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TMAO and Heart Health by Christina Badaracco, MPH, RD

There are many reasons why consumers—from cardiovascular disease patients to activist youth—may choose to reduce their intake of red meat. The long-standing concern about saturated fat, which is more prevalent in red meat than many other forms of protein, drives people to choose protein sources with less fat. Some people are adamantly opposed to eating food derived from animals, while others limit their intake of animal products to those from animals raised on sustainable, pasture-filled ranches and farms. Many are also concerned about the environmental impacts of red meat production, which is indeed one of the most resource-intensive forms of food production. In recent years, emerging evidence about the potential harmful production of trimethylamine N-oxide, or TMAO, adds another complication to this dietary decision-making. What is trimethylamine N-oxide (TMAO)? TMAO is a molecule produced in the body following digestion of mostly animal products and a few plant materials containing choline, lecithin and L-carnitine. These molecules are all involved to some extent in normal metabolism. When we digest lecithin (which contains phosphatidylcholine, a source of choline) and choline in our diets, our gut microbiota (or bacteria in the gut) metabolize the products into trimethylamine, or TMA. L-carnitine is believed to undergo an additional step of conversion to γ-butyrobetaine. The final step of production occurs in the liver, where enzymes oxidize TMA into TMAO.


Pathway of TMAO production

TMAO concentrations vary widely between individuals and are determined by factors such as diet, gut microbial populations and kidney function. The effect of kidney disease, in particular, is quite pronounced: pre-dialysis patients may have twice the level of TMAO, and hemodialysis patients may have 10 times the level of TMAO as otherwise healthy patients. The primary dietary contributors are animal foods. See the figure below for foods containing the most L-carnitine and choline. Note that while red meat appears to have the greatest concentration, the protein supplements many Americans take today—through things like smoothies and protein shakes—may provide 500 mg or more per serving. Additionally, lecithin is often added to processed foods as an emulsifier. Since lecithin contains choline, foods listed with lecithin contain higher amounts of choline.


How does TMAO impact human health? Emerging evidence has shown high circulating levels of TMAO to be associated with a greater risk of cardiovascular disease (CVD) and death in humans. A landmark study by Tang et al. in 2013 first suggested the increased risk of cardiovascular events among those with high blood levels of TMAO. A 2017 meta-analysis reinforced these findings. This increased risk is due to a variety of factors, such as an altered cholesterol and bile acid metabolism and activation of inflammatory pathways. In arteries, more TMAO leads to an increased deposition of cholesterol from the blood, which can lead to atherosclerosis. Inflammatory effects may also progress kidney disease and promote metabolic syndrome and/or type 2 diabetes mellitus. Ultimately, severe cardiovascular disease, particularly with comorbidities, can lead to mortality. Precise mechanisms are still being investigated, and a small number of studies have found conflicting results. A particularly vexing question is how fish, which have high levels of TMAO in their flesh, have consistently been shown to yield health benefits when consumed by humans.



Adding to the uncertainty in the field, a 2018 study by Lemos et al. indicated that following a diet high in either egg or choline supplement intake for one month each didn’t result in a change in TMAO concentrations, indicating moderate consumption may not noticeably increase heart health risks. This contradicted previous evidence about the positive association between egg and choline supplement consumption and TMAO production. How does the microbiome relate to TMAO? In the microbiome, certain species of bacteria appear to play a role in modulating the production of TMAO. Strains such as Firmicutes and Proteobacteria, often associated with poor human health, have been shown to produce TMAO. A strain of Bacteriodetes, found more abundantly in the guts of healthy individuals, has been inversely associated with serum levels of TMAO. Bacteriodetes have repeatedly been shown to positively affect human health by producing short-chain fatty acids that reduce inflammation, insulin resistance and other related diseases.  Other recent research from the Cleveland Clinic suggests that a molecule called dimethyl-1-butanol (DMB) can inhibit bacterial production of TMAO. DMB can be consumed through a variety of foods found in a typical Mediterranean diet, such as olive oil and red wine. Vegans’ gut microbiota have also been shown to produce much less TMAO, even following a “carnitine challenge.” A 2013 study by Koeth et al. found that not only do vegans and vegetarians have lower fasting levels of TMAO, but even after consuming a diet rich in L-carnitine for a year, they still only produced a minimal amount of TMAO. This result indicated a direct connection between gut microbiota, diet and TMAO levels and suggested that a plant-based diet may be protective against this contributor to heart disease. What can I do to reduce my body’s production of TMAO? Because levels of TMAO in the blood are strongly linked to dietary intake, dietary modifications can be a significant way to reduce risk.​

  • Because the metabolism of white meat, seafood, dairy and plant-based proteins, in particular, leads to less production of TMAO, they should comprise the majority of your protein sources.

