Choline and TMAO: Eggs Still Don’t Cause Heart Disease

A 2013 study by published in the New England Journal of Medicine (NEJM) has proposed a new link between eggs and coronary heart disease (CHD) that doesn’t involve cholesterol. A team of researchers, led by Dr. Stanley Hazen, showed that dietary choline—a nutrient found largely in eggs, beef liver, and other animal foods—is metabolized by bacteria in our gut and then converted by the liver into TMAO.

They demonstrated this with a “choline challenge:” feeding volunteers two large hard-boiled eggs (with approximately 250 mg of choline each) along with 250 mg of supplemental choline that was tagged with a heavy isotope. The isotope acts like a chemical “label” that allowed the researchers to track what happened to the choline after it was ingested. Their data did indeed show an increase in both labeled TMAO and total TMAO (in urine and blood) in the volunteers after they consumed the eggs and supplemental choline.

In a second study, Dr. Hazen’s group showed that increased levels of TMAO in the blood are associated with cardiovascular disease (CVD). The researchers followed roughly 4,000 adults for three years. At the end of the study period, those with the highest levels of TMAO had a 2.5-fold increased risk of heart attack, stroke and death.

On the surface this sounds like very bad news for omnivores. But let’s take a closer look at the studies to see if it’s really time to swap your morning eggs for a tofu scramble.

Do Choline-Rich Foods Increase TMAO Levels?

Dr. Hazen’s team did show a temporary increase in total TMAO after eating eggs. However, as Dr. Chris Masterjohn pointed out to me in an email dialog, the researchers’ own data show that there’s no way that the “choline challenge” could have contributed to this increase in total TMAO. If it had, we would expect to see an initial increase in labeled TMAO followed by an increase in labeled TMAO. This would indicate that the labeled choline supplement (that participants ate with the eggs) had been metabolized by the gut bacteria and then converted into TMAO in the liver.

But that’s not what happened. I re-created Figure 1C and 1D from the study. Figure 1C (below) shows an increase in total serum TMAO at one hour after the choline challenge. But by hour four, total TMAO is back to baseline and by hour 8 it’s even below baseline (i.e. the participants had lower TMAO at 8 hours than they did before they ate the eggs/choline).

However, Figure 1D (below) shows that labeled TMAO did not increase at all until hour four, and it didn’t increase significantly until hour six! This shows that the eggs and supplemental choline the participants ate had nothing to do with the increase in total TMAO that occurred one hour after the challenge.

What’s more, the researchers didn’t mention that other commonly eaten foods have a much more significant impact on TMAO than eggs. A 1999 study tested the effects of 46 different foods on the urinary excretion of TMAO in 6 human volunteers. (1) Eggs had no effect on TMAO excretion compared to a light control breakfast, yet 19 out of 21 types of seafood tested did. In fact, halibut generated over 53 times as much TMAO as eggs! This is not surprising, because although all species of seafood contain lower amounts of choline than eggs, they do contain trimethylamine and TMAO. Dr. Hazen’s team was aware of this study, because they referenced it briefly in the discussion section of the NEJM paper. They acknowledged that “TMAO has been identified in fish” and “the ingestion of fish raises urinary TMAO levels.” But remarkably, they did not explain how much greater fish’s impact on TMAO was when compared to eggs.

They said: “the high correlation between urine and plasma levels of TMAO argues for effective urinary clearance of TMAO.” In other words, even if eating food does increase total TMAO levels, most people are able to quickly and efficiently clear that TMAO from their blood by excreting it in the urine. This makes it doubtful that dietary factors alone explain chronic elevations in TMAO.

Instead, there are several other factors that are more likely to explain such an increase, including:

• Impaired urinary clearance of TMAO due to impaired kidney function: This is at least partially supported by data in the NEJM paper. Those with the highest levels of TMAO had an average glomerular filtration rate (GFR) of 69 mL/min. According to National Kidney Foundation guidelines, a GFR between 60–89 ml/min is indicative of a reduced capacity to filter blood through the kidneys. (2)
• Differences in the gut microbiota that predispose toward increase TMAO production: Previous work by Dr. Hazen’s group has shown that people with higher levels of Prevotella bacteria in their gut produce higher levels of TMAO. (3) (Interestingly enough, other research has shown that consumption of whole grains—not animal products—is associated with higher levels of Prevotella bacteria.) (4)
• Enhanced conversion of trimethylamine to TMAO in the liver: An enzyme called Fmo3 carries out this conversion, and its activity is affected by genetic factors, iron or salt overload, and a number of common pharmaceutical drugs used to treat arthritis, GERD, and infections. (5)
• Diabetes and metabolic syndrome: Fmo3 activity is upregulated in cases of insulin resistance and insulin deficiency. (6)

If food really did make a significant contribution to TMAO levels, and high TMAO levels cause heart disease, then we’d expect to see much higher rates of CHD among people who eat more fish—since fish has a much greater effect on TMAO than eggs. Yet this is the opposite of what studies indicate: Eating more fish (especially cold-water, fatty fish) has consistently been shown in both observational and randomized controlled trials to reduce the risk of death from heart disease. (7, 8)

Do Choline-Rich Food Cause Heart Disease?

At the end of their paper, Dr. Hazen’s group cautions against “excessive consumption of dietary phosphatidylcholine and choline” and recommends a high-fiber, vegetarian diet as a means of protecting your heart health.

Yet as I’ve argued above, they failed to present convincing evidence that eating eggs significantly increases TMAO over time—especially when compared to other foods like fish. Moreover, if eating choline-rich foods did increase the risk of heart disease (via TMAO or any other mechanism), we’d expect to see higher rates of CHD in those that eat more eggs. Yet numerous studies have failed to find any such association. For example, a meta-analysis of prospective studies involving a total of 474,000 participants followed from 8 to 22 years published in the British Medical Journal found no association between higher egg consumption (up to one per day) and CHD or stroke. (9) An analysis of data from the National Health and Nutrition Examination Study found an inverse association between egg consumption and stroke, and a cohort study from Japan found that consumption of animal products including eggs was associated with reduced risk of death from stroke. (10, 11) The lack of association—or inverse association—between egg consumption and CHD is even more impressive when you consider that those who eat more eggs are also more likely to smoke and be physically inactive. (12)

This same study found that egg consumers had diets higher in nutrients that have been shown to reduce the risk of cardiovascular disease compared to non consumers, including vitamins E, B12, and folate.

Finally, as I pointed out above, some research suggests that consuming large amounts of whole grain increase Prevotella bacteria in the gut, which were associated with the highest levels of TMAO in Dr. Hazen’s previous study on TMAO. If this is the case, consuming large amounts of fiber from whole grains may actually increase the risk of heart disease.

The hypothesis that increased serum TMAO is associated with heart disease is interesting and should be investigated further. But the data presented by Dr. Hazen’s group doesn’t support the conclusion that dietary choline is a major cause of increased TMAO, nor does it support their advice to avoid choline-rich foods like eggs, liver, beef, and pork.

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