Choline and TMAO: Eggs Still Don't Cause Heart Disease | Chris Kresser

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

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Could the choline in these eggs contribute to heart disease?
Do choline-rich eggs increase TMAO levels? Stockbyte/Stockbyte/Thinkstock

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).

Figure 1C choline and eggs Chris Kresser

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.

figure 1D choline and eggs Chris Kresser

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.

Finally, this paper did not prove that eating choline-rich foods (or any other foods) increases TMAO levels over time. In fact, the researchers themselves seem to suggest this is unlikely in the discussion section of the paper.

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. (78)

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. (1011) 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)

Some studies suggest that eggs may even prevent heart disease. Egg consumption leads to the formation of larger, less dense LDL and HDL particles, which may be protective against atherosclerosis. (13) Eating eggs frequently may even lead to lower cholesterol; one study found that those eating four or more eggs per week had lower total serum cholesterol than those eating one or fewer per week.  (14)

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.

Now, I’d like to hear from you. Do you eat eggs (or another source of dietary choline) regularly? What are your thoughts on this research? Comment below and let me know.  

  1. Human populations with their regional diet have their own intestinal bacteria specifically evolved for that type of diet. Therefore, a certain type diet can be detrimental to a new group of people but perfectly OK for the native people.

    • I worked in a place in China, where they turned off the water to 30 toilets nightly. I was the first one there in the morning, and had to look to find a clean Stall. Well I saw, for six weeks what they were excreting. It looks like yellow baby custard poo. More interesting still, is that after a few weeks there, I picked up this intestinal variant. Only when returning to Chicago did things return to “normal”

  2. As always if you take one single constituent of a food and you study it, you come to misleading conclusions.

    As it is for fructose for example: extracted stand-alone fructose is like a weapon of mass destruction.. so what? No more eating fruit?

    Wait no.. turns out that the little fructose in a fruit is more then well balanced out from all the other good things that come with fruit.

    To me it seems tha same for choline. Choline seems to produce TMAO. So what? no more eating choline-containing foods? eggs and fish are bad?

    No, eggs and fish are awesome. And avoiding them is riskier than eating them.

  3. I find it interesting that last year (2013) Dr. Stanley Hazen did another research on Lp(a) cholesterol confirming that it was an indicator of heart disease more so than LDL levels. However, there are no medication and they have no idea how to control the Lp(a) therefor he recommends to further reduce LDL with statin drugs in an attempt to lower Lp(a). I also find it interesting that Lecithin and choline have been very beneficial to many in lowering cholesterol levels. And for myself Lecithin in particular has assisted me in reducing my CVD in the form of PAD by reducing the plaque in my aorta and iliac arteries without the use of statin drugs. An aside: I eat meat of all kinds including fish, pork, beef, etc. Now he comes out with the finding that it interacts with gut bacteria and supposedly increases TMAO associated with CVD. If we do not eat food or take supplements with these things in then then how will our bodies get what they need to make it. I also, find it interesting that if you cook your egg too hard that it destroys the lecithin inside the yoke (from what I have read online). Yet, his “research” was conducted with hard boiled eggs and supplements that may or may not have been heated to process. I also find it interesting lecithin clears fat from the liver, lowers cholesterol and helps remove plague from the arteries and therefor is competing against statin drugs in the movement towards natural medicine. Additional interest to me is the fact that Dr. Stanley Hazen sits on many boards and receives research money from pharmaceutical companies that manufacture/sell statin drugs to reduce cholesterol. He is on the scientific advisory board for BG Medicine, Inc.; is on the speakers bureau for Merck & Co., Inc.; is a consultant and on the speakers bureau for AstraZeneca Pharmaceuticals, Inc., Eli Lilly and Company, and Takeda Pharmaceuticals North America, Inc.; is an inventor for Frantz BioMarkers; is a consultant for Esperion Therapeutics, Inc.; is a consultant and on the scientific advisory board and receives grant/research support from CHL Medical Partners; is a consultant and on the advisory board for Pfizer Inc; and is an inventor and on the speakers bureau and receives grant/research support from Abbott Laboratories. Its, all very interesting, in my opinion..

    • Good points, Rosemary. I would only say that “interesting” isn’t the term I’d use. There have been numerous studies, going back to the mid-1990s, that demonstrate the effects of funding bias on study results, as well as numerous books, such as Overdosed America and Bad Pharma. The evidence consistently shows that an industry-funded study is “X” times more likely to produce a result favorable to the funders’ product, treatment mode or whatever they are selling, as an independent study would. The “X” factor varies with the study, but I don’t recall any that are less than twice as likely. So, instead of “interesting”, it’s evidence of the corrupting role of money in science. It’s still true that “he who pays the piper calls the tune”.

