Conventionally recognized dietary factors known to promote atherosclerosis (plaque in the arteries) and that involve animal products include saturated fat, dietary cholesterol, low fiber intake, and excess iron. Bioaccumulation of environmental toxins such as herbicides, pesticides, antibiotics and hormones are excluded in this article and another matter entirely. There is an interesting fact though; not all people who have higher cholesterol and consume animal products get heart disease, stroke and atherosclerosis. Despite similar cholesterol levels, physical activity and lifestyle, some get it and some are spared–why is this? There are many reasons we get atherosclerosis and the role of animal foods in human disease is much more complex than previously thought.
The Link Between Trimethylamine-N-Oxide (TMAO) and Heart Disease
In 2011, researchers discovered a substance called trimethylamine-N-oxide also known as TMAO. TMAO is a byproduct of egg, meat, fish (yes fish), and milk consumption. Researchers found that people with higher levels of TMAO may have more than twice the risk of heart attack, stroke, or other cardiovascular problems, compared with people who have normal levels. TMAO can cause damage to your kidneys, heart, liver and blood vessels through different mechanisms.
TMAO causes changes in cholesterol levels, activation of inflammatory pathways and promotion of foam cell formation , a critical step in atherosclerosis. TMAO levels increase as kidney function worsens and is associated with a poor outcome in patients with chronic kidney disease. Unlike cholesterol, which does always cause arterial plaque and heart disease, TMAO may be the missing link between animal foods and heart disease. Those of us in the field of preventive cardiology now view TMAO as one important new contributor the atherosclerosis.
In 2015, researchers at the Cleveland clinic were able to show that by blocking the production of TMAO a critical pathway that leads to arterial plaque can be disrupted. TMAO appears to be an important link between animal foods, the intestinal microbiome, atherosclerosis and the heart attacks. TMAO can even cause hardening of the arteries.[i]
It also helps explain why some populations that eat the same amount of eggs, meat and animal fat have differing levels of artery disease despite most other things being the same. Later I will tell you why not all people are affected the same way. Hint: think of things the French do that we do not.
In the recent film called The Game Changers, a documentary about elite athletes who follow a plant-based diet, TMAO is briefly discussed. I was impressed by this. Sometimes I feel like I am the only one who knows about it; including cardiologists! Since I do so many artery ultrasounds, I have even been able to see substantial reduction of plaque by lowering TMAO.
So, how exactly do our bodies make this stuff? Nutrients such as phosphatidylcholine (also known as lecithin), choline, and L-carnitine are the key components that are to blame. These are abundant in animal-derived products such as red meat, egg yolk and full-fat dairy products. Red meat appears to be the worst though. Fish have high levels of TMAO [ii] because it protects against the protein-destabilizing effects of urea. L-Carnitine, lecithin, and choline are popular supplements taken for cognition and cardiovascular health but can also elevate TMAO levels. Because of this I only allow them if TMAO is not high while taking them. When consumed, these nutrients are processed by certain gut bacteria resulting in the release of various metabolites including TMA (trimethylamine). TMA is then transported to the liver where it may be converted into TMAO. This conversion does not ALWAYS occur because it is dependent on a person’s microbiome or gut flora.[iii]
Interestingly, the more red meat you eat, the more of these TMAO producing bacteria are produced. [iv] Exposure to red meat changes the gut flora. Some expert say that we then crave these foods more because of changes in the gut flora. There are over 100 trillion microorganisms in the human digestive tract with a thousand different species of bacteria. These bugs outnumber human cells by ten to one and the number of microbial DNA in your gut is 200 times greater than the entire human genome. Also known as the microbiota, in total, your gut flora weighs about 2 kg in the typical person and is an important player in a number of diseases. How can we block this conversion of TMA to TMAO? Can we change the gut flora, change our eating habits, or take a pill? All of the above work and is discussed below.
 Foam cells are white blood cells that are filled with cholesterol particles
[i] Randrianarisoa E, Lehn-Stefan A, Wang X, Hoene M, Peter A, Heinzmann SS, Zhao X, Königsrainer I, Königsrainer A, Balletshofer B, Machann J, Schick F, Fritsche A, Häring HU, Xu G, Lehmann R, Stefan N. Relationship of Serum Trimethylamine N-Oxide (TMAO) Levels with early Atherosclerosis in Humans.Sci Rep. 2016 May 27;6:26745. doi: 10.1038/srep2674
[ii] Velasquez MT, Ramezani A, Manal A, Raj DS. Trimethylamine N-Oxide: The Good, the Bad and the Unknown. Toxins (Basel). 2016;8(11):326. Published 2016 Nov 8. doi:10.3390/toxins8110326
[iii] Janeiro MH, Ramírez MJ, Milagro FI, Martínez JA, Solas M. Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target. Nutrients. 2018;10(10):1398. Published 2018 Oct 1. doi:10.3390/nu10101398
[iv] Robert A. Koeth, … , Jose Carlos Garcia-Garcia, Stanley L. Hazen. l-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans
Citation Information: J Clin Invest. 2019;129(1):373-387.
