It is hardly news that substances found in red meat and eggs promote atherosclerosis and lead to coronary artery disease (CAD). Both eggs and red meats contain saturated fatty acids and cholesterol, which have both been proven to raise LDL-C levels in the blood. Furthermore, elevated LDL-C levels in the blood are a well-established promoter of CAD. Importantly, dietary interventions that significantly reduce LDL-C levels also reduce the risk of suffering a heart attack, and so have long been the cornerstone of prevention and treatment plans for CAD (1). Although an article published in the NY Times stated, "In fact, these scientists suspected that saturated fat and cholesterol made only a minor contribution to the increased amount of heart disease seen in red-meat eaters,” this is not correct according to the study's lead researcher, Dr. Hazen, at the Cleveland Clinic.
In April 2013, researchers at the Cleveland Clinic reported that a substance (L-carnitine) in red meat appears to promote atherosclerosis in both mice and human subjects. Increased L-carnitine in the blood was only associated with more CAD and subsequent cardiovascular disease (CVD) events when it was converted into trimethyl-amine-N-oxide (TMAO). These researchers also showed that TMAO could only be produced in mice and people after bacteria in their intestines first metabolized the L-carnitine into trimethylamine (TMA). This study also reported that increased serum L-carnitine levels were associated with significantly more atherosclerotic plaque in the 2,595 people who underwent elective cardiac screening, but only in those whose TMAO levels were also elevated. Red meats (i.e., beef, pork, & mutton) contain much more L-carnitine than dairy products, eggs, poultry or seafood and far more than plant foods. See Table 1.
This same research team led by Dr. Hasen at the Cleveland Clinic (along with UCLA researchers) had previously published data showing that gut bacteria in mice and people can also convert other food chemicals with a similar chemical structure to L-carnitine into TMA. For example, dietary choline, betaine, and lecithin can all be used by certain gut bacteria to produce TMA. These bacteria produce TMA, which is then converted to TMAO by the liver enzyme flavin monooxygenase (FMO). FMOs are found in the livers of humans and most other animals. Eggs and liver are among the richest dietary sources of choline/lecithin, although other animal foods also supply significant amounts of choline as well. Unfortunately, the regular consumption of these animal foods also leads to higher TMA production in the gut and ultimately to much higher TMAO levels in the blood than seen in people (or mice) consuming more vegetarian diets. The necessary role of gut bacteria in this process was demonstrated when either L-carnitine or choline were fed to mice reared in a germ-free environment. These germ-free mice have no gut bacteria and so cannot make TMAO no matter how much choline or L-carnitine they were fed. However, when these germ-free mice were then put into a non-sterile environment for a few weeks, their guts were colonized with bacteria that started converting the dietary choline and L-carnitine into TMA and led to increasing TMAO levels in their blood. In addition, these researchers showed that giving antibiotics to normal mice to wipe out their gut bacteria eliminated the production of TMA for either L-carnitine or choline and so also stopped TMAO production.
The type of bacteria living in our digestive tracts are largely dictated by our long-term dietary patterns. A diet high in L-carnitine or lecithin actually shifts our gut microbe composition to those that utilize L-carnitine and choline. This is why meat eaters tend to end up with much more TMAO in their blood than vegetarians.
A few people have a genetic defect for making a functional FMO enzyme system that converts TMA to TMAO, and so TMA accumulates in their bodies and produces a strong fishy odor. This disease is called trimethylaminuria as high levels of TMA can be found in their urine too. These people have very high levels of TMA in their blood, especially when consuming foods rich in L-carnitine and choline. It is known that many individuals with trimethylaminuria often become vegans largely because eliminating dietary animal products rich in L-carnitine /choline/lecithin markedly reduces TMA production by their gut bacteria and so markedly reduces the associated odor.