  4. your analysis is full of logical errors … almost paragraph by paragraph there are errors… and you completely ignored their control measure of the anti-biotic and the resulting decrease in inflamation. What is your goal here?

    • The thrust of this article, Steve, is NOT so much whether or meat/eggs cause heart disease but whether this (if true) is due to TMAO from eating choline-rich foods. Similar claims have been made about carnitine-rich foods.
      I do not eat eggs, nor much red meat, but I do take choline and carnitine (acetyl-l-incarnitine) as dietary supplements. They do not cause heart disease and even if they did, I would continue to take choline as it noticeably improves my memory. There are other supplements one can take, in addition to exercise that can reduce heart disease.

      And if ‘vegans’ do live longer, btw, the reason could be due to other healthy life styles that vegans undertake such as not smoking, exercising more, etc. Obviously, vegans are more health-conscious than the general population.

  5. When you write: “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)” I really wish you and the other paleo bloggers would understand what this study says. People keep quoting it as saying eggs do not cause CHD … Hey bloggers, learn to read what is really going on. It does not say that. It says that if you already have a meat/egg rich diet adding one more egg does not seem to make you get more CHD than you had before. Quoting other peoples mistakes does not make good research. Learn to read studies for yourself. A false negatives say nothing about the positive correlations of cause and effect. It is really easy to misquote science especially since false negative are such a common error for non-research scientists quoting scientific statistics. The positive correlation that has been demonstrated is that Vegans live longer than meat/egg eaters (do not rely on false negative effect pseudo analysis).

    • “Is this guy legit…or, a crackpot?”

      This is a website for intelligent discussion about health and nutrition. The extremely complex nature of human body chemistry, which differs among billions of people, leaves a lot of room for respectful disagreement. If you believe calling someone a ‘crackpot’ because his findings differ from those of another researcher (presumably not a ‘crackpot’), then you should probably be taking supplemental choline – which is a precursor to the vital neurotransmitter, acetylcholine. It might help you think a little better.

    • Michael G., you ask a legitimate question, and, no, you are not out of line to ask if Greger is a crackpot. I suppose you could label him as such — he is a militant vegan who sees “links” where legitimate scientists do not, and foolishly cites work that does not support his opinions. But most readers of his rants probably do not go to read the work he cites. You might be amused at some of his articles on the Care2 website. And, while I agree that everyone is entitled to his opinion, everyone is not entitled to his own facts. It is interesting that, in an early paragraph of Greger’s article, he says that “studies” have shown a link between choline intake and cancer mortality. Yet, when you click on the “studies” link, there is one study, wherein the authors clearly state in their abstract that no statistically significant relationship between choline intake and cancer mortality was found, based on quite a large sample. Perhaps citing a study that undermines one’s hypothesis does not make one a crackpot, but perhaps just cynical … or confused. .

      • AnnieLaurie,

        Thank you for the considerate reply. I appreciate it.

        I’m sure that Dr. Greger has the best of intentions. Were I to ask the question again, I would word it differently.

        In the “Studies” link, I also noted the following:

        “Diet was assessed with a validated questionnaire 6 times during 22 y of follow-up.”

        So, that’s one questionnaire every 3.67 years? Interesting.

        Wishing you well,

        Mike

      • I probably should be more careful in my wording. When I noted that the “studies” link produced one study that refuted Greger’s contention about choline and cancer, I did not mean to imply that there were other studies at the link that supported it. The link shows only one study (not “studies” as labeled) and that study found no statistical relationship between choline consumption and cancer mortality.

  6. The study makes no sense. First of all, the correlation between meat, animal products and “bacteria formation” in the gut makes little sense logically speaking. Bacteria are created to digest cellulose foods and sugars; this speaks little to whether or not said person ate eggs with ketchup as a burrito or steak and potatoes. Indigestible food combinations create fermentation in the intestines, leading to putrefaction and the problem with bacteria and viral overload. Hidden sugars in milk, plus the fact that pasteurized dairy is already an indigestible food product add to the problems. Possibly when someone does a study which contains proper food selection for humans will I take it seriously.

  7. A recent Mayo Clinic meta-analysis shows that carnitine supplements are associated with decreased cardiovascular risk. High TMAO levels may show that carnitine is being metabolized by gut bacteria and not being absorbed. High TMAO levels would then be markers for choline and carnitine deficiency with high TMAO levels an indicator that carnitine which has prove heart benefits and lecithin which is needed for brain function should be supplemented rather than avoided.

