TMAO and Red Meat - What is it and is it Harmful | Chris Kresser

Red Meat and TMAO: Cause for Concern, or Another Red Herring?

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What is the impact of red meat consumption on TMAO in the bloodstream? iStock.com/Eraxion

This article is part of a special report on Red Meat. To see the other articles in this series, click here.

I’m sure many of you have seen reports on a recent study published in the journal Nature suggesting a possible mechanism linking red meat consumption to heart disease. The day after one such report was published in the New York Times, I received numerous emails and numerous Facebook and Twitter messages from concerned red meat enthusiasts. This is understandable, but rest assured it’s not yet time to switch over to soy burgers.

The researchers in this study published a paper a while back proposing that a chemical called TMAO (trimethylamine N-oxide) increases the risk of heart disease. In this study, they hypothesized that eating red meat may increase levels of TMAO in the bloodstream, which would in turn ramp up your chances of having a heart attack. Sounds plausible, right?

There’s another hypothesis that also seemed plausible for why red meat increases the risk of heart disease (if we even accept that, which I do not; more on this in a moment). It’s called the “diet-heart hypothesis”, and you’re all very well aware of it whether you know it by name or not. It holds that eating cholesterol and saturated fat increase cholesterol levels in the blood, and high cholesterol levels in the blood cause heart disease. This theory became so widely accepted that few people even question it anymore. The problem is it’s simply not true. Recent research has shown that dietary saturated fat and cholesterol are not associated with heart disease after all, and even if they were, high cholesterol levels in the blood are not the culprit. I’ve written about this extensively in the past, and I will be starting a brand new series with updated information this month.

Is TMAO the new cholesterol? Find out why red meat is still innocent.Tweet This

The mistaken blame of saturated fat and cholesterol as drivers of heart disease led to a decades-long campaign to encourage low-fat, high-carbohydrate diets. Unfortunately, the effects of this campaign were not harmless. Not only did it unnecessarily deprive people of nutrient-dense, nourishing (and delicious!) foods like meat, butter and eggs, it may have indirectly contributed to the epidemics of obesity, heart disease and diabetes. Studies have shown that when people replace saturated fat with carbohydrates, the risk of heart disease doesn’t go down—it goes up. (1) This is not because of the carbohydrates, per se, but because 85% of the grain consumed in the U.S. is in the highly refined form. (2)

The diet-heart hypothesis should be a cautionary tale that prevents us from jumping to rash conclusions based on limited evidence. Alas, the almost complete lack of criticism or scrutiny in the popular media reports on this study indicate that caution has been thrown to the wind. Let’s now examine three reasons why I’m not yet ready to take the conclusions of this study (i.e. red meat causes heart disease via TMAO) at face value.

Epidemiological Evidence Is Inconsistent

If red meat consumption elevates TMAO, and elevated TMAO increases the risk of heart disease, we’d expect to see higher rates of heart disease in people that eat more red meat. The epidemiological evidence examining this question is mixed. A large meta-analysis published in Circulation by Micha et al. covering over 1.2 million participants found that consumption of fresh, unprocessed red meat is not associated with increased risk of coronary heart disease (CHD), stroke or diabetes. (3) On the other hand, a smaller prospective study including about 121,000 participants from the Nurses Health Study and Health Professionals Follow-up Study did find an association between red meat consumption (both fresh and processed) and total mortality, cardiovascular disease (CVD) and cancer. (4)

If eating meat increases heart disease risk we might expect lower rates in vegans and vegetarians. Early studies suggested this was true, but later, better-controlled studies suggest it’s not. The early studies were poorly designed and subject to confounding factors (i.e. vegetarians tend to be more health conscious on average than general population, so there could be other factors explaining their longevity, such as more exercise, less smoking, etc.). Newer, higher quality studies that have attempted to control for these confounding factors haven’t found any survival advantage in vegetarians. For example, one study compared the mortality of people who shopped in health food stores (both vegetarians and omnivores) to people in the general population. They found that both vegetarians and omnivores in the health food store group lived longer than people in the general population. (5) This suggests, of course, that eating meat in the context of a healthy diet does not have the same effect as eating meat in the context of an unhealthy diet. (Hold this thought: we’ll be coming back to it shortly.) A very large study performed in the U.K. in 2003 including over 65,000 subjects corroborated these results: no difference in mortality was observed between vegetarians and omnivores. (6)

Taken together, these data do not suggest a strong relationship between red meat and heart disease. It’s also crucial to remember that epidemiological evidence does not prove causality. Even if red meat intake is associated with a higher risk of CVD (or any other health problem), such studies don’t tell us that red meat is causing the problem. If you’re new to this concept, I suggest reading these excellent articles by Denise Minger and Chris Masterjohn.