The French Paradox: Fatty Foods but Less Heart Disease
The French paradox is named so because of the relatively high percentage of cholesterol and saturated fat intake in the French diet and yet the fact that coronary heart disease deaths are much lower in France compared to other Western countries. France is not the healthiest country by the way (Spain, Italy and Cyprus have less total overall causes of death). France has less artery disease but more cancer than many other European countries.
If anyone is not familiar with how the French eat, I will tell you. First, they have not gotten the memo about health food or about why smoking is a bad idea. Asking for gluten and dairy free will get you a quizzical stare from the waiter. The way they eat is traditional. More food is grown and consumed locally, and more care is put into food production; think quality over quantity. Eating is an oral experience to be savored and more time is spent sitting during meals. Portions are smaller. Eating a steak the size of one’s head is not cool. A study was even done at a McDonald’s in Paris. The French customers spent considerably more time eating, and interestingly, the serving sizes are smaller at the golden arches there as well!
The French frequently consume meat, poultry, fish, animal fats and cheese including items such as pate (made from goose liver), eggs, egg yolks, cholesterol-laden sauces and generally more saturated fat and cholesterol than The American Heart Association would find acceptable.
What they do not eat much of is fast food (example from above excluded), prepared foods, junk, unhealthy snacks, and they drink much less soda. The pastries are freshly made with butter, not partially hydrogenated oils like most of the decadent foods in the United States, etc. The meals are smaller, and people are more physically active as a population in general, despite the smoking. Incidentally, compared to Britain the French do not smoke much more.
When looking at Europe as a whole death rates from heart attacks drop as one looks further and further south. An extreme example is the death rate between Glasgow, in the United Kingdom and Toulouse, in southwestern France. Both cities eat approximately 38% of total energy as saturated fat however heart attack death rates are 332 per 100,000 versus 53 per 100,000 respectively.
So, why? Some reasons could include less binge drinking in France compared to other countries (like Britain) even though there is more red wine consumption (and alcohol) per capita. There are more fruits and vegetables in the diet and a slower, more social, eating style. More emphasis is placed on the joy of food and in the ritual of preparing it, and higher quality food is important. There is also less obesity in France, less reported stress, and more exercise.
Effective Ways to Lower TMAO
Obviously, one does not need to be a nutritional expert to see that there are many differences here that can affect health. Some studies point to the role of red wine (resveratrol) and its effect on heart health by raising the good cholesterol, mildly lowering blood pressure, preventing platelet stickiness and acting as an antioxidant.
Consuming zero animal foods is the best and most effective way to lower TMAO. Increasing fruit, nuts, seeds, legumes, whole grains and vegetables also helps. As does red wine or red wine extract as well as pure grape juice. The resveratrol in red wine is also a potent inhibitor of TMA conversion to TMAO. [i] Resveratrol blocks the conversion of the important precursor, TMA, in the liver. There are other inhibitors as well such as olive oil, fresh fruit and vegetables, fiber, grapeseed oil and allicin, one of the most active constituents of garlic. It’s likely that other polyphenols such as those found in green tea also work. Changing the gut flora can also help with use of probiotics (esp. the species planarum).
Consideration of dietary changes is warranted. The Mediterranean diet includes much more olive oil, red wine, and garlic compared to other Western diets. Production of TMAO in populations eating plant-based diets show low levels.[ii]
[i] Chen ML, Yi L, Zhang Y, et al. Resveratrol Attenuates Trimethylamine-N-Oxide (TMAO)-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota. MBio. 2016;7(2): e02210–e2215. Published 2016 Apr 5. doi:10.1128/mBio.02210-15
[ii] Robert A. Koeth, … , Jose Carlos Garcia-Garcia, Stanley L. Hazen. l-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans
Citation Information: J Clin Invest. 2019;129(1):373-387.
Summary: TMAO and Your Diet
One of the most scientifically probable links between eating animal foods and risk of heart disease is TMAO. It’s the phosphatidylcholine, choline and L-Carnitine in animal food that turn into TMAO. In the case of fish, it’s in the flesh already. Also eating these foods (especially red meat!) ramps up the gut bacteria that make TMAO in the first place. Olive oil, fresh fruit and vegetables, fiber, grapeseed oil, garlic, red wine, grape juice, grapes, and resveratrol capsules all help lower TMAO. Plant based diets lower TMAO within a few weeks. Resveratrol is the most effective blocker. I will sometimes help patients change their gut bugs too by taking certain strains of probiotics.
TMAO is only one important blood test to do if you are looking to improve arterial health. Start with checking your blood level. Not all meat eaters have high levels but if you do, it can cause disease! This test is available through my office.
Call our office today to schedule your test.