    The Mayo Study:
    Mayo Clin Proc. 2013 Jun;88(6):544-51. doi: 10.1016/j.mayocp.2013.02.007. Epub 2013 Apr 15.

    L-carnitine in the secondary prevention of cardiovascular disease: systematic review and meta-analysis.

    DiNicolantonio JJ, Lavie CJ, Fares H, Menezes AR, O’Keefe JH

  8. I am a med student with a passion for holistic preventative health care. I spend hours researching topics of interest and tend to keep looking until I have all my questions answered. When it comes to nutrition and the research done on the effects of different diets and food groups on the health of individuals, I can honestly say that I NEVER believe anything I read anymore. How is it possible that there is not a single fact regarding nutrition that is agreed upon among all scientists and medical professionals? Leaving conspiracy and fraud aside, how is it possible that different studies can produce such variable results? It is an undeniable fact that there is no single diet or food group that causes the same harm or has the same benefits among different individuals. I am not a qualified professional (yet), but my common sense cant help but wonder whether the answer lies in the diversity of the human being as an adaptive species. Is it not possible that one food group can have a certain effect on one individual and a different effect on the next? Is it ludicrous to think that my plant based diet that has changed my life and cured me of numerous chronic ailments might be detrimental to the health of another? Just as we adapt to our environments on a mental and emotional level and subsequently react in our own individual ways; are we not doing the same on a physiological level? There is no doubt about the fact that a down right unhealthy diet ridden with animal fat, sugar and additives will be detrimental to any person’s health, but in my opinion, the debate about the best food group vs. the worst food group will be the battle of the ages and I am confident enough to say that there will never be a victor.

    • Christie, I totally agree with your perspective. I would add another reason for the wide variance in results and conclusions from various studies. That would be that there are many different agendas/biases among those who conduct the studies or analyze the information. These agendas and beliefs are might be more powerful forces than we realize. Unless we knew these biases and agendas ( which we usually don’t) then we cannot interpret objectively.

  9. To the author: perhaps it would take the liver longer to metabolize the isotope version of phosphatidylcholine, after all, look at the units of the actual study. The radioisotope is in nM and the eggs are in microM, implying that the liver is having a more difficult time metabolizing the radioisotope than the fat from the eggs.

    Given this, they DO BOTH INCREASE making the study kinda cool.

    Regarding what you wrote about fish. That is a pretty logical argument. However, there is such a thing as dose dependancy. Who is to say that zero TMAO is good for the heart, a little TMAO is bad for the heart, but a whole lot of TMAO is really good for the heart?

  10. So, another study where the researchers start out with the assumption that animal products must be unhealthy (and that “a high-fiber, vegetarian diet” is in all ways superior), and then try really hard to contrive whatever they find to support said assumption? No news here.

  11. You should all actually read the paper. The point wasn’t to say that you shouldn’t eat eggs or beef. They have essential nutrients that we all need, and eating it a few times a week won’t make you drop dead from atherosclerosis. The point is to understand the mechanism of atherosclerosis and cardiovascular disease better. We need to understand the relationship between the gut flora and the rest of our body, because it plays an essential role. Once we understand how TMAO acts, we may be able to find better preventative measures, drugs, or supplements to help us all stay healthy. They didn’t once conclude that eggs are bad for you.

  12. Regarding your article ‘Choline and TMAO: Eggs Still Don’t Cause Heart Disease’ you don’t address another recent finding concerning choline in eggs, and the consumption of eggs and the link it prostate cancer.