The “Healthy User Bias” Strikes Again

The healthy user bias is the scientific way of explaining the phenomenon I described above, where people that engage in one behavior that is perceived as healthy (whether it is or not) are more likely to engage in other behaviors that are healthy. (7, 8) Of course the flip-side is also true: those that engage in behaviors perceived to be unhealthy are more likely to engage in other unhealthy behaviors. The healthy user bias is one of the main reasons it’s so difficult to infer causality from epidemiological relationships. For example, say a study shows that eating processed meats like bacon and hot dogs increases your risk of heart disease. (9) Let’s also say, as the healthy user bias predicts, that those who eat more bacon and hot dogs also eat a lot more refined flour (hot dog and hamburger buns), sugar and industrial seed oils, and a lot less fresh fruits, vegetables and soluble fiber. They also drink and smoke more, exercise less and generally do not take care of themselves very well. How do we know, then, that it’s the processed meat that is increasing the risk of heart disease rather than these other things—or perhaps some combination of these other things and the processed meat? The answer is, we don’t. Good studies attempt to control for some of these confounding factors, but inevitably some will not be controlled for. And one of the most important potential confounding factors that is never controlled for is the gut microbiome.

Numerous studies, which I’ve written about on this blog and spoken about on my podcast, suggest that the balance of bacteria in our gut may be one of the most important factors—if not the most important—that determines our overall health. Gut dysbiosis (an imbalance between healthy and unhealthy bacteria in the gut) and small intestine bacterial overgrowth (SIBO, a condition involving an inappropriate overgrowth of bacteria in the gut) have been linked to health problems as diverse as skin disease, depression, anxiety, autoimmunity, and hair loss.

The study we’re discussing here found that those who eat red meat produce TMAO, whereas vegans and vegetarians who hadn’t eaten meat for at least a year do not. The researchers claimed that this means eating red meat must alter the gut flora in a way that predisposes toward TMAO production. However, there’s another explanation that I believe is much more plausible: the red meat eaters are engaging in unhealthy behaviors that have led to dysbiosis and/or SIBO. This could include eating fewer fruits and vegetables and less soluble fiber, and more processed and refined flour, sugar and seed oils. All of these behaviors have been shown to be more common in the “average” red meat eater, and all of them have been associated with undesirable changes in the gut microbiota. (10, 11, 12) In other words, the problem isn’t the red meat, it’s the gut bacteria. This is supported by the finding in the study that the red meat eaters did not produce TMAO after a course of antibiotics. It is also supported by data indicating that a breakdown in the intestinal barrier, which occurs in dysbiosis and SIBO, may increase heart disease risk by elevating the number of circulating LDL particles in the bloodstream. (13) I will be covering this (i.e. the connection between LDL particles and heart disease) in my updated series on heart disease.

In the last section I presented evidence suggesting that eating meat in the context of a healthy diet does not have the same effect as eating it in the context of an unhealthy diet. This study is likely yet another example. In order to know whether red meat is really to blame for changes in the gut flora that increase TMAO production, we’d have to do another study with two groups: one that follows a Paleo diet rich with fruits, vegetables and soluble fiber, as well as red meat; and another vegan/vegetarian diet with equivalent amounts of plant matter and no meat. If the Paleo diet followers still had higher levels of TMAO, this hypothesis would be a lot stronger.

The Jury Is Still out on TMAO

The evidence linking TMAO production to eating red meat, and serum TMAO levels to heart disease, is not as cut-and-dry as the study authors suggest. For example:

  • The Nature paper on TMAO contained data from two studies: an epidemiological study on humans, and a clinical study on mice. The human study compares a single vegan that they managed to convince to eat a steak to five “representative” meat-eaters. A sample size of six people, with only one in the vegan group, is hardly adequate to draw firm conclusions from.
  • The mouse study used a carnitine supplement. While it is well established that free carnitine increases TMAO production, previous studies have not shown that carnitine-rich foods like red meat increase TMAO. In fact, in one 1999 study, out of 46 different foods tested, including red meat, only one food elevated TMAO levels in the participants: seafood (see graph to right, from Chris Masterjohn’s article referenced below). This makes perfect sense since trimethylamine occurs naturally in seafood. Does this mean we should cut back on fish and shellfish because they’re going to give us a heart attack?(15)

