. The fish paradox. Saltwater fish and shellfish naturally contain preformed TMAO, which marine animals use to stabilize their proteins against ocean pressure. In a Harvard study of 620 healthy men, fish intake was the strongest dietary predictor of TMAO, while red meat was not (Hamaya et al., 2020). Yet fish consumption is consistently linked with cardiovascular benefit. This is why TMAO must always be interpreted in context and never as a stand-alone verdict on someone's diet (Lombardo et al., 2021).

4. Kidney function and genetics. Because the kidneys clear TMAO, even mild declines in renal function can raise levels. Variations in the liver enzyme FMO3 also influence how efficiently TMA is converted to TMAO.

Testing Your TMAO Level

TMAO is a simple blood test, available through major reference laboratories with a physician's order. It is not part of a standard cholesterol panel, so most people have never had it checked.

The widely used Cleveland HeartLab assay, now performed through Quest Diagnostics, reports these cut-offs (Warde Medical Laboratory sample report):

Result (µM)	Relative cardiovascular risk
Below 6.2	Optimal
6.2 to 9.9	Intermediate
10.0 or higher	High

Preparing for the test. Fast overnight, and avoid fish and seafood the day before the draw, since they can falsely elevate results (Michigan Medicine Laboratories).

Who may benefit from testing:

People with a family history of early heart disease
Those who have had a cardiac event despite "normal" cholesterol
Patients with diabetes, metabolic syndrome, or chronic kidney disease
Individuals taking L-carnitine or choline supplements
Anyone seeking a deeper, root-cause cardiovascular evaluation

An elevated result is never interpreted alone. In our practice, we review it alongside kidney function, advanced lipid markers, inflammation markers, diet history, and digestive health.

A Functional Medicine Approach to TMAO

At Body of Harmony, an elevated TMAO is treated as a clue, not a diagnosis. Our goal is to understand why it is elevated in this particular person, then address each contributing layer.

Layer 1: Rebalance the plate. Red meat is the most modifiable driver, and reducing it can lower TMAO within about four weeks (Wang et al., 2019). A plant-forward, Mediterranean-style pattern rich in vegetables, legumes, whole grains, and extra-virgin olive oil shifts both precursors and the microbes that process them. We individualize rather than eliminate: eggs and fish still have a place for most people.

Layer 2: Review supplements. L-carnitine and high-dose choline supplements, popular for energy and athletic performance, are direct TMAO precursors. For patients with elevated levels, we reassess whether the benefit justifies the cost.

Layer 3: Restore the microbiome. Diverse dietary fiber feeds bacteria that compete with TMA producers. We evaluate digestive health comprehensively, including stool testing when appropriate, to identify dysbiosis rather than guessing.

Layer 4: Protect the kidneys. Because TMAO is cleared renally, we assess kidney function, blood pressure, hydration, and blood sugar control. Supporting the kidneys supports TMAO clearance.

Layer 5: Look at the whole cardiovascular picture. TMAO is one piece of a broader evaluation that includes advanced lipid testing, inflammatory markers, insulin resistance, and lifestyle factors such as sleep, stress, and movement.

On the horizon. Researchers are developing compounds that block microbial TMA production without killing gut bacteria. In mice, one such compound, 3,3-dimethyl-1-butanol (DMB), lowered TMAO and reduced plaque formation without changing cholesterol (Wang et al., 2015). These approaches are not yet established human therapies, but they confirm the gut as a promising target for cardiovascular prevention.

The Bottom Line

TMAO reminds us that heart health begins far from the heart. It reflects a conversation between your plate, your microbiome, your liver, and your kidneys, and that conversation can be changed.

If you have a family history of heart disease, have had a cardiac event despite normal cholesterol, or simply want a deeper understanding of your cardiovascular risk, a TMAO evaluation may be a valuable addition to your care.

Ready to look deeper? Schedule a consultation at Body of Harmony Institute of Health & Healing in Beverly Hills or Miami at bodyofharmony.com. Together, we will identify the root causes and build a plan designed for you.

This article is for educational purposes and does not replace individualized medical advice. Please consult your physician before changing your diet, supplements, or medications.

References

Research articles retrieved via PubMed.

Wang Z, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011;472:57–63. doi:10.1038/nature09922
Tang WHW, et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013;368:1575–84. doi:10.1056/NEJMoa1109400
Koeth RA, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013;19:576–85. doi:10.1038/nm.3145
Wang Z, et al. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell. 2015;163:1585–95. doi:10.1016/j.cell.2015.11.055
Zhu W, et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell. 2016;165:111–24. doi:10.1016/j.cell.2016.02.011
Schiattarella GG, et al. Gut microbe-generated metabolite TMAO as cardiovascular risk biomarker: a systematic review and dose-response meta-analysis. Eur Heart J. 2017;38:2948–56. doi:10.1093/eurheartj/ehx342
Wang Z, et al. Impact of chronic dietary red meat, white meat, or non-meat protein on TMAO metabolism and renal excretion. Eur Heart J. 2019;40:583–94. doi:10.1093/eurheartj/ehy799
Yao ME, et al. TMAO has prognostic value in coronary heart disease: a meta-analysis and dose-response analysis. BMC Cardiovasc Disord. 2020;20:7. doi:10.1186/s12872-019-01310-5
Hamaya R, et al. Association of diet with circulating trimethylamine-N-oxide concentration. Am J Clin Nutr. 2020;112:1448–55. doi:10.1093/ajcn/nqaa225
Lombardo M, et al. Association of urinary and plasma levels of TMAO with foods. Nutrients. 2021;13(5):1426. doi:10.3390/nu13051426
Li X, et al. Trimethylamine N-oxide in heart failure: a meta-analysis of prognostic value. Front Cardiovasc Med. 2022;9:817396. doi:10.3389/fcvm.2022.817396
Canyelles M, et al. Gut microbiota-derived TMAO: a causal factor promoting atherosclerotic cardiovascular disease? Int J Mol Sci. 2023;24(3):1940. doi:10.3390/ijms24031940
Zhang C, et al. TMAO as a novel predictor for adverse cardiovascular events after PCI: a systematic review and dose-response meta-analysis. Nutr J. 2025;24:91. doi:10.1186/s12937-025-01159-9
Warde Medical Laboratory. TMAO sample laboratory report (Cleveland HeartLab cut-offs). wardelab.com
Michigan Medicine Laboratories. Trimethylamine N-oxide, serum (TMAO). mlabs.umich.edu

Disclaimer: These statements have not been evaluated by the Food and Drug Administration (FDA). This Information / product is not intended to diagnose, treat, cure, or prevent any disease. Always consult with your physician or qualified healthcare provider before starting any new dietary supplement, especially if you are pregnant, nursing, taking medications, or have a medical condition. Discontinue use and consult a healthcare professional if any adverse reactions occur.

This article is for educational purposes and is not a substitute for professional medical advice. Talk to a qualified healthcare professional about your test results and any symptoms you're experiencing.

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