Part 1: TMAO

If you read my recent blog entitled “Why is Eating Meat So Damaging to Human Health Part 1”, you might remember a dangerous little nutrient called TMAO (trimethylamine N-oxide). It is a product of the digestion of a food nutrient called carnitine which, in the human diet, comes mostly from red meat, poultry, fish and milk. The problem with TMAO is that it injures the lining of arteries hampering their ability to dilate; it creates inflammation; it promotes blood clotting and increases the build-up of cholesterol and other substances within atherosclerotic plaques in the blood vessels (1). Studies have found that TMAO level can successfully predict the risk of future cardiac events, even in those not identified through traditional risk factors. People with the most TMAO circulating in their bloodstreams increase their risk of stroke, myocardial infarction and death by two and a half times (2,3,4). A 2017 meta-analysis of eleven prospective cohort studies found that higher circulating TMAO was associated with 23% higher risk of cardiovascular events and 55% higher risk of early mortality (5).

Two new studies from the Cleveland Clinic Center in the US were published this December and are revealing new information about TMAO and the powerful effect of lifestyle on cardiovascular health.

 

THE FIRST STUDY…

was published on December 10, 2018 (6). This randomized crossover trial enrolled 113 healthy men and women who were randomly assigned one of three meal plans that provided an equal number of calories but varied in their protein sources. Red meat (steak or beef patties), white meat (poultry) or vegetable protein sources (legumes, nuts, grains, soy) were used and provided 25 percent of daily calories. Participants followed the first meal plan for four weeks then returned to their regular eating habits for another four weeks. This step would “wash out” the effects of the first diet. Next they would start a second meal plan and then the third one, following the same procedures as for the first one. In addition half of the participants were placed on high-fat versions of the three diets.

After four weeks the average blood and urine levels of TMAO in the red meat-eating group were almost tripled compared to those eating either white meat or vegetable protein. In some red meat-eaters the TMAO level was closer to ten times higher (6). Although all meats contain carnitine, its levels in red meat are about ten times greater than those in white meats such as poultry and fish and about 1000 times higher than those in any plant food (7). The participants eating the high-fat versions of the diets showed similar TMAO level results signifying that dietary fat intake had no impact on TMAO production. In addition this study illustrated that chronic red meat consumption reduced excretion of TMAO by the kidneys through the urine, an effect that would have caused some of the increase in TMAO levels. Lastly, and perhaps most interestingly, the study revealed that when ingestion of red meat was stopped, TMAO levels gradually dropped back to baseline level after about 4 weeks (6).

 

THE SECOND STUDY…

published on the same day in a different medical journal, was the first science looking into the particulars of the conversion of carnitine to TMAO in human beings. Studies in mice had shown that the process requires two separate steps to result in the end-product of TMAO however the microbial pathways of this process in humans was unknown. This study used carnitine supplements as their carnitine source and looked at TMAO production in both omnivores and vegans/vegetarians.

A note on carnitine supplements: Carnitine is a nutrient produced by the body from amino acids and used for energy production. Normally the liver and kidneys produce more than enough carnitine for human needs but there are rare cases of carnitine deficiency (9). Carnitine supplements are useful in these situations. There is some controversy surrounding other uses of carnitine supplements. For example, because of the role of carnitine in energy production some athletes use carnitine supplements in an attempt to improve their performance. There is no consistent evidence that carnitine supplementation can improve physical performance in healthy people (10). On a negative note, carnitine supplementation can cause nausea, vomiting, abdominal cramps, diarrhea and a “fishy” body odour along with less common side effects of muscle weakness in those with kidney insufficiency and seizures in those with seizure disorders (9).

Results of this study revealed that the conversion of carnitine to TMAO is indeed a multi-step process. The first step requires a specific set of gut bacteria and is identical in both vegetarians and meat-eaters. However, the second step, involving a different group of gut bacteria, produces much greater amounts and more rapid formation of carnitine to TMAO in those who eat meat (omnivores) than in vegetarians or vegans. At the start of the study the vegans/vegetarians had limited ability to produce TMAO while meat eaters could produce it rapidly. However, after two or more months of carnitine supplementation, about 50% of the vegans/vegetarians were producing TMAO similarly to the meat eaters while the other half remained unable to produce TMAO. Researchers speculated that the carnitine supplementation had encouraged growth of any meat-loving type of bacteria present in the guts of half of the vegans/vegetarians thus increasing their TMAO production. The other half simply lacked any of the gut bacteria that have the capability to promote this transformation (8).

 

THE SIGNIFICANCE OF THESE RESULTS

There is a simple, quick and inexpensive test that can be performed in a laboratory to measure TMAO levels. But such a test is not really necessary. These studies illustrate that consuming any form of carnitine will increase TMAO levels. They are also the first investigations to demonstrate that lowering the amount of carnitine in the diet will lower TMAO levels and subsequently reduce the risk of cardiovascular disease. By the simple lifestyle alteration of eating less meat, especially red meat, and avoiding carnitine supplements, we have the power in our own hands to significantly lower our risk of devastating cardiovascular events such as atherosclerosis, heart attacks and strokes.

 

SOURCES:

1 Velasquez, M.T., Ramezani, A., Manal, A., Raj, D.S. Trimethylamine N-Oxide: The Good, the Bad and the Unknown. Toxins (Basel) Nov 2016; 8(11): 326.

2 Koeth, R.A., Wang, Z., Levison, B.S., Buffa, J.A., Org, E., Sheehy, B.T., et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nature Medicine. May 2013; 19 (5): 576–585.

3 Tang, W.H.W., Wang, Z., Levison, B.S., Koeth, R.A., Britt, E.B. et al. Intestinal Microbial Metabolism of Phosphatidylcholine and Cardiovascular Risk . N Engl J Med 2013; 368:1575-1584.

4 Mente, A., Chalcraft, K., Ak, H., Davis, A.D., Lonn, E. et al. The Relationship Between Trimethylamine-N-Oxide and Prevalent Cardiovascular Disease in a Multiethnic Population Living in Canada. Can J Cardiol. 2015 Sep; 31(9):1189-1194.

5 Qi, J., You, T., Li, J., Pan, T., Xiang, L., Han, Y., Zhu, L. 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. 2018 Jan; 22(1):185-194.)

6 Wang, Z., Bergeron, N., Levison, B.S., Li, X.S., Chiu, S., Jia, X., Koeth, R.A., Li, L., Wu, Y., Tang, W.H.W., Krauss, R.M., Hazen, S.L. Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women. European Heart Journal. 10 December 2018; ehy799: https://doi.org/10.1093/eurheartj/ehy799.

7 https://ods.od.nih.gov/factsheets/Carnitine-HealthProfessional/

8 Koeth, R.A., Lam-Galvez, B.R., Kirsop, J., Wang, Z., Levison, B.S., Gu, X., Copeland, M.F., Bartlett, D., Cody, D.B., Dai, H.J., Culley, M.K., Li, X.S., Fu, X., Wu, Y., Li, L., DiDonato, J.A., Tang, W.H.W., Garcia-Garcia, J.C., Hazen, S.L. l-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans. The Journal of Clinical Investigation. December 10, 2018: 10.1172/JCI94601.

9 Rebouche, C.J. Carnitine In: Modern Nutrition in Health and Disease, 9th Edition (edited by Shils ME, Olson JA, Shike M, Ross, AC). Lippincott Williams and Wilkins, New York, 1999, pp. 505-512.

10 Brass, E.P. Carnitine and sports medicine: use or abuse? Ann N Y Acad Sci. 2004 Nov; 1033:67-78.