TMA1-267x300

Another obvious question we should ask is whether there are alternative explanations for why we see elevated TMAO levels in meat or seafood eaters (if indeed we do see them in a wide sample of meat eaters, which at least one earlier study didn’t support)? According to a 2011 article by Chris Masterjohn touching on TMAO in a different context: (16)

Elevated TMAO could reflect dietary trimethylamine or TMAO from seafood, but it could also reflect impaired excretion into the urine, or enhanced conversion of trimethylamine to TMAO in the liver.

The enzyme Fmo3 carries out this conversion, mainly in the liver, as reviewed here. There are a number of genetic variants affecting the activity of this enzyme, some of which appear only in certain ethnicities, and the enzyme also processes a number of drugs used to treat psychoses, infections, arthritis, gastro-esophageal reflux disease (GERD), ulcers, and breast cancer. Iron or salt overload may also increase the activity of the enzyme. TMAO could, then, be a marker for ethnicity, drug exposure, genetically determined drug efficacy, or other conditions.

As you can see, it’s overly simplistic to suggest that eating red meat causes elevated TMAO; there are many other factors at work.

But even if Paleo meat eaters have higher TMAO levels than vegans and vegetarians, we still don’t have evidence proving a causal relationship between TMAO and CVD. Once again, the supposed link between cholesterol and saturated fat and heart disease should serve as a reminder not to jump to hasty conclusions that unnecessarily deprive people of nutrient-dense, healthy foods. It is virtually impossible to control for all of the possible confounding factors, and the study we’re discussing in this article only further highlights this problem.

Conclusions

I’d like to end with an observation from the discussion section of the TMAO paper. The authors state:

Numerous studies have suggested a decrease in atherosclerotic disease risk in vegan and vegetarian individuals compared to omnivores; reduced levels of dietary cholesterol and saturated fat have been suggested as the mechanism explaining this decreased risk. Notably, a recent 4.8-year randomized dietary study showed a 30% reduction in cardiovascular events in subjects consuming a Mediterranean diet (with specific avoidance of red meat) compared to subjects consuming a control diet.

This might sound like damning evidence against red meat. However, when you look at Table One in Mediterranean Diet trial, you’ll find that the Mediterranean diet allowed more red meat than the control diet (a low-fat diet)! The Mediterranean Diet allowed for “one serving or less of red or processed meat per day“, whereas the low-fat diet only permitted “one serving or less of red or processed meat per week“. (You can see this for yourself. Click here to access the PDF version of the study, then scroll down to Table One.) Clearly this paper does not support the authors’ conclusion that red meat increases the risk of heart disease. [UPDATE: Stephan Guyenet brought my attention to the Article Supplement, which I had missed before. On  Page 9, it does show that the investigators asked those on the Mediterranean diets to choose white meat instead of red. However, on Page 26 the data indicate that the amount of red meat consumed during the study by the Mediterranean diet groups was virtually the same as the amount consumed by the low-fat/control group. This is a common problem in diet studies: the participants don’t always do what they’re told! What this means, of course, is that the 30% decrease in CVD observed in the Mediterranean group was caused by something other than reducing red meat consumption—which the Mediterranean group did not do.]

They also claim that vegan and vegetarian diets reduce the risk of atherosclerotic disease compared to omnivorous diets; but the studies they reference fail to adequately control for the “healthy user bias”. The study I mentioned in the beginning of this article compared heart disease risk amongst omnivores and vegetarians that shop at health food stores (which is a big step toward reducing healthy user bias), and did not find a difference in deaths from heart disease, stroke or all causes.

If you read the media reports and full-text of this study, you might have noticed something interesting. The study itself, and even most of the media article about it, quite simply and without much fanfare stated that saturated fat and cholesterol have little to do with the supposed increase in heart disease observed with red meat consumption. Hold the press! Shouldn’t THAT be front-page news?!? Apparently not. Of course, they’re only willing to admit this publicly in the context of an article where they’re proposing yet another mechanism for how red meat will kill you.

