It has been known for many years that atherosclerosis, the process of plaque build-up inside blood vessels, leads to coronary heart disease, stroke and peripheral arterial disease (aka atherosclerotic cardiovascular disease or ASCVD). Additionally, studies have shown a connection between higher blood levels of a substance known as trimethylamine N-oxide (TMAO) and increased risk of harmful cardiovascular events. However, the role of TMAO has been controversial with a mechanism not readily explained. But scientific investigations are ongoing and an observational study from August 2022 shed some light onto this subject. (1)
Trimethylamine N-oxide (TMAO) is a chemical produced through the breakdown by microbes in the intestine and the subsequent action of the liver on certain compounds present in meat and other animal-sourced foods. Some nutrients from these foods are absorbed through receptors in the small intestine. However, there is a limit to this absorption capacity and the excess ends up in the large intestine. Once there, microbes partially digest these animal-sourced nutrients, producing a gas called TMA which quickly enters the blood stream through the intestinal wall. When TMA reaches the liver it is oxidized to TMAO and then re-enters the blood and ends up in body tissues. TMAO is known to activate inflammation, reduce the metabolism of cholesterol, increase the risk of thrombosis (blood clots) and promote foam cell formation. Foam cells are the main component of atherosclerotic plaques. They are formed when monocytes, a type of white blood cells, adhere to the surface of the inner lining of blood vessels, dig deep into the cells and transform into macrophages. The macrophages then swallow large amounts of oxidized low-density lipoprotein cholesterol (LDL-cholesterol) and form large foam cells, the basis of the development of atherosclerotic plaques. (2,4)
The August 2022 study was performed by researchers at Tufts University in Massachusetts and was published in a journal of the American Heart Association. It included 3931 healthy participants 65 years of age and older from the Cardiovascular Health Study. Their intakes of animal-sourced food and their blood levels of trimethylamine N-oxide (TMAO) and its intermediates were obtained and followed up for an average of 12.5 years with some participants tracked for up to 26 years. (1)
This investigation concluded that at least some of the elevated risk for unhealthy, clogged arteries observed in people who consume higher amounts of meat comes from the metabolism of the L-carnitine, phosphatidylcholine and betaine present in red meat (beef, pork, bison, venison) and in other animal-sourced foods by bacteria residing in the lower intestinal tract. Compounds resulting from this process include trimethylamine-N-oxide (TMAO) and its main intermediates, gamma-butyrobetaine and crotonobetaine; all three appear to be involved in about 10% of the added ASCVD risk. (1)
Results from this report show that higher ingestion of processed and unprocessed red meat, total meat, and total animal-sourced food intake is associated with higher risk of ASCVD. (1)
- Higher intake of processed meat is associated with 11% increased risk of ASCVD.
- Higher intake of unprocessed red meat is associated with 15% increased risk of ASCVD .
- Higher intake of animal-sourced foods in general is associated with 18% increased risk of ASCVD.
- Higher total meat intake is associated with 30% increased risk of ASCVD.
Researchers from this study quantified these effects as follows (1);
Eating 1.1 serving of red meat every day (3.42 ounces or 100 gm of red meat) appears to increase atherosclerotic cardiovascular disease risk by 22%.
Eating meat at all three meals in a day would be associated with an 82% increased risk of atherosclerotic cardiovascular disease.
High blood sugar and insulin levels from consuming meat as well as systemic inflammation from eating processed meat also appear to contribute to the higher cardiovascular risk from meat consumption while blood pressure and blood cholesterol levels were not associated in this study with increased cardiovascular risk. This analysis also found no significant associations of increased cardiovascular disease with intakes of fish, poultry and eggs. (1)
Earlier papers have pointed out the link between TMAO derived from nutrients that are abundant in red meat and heart disease. In 2018, study participants were given prepared meals for a month. The meals included three different diets, all of which contained 25% of calories from protein, with the dietary proteins coming from either red meat, white meat or non-meat sources. On the red meat diet, in which the participants consumed the equivalent of 8 ounces of steak or two quarter-pound beef patties daily, blood levels of TMAO were three times higher than those of the participants eating either white meat or non-meat protein. In addition, half of the participants were placed on high saturated fat versions of the three diets (all with equal calories) and results revealed that saturated fat had no additional effects on TMAO levels. When participants discontinued eating the red meat diet and ate either the white meat or non-meat diet for another month, their TMAO levels decreased. (3)
What does all this boil down to? The association between eating animal-sourced foods and cardiovascular disease has long been recognized. This new science has given us information about one mechanism that is a likely causal factor of this link. Additionally, it has quantified the rise in disease risk resulting from eating a given amount of meat. Eating a daily serving of meat of about the size of a standard deck of playing cards can increase atherosclerotic cardiovascular disease risk by 22%. It is up to each one of us to decide how much cardiovascular risk we are comfortable with and to eat accordingly.
One final note, if you are a fitness enthusiast you may recognize L-carnitine as a popular fitness supplement. Until the health effects of these supplements are better understood and it is determined whether or not TMAO is produced from supplemental L-carnitine, people should be very wary of their use. At this point there is no evidence that such supplements are beneficial and significant support for their possibility to do harm.
1 Wang, M., Wang, Z., Lee, Y., Lai, H.T.M., de Oliveira Otto, M.C., Lemaitre, R.N., Fretts, A., et al. Dietary Meat, Trimethylamine N-Oxide-Related Metabolites, and Incident Cardiovascular Disease Among Older Adults: The Cardiovascular Health Study. Arteriosclerosis, Thrombosis, and Vascular Biology. 2022; 42: e273–e288. Originally published1 Aug 2022https://doi.org/10.1161/ATVBAHA.121.316533 .
2 Jing, L., Zhang, H., Xiang, Q., Shen, L. et al. Targeting Trimethylamine N-Oxide: A New Therapeutic Strategy for Alleviating Atherosclerosis. Front. Cardiovasc. Med., 13 June 2022. Sec. Atherosclerosis and Vascular Medicine. https://doi.org/10.3389/fcvm.2022.864600.
3 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. Eur Heart J. 2018 Dec 10. Doi: 10.1093/eurheartj/ehy799.
4 Rath ,S,. Heidrich, .B, Pieper, D.H., Vital, M. Uncovering the trimethylamine-producing bacteria of the human gut microbiota. Microbiome. 2017 May 15; 5(1): 54. Doi: 10.1186/s40168-017-0271-9. PMID: 28506279; PMCID: PMC5433236.