Bottom Line: This research certainly questions the wisdom of taking food supplements of lecithin/choline and L-carnitine unless there is evidence such supplements have proven benefits in cases of deficiency or for the treatment of some disease. Many energy drinks also contain L-carnitine and probably should be avoided as well. This research, contrary to some naïve media reports, in no way undermines the dangers of eating foods high in saturated fat and cholesterol or discredits their central role in raising LDL-C and promoting the growth of atherosclerotic plaques. However, it does provide a bit more evidence as to how a diet high in animal products may promote CAD and suggests a plausible mechanism to help explain why a low-fat, near vegetarian diet appears more effective than statin drugs for reversing atherosclerosis, even though the drugs are more effective in high doses at lowering LDL-C levels. There is no reason to suspect statins would alter TMAO production. Coincidentally, some of the same foods highest in saturated fat and cholesterol such as red meats, eggs, fatty dairy products, and liver are also the same foods that are more closely linked to CAD, perhaps because they increase the production of TMA by gut bacteria more than other foods. Thanks to the research of Dr. Hazen and associates, we know that this bacterially-produced TMA gets converted to TMAO in our livers, and TMAO appears to speed up atherosclerosis by interfering with the RCT system.
By James J. Kenney, PhD, FACN
1. Krauss RM, et al. AHA Dietary Guidelines: revision 2000: a statement for healthcare professionals from the Nutrition Committee of the American Heart Association. Circulation 2000;102:2284-99.
2. Gina Golata, New York Times, April 8, 2013.
3. Nature Medicine, published online 7 April 2013; doi:10.1038/nm.3145.
4. Wang Z, et al. Gut Flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011;472:57-65.
More Evidence: A Follow-Up
Another important article linking the gut microbial production of TMAO from dietary phosphatidylcholine (a.k.a. lecithin) appeared in the April 25, 2013 issue of the New England Journal of Medicine. This article discusses two studies conducted by Dr. Hazen and his colleagues, both at the Cleveland Clinic and elsewhere.
The first study fed 40 healthy subjects two hard boiled eggs and a supplement of deuterium-labeled lecithin and monitored the amount of TMAO that appeared in their blood over the next 8 hours. They again showed that TMAO levels rose dramatically, starting a few hours after eating the lecithin-rich egg meal. They then gave 6 of these subjects broad spectrum antibiotics to wipe out their gut bacteria and re-tested them with same 2 egg meal, plus a labeled lecithin supplement and found virtually no TMAO appeared in their blood. After a month off the antibiotics, subjects were tested a third time and showed that already TMAO levels were again increased after the choline-rich challenge meal.
The second study examined 4007 subjects (mean age 63 years old, 2/3 of subjects were male) who underwent an elective angiogram to assess the extent of CAD. The subjects were then followed over 3 years to see if the TMAO levels in their blood at the time of their angiogram was correlated with future CVD events. Compared to the 25% of subjects with the lowest plasma TMAO levels at baseline, the 25% with the most TMAO in their blood were 2-3 times more likely to suffer a nonfatal heart attack, a stroke, or a fatal CVD event. This association with increased risk of CVD with higher TMAO levels was reduced but not eliminated when the authors adjusted their data for other known CVD risk factors, thus establishing higher TMAO levels as an independent risk factor for heart attacks and strokes (1). There is still a need to find a probiotic, food supplement, and/or drug that can block TMA synthesis by gut microbes to lower TMAO levels in the blood. Even when such a supplement/drug can be found it will still need to be shown that lowering TMAO levels can reduce CVD events. In the meantime, the only way to dramatically reduce TMAO levels is to avoid foods high in L-carnitine and lecithin/choline. This would be red meats, egg yolks, liver, and fatty dairy products, along with avoiding supplements and energy drinks that contain these biochemicals. Fortunately, Dr. Hazen has already shown that people following a vegan or low-fat vegetarian diet with little or no red meat or eggs have gut microbes that make very little TMA, even in response to an occasional meal with a lot of L-carnitine or choline. Such a diet lowers LDL-C too and so this research just reinforces current dietary advice to reduce the risk of CVD.
By James J. Kenney, PhD, FACN
1) Tang WH, et al. N Engl J Med 2013;368:1575-84.
Stephanie Ronco has been editing for Food and Health Communications since 2011. She graduated from Colorado College magna cum laude with distinction in Comparative Literature. She was elected a member of Phi Beta Kappa in 2008.