Finally, the most remarkable and sad part of this for me is seeing just how deep most people’s fear and distrust of red meat is, even if they’ve been following a Paleo diet for a long time. The day after the TMAO study was published, I woke up to no fewer than 20 emails and the same number of Facebook messages and Tweets from people expressing concern that their choice to eat red meat might be killing them. It really is a testament to the power of brainwashing. Most of us grew up with the idea that red meat is harmful, and it’s perhaps not so easy to leave that behind—even when you think you have.

Chris Masterjohn has also published a superb, detailed analysis of the underlying data in the study, and I highly recommend reading it. Frankly, the conclusions of the authors (that eating red meat increases the risk of heart disease via TMAO production) are so incongruous with the data in the study that it’s difficult to imagine how it could have passed peer review.

I believe we may be seeing more “red meat is bad because of TMAO” studies in the near future, so as always, when you see a media report on such a study, take it with a heavy grain of salt (which, by the way, doesn’t cause high blood pressure in most people!).

110 Comments

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  1. Thanks, Chris! I do want to point out, however, that the previous study mentioned by Chris Masterjohn measured urinary *excretion*, which could be quite different than plasma level. It’s even possible that a higher excretion level of TMAO (e.g. seafood) correlates with a lower plasma level, not higher. Many, many questions to be answered, still 🙂

    • The kidney filters TMAO from the serum. So while the levels may not be equivalent, it’s difficult to guess how urinary levels could be high without serum levels also being high at some point, unless the rate of kidney filtration and excretion is ramped up significantly.

  2. Hi Chris, it seems like it could be quite some time before the results of new studies using paleo candidates could inform us on this important subject. So, I’m wondering if you would have your own TMAO levels tested and be willing to publish the results, so we could all feel more content with our meat eating ways? I know I would feel happier, and you too Must be a little curious…

  3. How come stupid people get so much press? Chris – you are the Jesus Christ of diet recommendations.

  4. …And when salt *does* increase blood pressure, it’s usually because your *insulin* is high!

    (Insulin being high triggers sodium retention… so eating more sodium pushes the BP up… etc.)

    Thanks for this. All I needed to know is I feel better with red meat in my diet, but “because I say so” doesn’t fly with people who are scared by the study, so…

  5. Very nice analysis and summary. I’m curious about the health food store shopping meat eaters vs vegetarians; one of your comments suggest the data is actually different. I’ll look it up.

    I wonder if it isn’t a residue of our long-standing Cold War with the Soviet Union that makes scientists hate “Red” meat so much?

  6. Thanks, Chris. I’ve been waiting for your analysis of this latest attack on red meat consumption. I did a double-take on the opener, “….saturated fat and cholesterol have little to do with the supposed increase in heart disease”. Say that again, and in BOLD, red, flashing text! I said to my husband they are grasping at straws now that the science cannot be ignored (at least by those willing to think rationally) and it isn’t the sat fat and cholesterol killing us by causing heart disease. I am curious as to what will be next demonizing red meat……

  7. Hi Chris,
    Great article and timely!. I especially enjoyed your keen observation that the recent Mediterranean Diet study cited in the paper does not support the conclusions. But can we really conclude that fruit and fiber (we agree on veggies, oils and too many carbs overall) are the knights in shining armor coming to the rescue?

    You states that “red meat eaters are engaging in unhealthy behaviors that have led to dysbiosis and/or SIBO. This could include eating fewer fruits and vegetables and less soluble fiber, and more processed and refined flour, sugar and seed oils. All of these behaviors have been shown to be more common in the “average” red meat eater, and all of them have been associated with undesirable changes in the gut microbiota. (10, 11, 12) In other words, the problem isn’t the red meat, it’s the gut bacteria”

    Reference 10, the Cordain paper is about Paleo eating but does not mention the impact on gut microbe populations, at least at my quick read.

    Reference 11, on the “Impact of diet in shaping gut microbiota” is of general interest though it’s well known that different diets promote different gut microbe populations. But it falls short of truly connecting the different populations (of microbes) to digestive disease or other diseases.