    Am J Clin Nutr. 2012 Oct;96(4):855-63. Epub 2012 Sep 5.
    Choline intake and risk of lethal prostate cancer: incidence and survival.
    Richman EL, Kenfield SA, Stampfer MJ, Giovannucci EL, Zeisel SH, Willett WC, Chan JM.
    Source
    Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, MA, USA. [email protected]
    Abstract
    BACKGROUND:
    Meat, milk, and eggs have been inconsistently associated with the risk of advanced prostate cancer. These foods are sources of choline-a nutrient that may affect prostate cancer progression through cell membrane function and one-carbon metabolism. No study has examined dietary choline and the risk of lethal prostate cancer.
    OBJECTIVE:
    Our objective was to examine whether dietary choline, choline-containing compounds, and betaine (a choline metabolite) increase the risk of lethal prostate cancer.
    DESIGN:
    We prospectively examined the intake of these nutrients and the risk of lethal prostate cancer among 47,896 men in the Health Professionals Follow-Up Study. In a case-only survival analysis, we examined the postdiagnostic intake of these nutrients and the risk of lethal prostate cancer among 4282 men with an initial diagnosis of nonmetastatic disease during follow-up. Diet was assessed with a validated questionnaire 6 times during 22 y of follow-up.
    RESULTS:
    In the incidence analysis, we observed 695 lethal prostate cancers during 879,627 person-years. Men in the highest quintile of choline intake had a 70% increased risk of lethal prostate cancer (HR: 1.70; 95% CI: 1.18, 2.45; P-trend = 0.005). In the case-only survival analysis, we observed 271 lethal cases during 33,679 person-years. Postdiagnostic choline intake was not statistically significantly associated with the risk of lethal prostate cancer (HR for quintile 5 compared with quintile 1: 1.69; 95% CI: 0.93, 3.09; P-trend = 0.20).
    CONCLUSION:
    Of the 47,896 men in our study population, choline intake was associated with an increased risk of lethal prostate cancer.

    • If choline intake increases the risk of lethal prostate cancer, then those such as myself who supplement with choline should also supplement with nutrients (such as Vitamin D, Saw Palmetto, etc) that decrease the risk of prostate cancer. In any case, for me, going around in a choline-deficient stupor for the rest of my life is definitely worse than shortening it by a few years via prostate cancer.

  13. I don’t eat eggs because a food allergy test showed that I am slightly allergic to both the yolks and whites. However, I do take a lot of supplemental choline, both phosphatidyl and bitartrate forms. Choline is the only nootropic substance I take with a noticeable benefit, that is, as soon as I stop taking it, I start forgetting things. So, needless to say, I will continue.

  14. Finally, an article that actually does some real investigative journalism regarding TMAO! Thank you! Other articles on this topic have been written by so-called journalists who didn’t even do a simple internet search to see what TMAO is and where it occurs in nature. I am a biologist who discovered (starting as far back as the late 1970s) that TMAO in fish and shrimp, where it is really high, is a potent protein stabilizer that helps marine animals deal with various stresses. That is, TMAO helps proteins fold into proper functional shapes when they are disturbed. Our discovery made the cover of Science (America’s #1 science journal) in 1982. Scientists following my work have shown that TMAO, at least in cultured cells, can “cure” mad cow disease and cystic fibrosis, among other protein-folding diseases.
    I asked Dr. Hazen directly why people who eat TMAO-rich foods do not have higher risk of heart disease, and he had no answer. Now, it is possible that too much TMAO in the absence of things that disturb protein shapes could be bad–that is, it could over-stabilize proteins. But it could also be that the Hazen discovery is just a correlation in which TMAO itself is not the culprit.

    • Thanks you for this comment … some logical thinking on the subject is very refreshing … possible correlation to inflammation is probably what is really going on … now we can start to follow the clues instead of simply debunking the demonstrated effects including the anti-biotic control

  15. Small amounts of zein peptides from corn and similar proteins from wheat etc. do get into animals that eat these, but such traces should only be a problem if you have active allergies to these proteins.
    However, it’s unlikely that year-round access to eggs was a feature of ancient history, as most animals lay eggs seasonally and the hen is an import from Burma that didn’t arrive elsewhere till later (the first mention of the bird in the Bible is during the crucifixion). Egg white protein is one of the most common allergens.
    Replacing eggs with chicken livers will tell you whether it is the feed or the egg itself that causes the problem. If it’s not the feed, separating eggs and cooking only the yolks should help.

    • Hep c has been cured, harvoni, which is the combination of two therapies, for 8 or 12 weeks, as well as other therapies potentiate that cure rates should be at about 100 percent.

  16. Since going largely paleo, I have started to experience nausea when eating eggs and commercially-produced mayo sometimes. I was recently listening to the Paleo View podcast, and they mentioned that the feed that chickens are given can cause people who are sensitive to soy or gluten to have negative reactions. I can’t find any research about this topic, but thought you might have some insight. I really enjoy the academic nature of your podcast and appreciate your thoughtful answers to listeners’ questions.

    • HEP C has been therapeutically indicated as cured. there are a number of different combinations including declatasvir, sofosbuvir, ledipasvir, ribivarin, simeprivir, other earlier developed treatments and combinations of these within the same therapeutic. Supplementing with Choline, Trimethylglycine and phospholipid factors, may help support hepatic function in a regenerative capacity.

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