  • Unless you are experiencing a protein deficiency and have talked with a doctor or dietitian about protein supplements, avoid supplements containing pure L-carnitine. Plant-based protein supplements, such as those made from peas or hemp seeds, may be better options (at least until the mechanism behind L-carnitine, choline and lecithin consumption and heart health is more fully understood).

  • Treat red meat as an occasional treat, aiming to buy grass-fed, grass-finished and pasture-raised beef, bison, lamb, etc. when possible.

  • When eating red meat, aim for up to four ounces per serving and choose leaner cuts or lean ground meat to avoid excessive saturated fat.

  • Regularly consume staple components of the Mediterranean diet—including extra-virgin olive oil, grapeseed oil, red wine and balsamic vinegar—to provide the DMB that can prevent your gut microbiota from producing high amounts of TMAO.

  • For people who are anemic (including a large percentage of women in the US), red meat is one of the best dietary sources of iron and is more bioavailable than plant-based sources and easier on the stomach than supplements. Try incorporating once per week as a therapeutic food. Also, consume vitamin C (from sources like tomato sauce and oranges) with plant-based iron sources (like beans and spinach) to boost iron absorption.

  • Blood tests for TMAO are currently being developed and validated (such as at the Cleveland Heartlab), so patients with an elevated risk of cardiovascular disease may ask their doctor about the availability of such a test to determine how strongly indicated a dietary modification would be.


Resources

  • Cleveland Heartlab. “The Gut, the Heart, and TMAO.” August 1, 2016. www.clevelandheartlab.com/blog/the-gut-the-heart-and-tmao/.

  • Koeth, R.A., Levison, B.S., et al. 2014. γ–Butyrobetaine is a pro-atherogenic intermediate in gut microbial metabolism of L-carnitine to TMAO. Cell Metab 20(5):799–812.

  • Koeth, R.A., Wang, Z., et al. 2013. “Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis.” Nat Med 19(5):576-85.

  • Lemos, Bruno & Medina-Vera, Isabel & Malysheva, Olga & Caudill, Marie & Fernandez, Maria. (2018). "Effects of Egg Consumption and Choline Supplementation on Plasma Choline and Trimethylamine-N-Oxide in a Young Population." Journal of the American College of Nutrition. 1-8. 10.1080/07315724.2018.1466213.

  • Qi, J., et al. 2018. “Circulating trimethylamine N-oxide and the risk of cardiovascular diseases: a systematic review and meta-analysis of 11 prospective cohort studies.” J Cell Mol Med 22(1):185–194.

  • Tang, W.H., et al. 2013. "Intestinal Microbial Metabolism of Phosphatidylcholine and Cardiovascular Risk." The New England Journal of Medicine 368(17):1575–1584.

  • Velasquez, M.T., et al. 2016. “Trimethylamine N-Oxide: The Good, the Bad and the Unknown.” Toxins 8(11):326.

  • Wang, Z. et al. 2015. “Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis.” Cell 163(7):1585-95.

  • Zhu, W., Zeneng Wang, Z., et al. 2017. “Gut Microbe-Generated Trimethylamine N-Oxide From Dietary Choline Is Prothrombotic in Subjects.” Circulation 135:1671–1673.


Christina Badaracco, MPH, RD


Christina is a registered dietitian and author who aims to improve access to healthy and sustainable food and educate Americans about the connections between food and health. She loves to experiment with healthy recipes in the kitchen and share her creations to inspire others to cook. Christina completed her dietetic internship at Massachusetts General Hospital and earned her Master of Public Health degree from the University of California, Berkeley. Previously, she graduated with a degree in Ecology and Evolutionary Biology from Princeton University, after conducting her thesis on sustainable agriculture and energy in Kenya. She has done clinical nutrition research at the National Institutes of Health, menu planning and nutrition education at the Oakland Unified School District and communications at the Environmental Protection Agency’s Office of Water. She has also enjoyed contributing to children’s gardens, farmers’ markets and a number of organic farms. cbadarac@gmail.com www.linkedin.com/in/christina-badaracco/


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