    Reference 12 cites a mouse study and the authors note: “However, there is a caveat about applying results obtained from gnotobiotic mice carrying mouse-derived microbial communities to humans: culture-independent comparisons have revealed that, although the distal gut microbiota of mice and humans harbor the same bacterial phyla (Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Verrucomicrobia, Cyanobacteria, TM7, Fusobacteria, and Spirochaeates), most bacterial genera and species found in mice are not seen in humans (6)”

    While I support the notion that a varied whole food diet is likely to promote the most diverse (and healthy) population of gut microorganism and agree with eating a ton of non starchy vegetables for optimal health, but there is quite a bit of evidence that fructose (high amounts in many fruits), resistant starch and many types of fiber actually promote SIBO, dysbiosis and functional gut problems as opposed to curing them. Note, my research focuses mostly on Western populations.

    It may very well be that rural tribes that have eaten high fiber diets for many generations have adapted with stable, healthy gut populations to help them breakdown these foods and don’t suffer from SIBO-related disease, but you might find the same thing in populations that have eaten a lot of animal products for many generations. I am open to reading these studies if they exist.

  8. There’s no question that it’s really, really hard to tease nutritional truths out of epidemiological data and careful reading of the various studies is required. Re: “If eating meat increases heart disease risk we might expect lower rates in vegans and vegetarians. Early studies suggested this was true, but later, better-controlled studies suggest it’s not.”

    You dismiss the early studies without citation, and go on to cite two studies that purportedly support your contention that there is no link between meat eating and heart disease. The first study is about health food store shoppers, and doesn’t compare meat-eaters to vegetarians at all. The second study is from the long-term EPIC-Oxford study, which does indeed find no significant difference in all-cause mortality. It does, however, find lower heart disease risk in vegetarians vs. non-vegetarians (http://www.ncbi.nlm.nih.gov/pubmed/23364007).

    I’d be careful with those accusations of agenda-driven data interpretation.

  9. The NY Times article also says: “It [Carnitine] is also found in other foods, he noted, including fish…”
    So that means it would be healthier to also stop eating salmon?!
    That seems absurd!

  10. I have a question although it isn’t really important. I was curious why a friend follows my advice on following a paleo diet which my blood work shows to be working great for me. It made his get even worse. So he switched back to lowering intake of meat to almost not eating any, and increasing a more vegetarian diet. His blood work showed a great improvement. My question is since he is a huge beer drinker does the beer make a paleo diet bad or is it just an individual response.

    • I’m no expert (I do a lot of research though, as I am working on healing my own gut), if i may, two things to look at in this situation: beer is acidic and contains gluten. Just a thought.

    • When you first go paleo it can send your cholesterol levels out of whack. This is normal. This is the body’s beginning of the healing process. Tell him not to worry about it right now. Give the diet time to do its job

    • Beer is a carb. Even if he doesn’t have a problem with gluten, the carbs will cause him to have more insulin output which will increase his cholesterol (especially the bad one). He needs to give up the beer.

  11. thank you Chris for your cool minded response to this “study” and their conclusions…
    i would be interested to see the same study done on Gauchos from Argentina and South Brasil,they have a heavy meat diet and i never heard of them dropping dead from heart attacks or higher incidence of cancer for that matter.
    so fortunately we still have reality to fall back on.

  12. Thank you for a very thorough and insightful follow up to the misleading report. As I read your counter I’m eating my grass fed ground beef and pastured egg with kimchee!

    I’ve been on paleo for nearly a year and not only do I feel better coming out of a raw vegan diet, my cholesterol result is better than it has been in the last several years!

    The published study is most likely biased judging by who sponsored it. Can’t wait to see the published peer reviews.

    • That term doesn’t mean what you think it means. The “peer review” process happens BEFORE a paper is published. Perhaps you mean “follow-up studies.”

  13. I appreciate your work and your thoroughness in looking at these type of ‘controversial’ subjects. There’s a lot to sort through and it’s great to have resources who take the time to look more thoroughly at some of these health topics and studies which often become generalized headlines.

  14. I cannot wait until the day when beef and other red meat can be looked as health gems – Remember when coconut was plagued as being terrible for you? Well look at where it is now! Your day will come red meat!

  15. gosh, thanks very much for this very thouvht-filled piece, Chris.

    Michael: you may wish to give supplemental taurine a try. One of the things taurine does is in the final stages of protein breakdown inside the mitochondria. Amino acids (depending on type) will break-down to either mercaptans(sulpher-containing & very smelly); or to, ammonia. BOTH of these are highly toxic . While ammonia is often-hard to detect; mercaptans are easy to find. The SMELL (like in natural gas) betrays their presence every time. You’ll notice tis smell even after a shower … it persists and persists.

    When experimenting, even a small amt of taurine (>250mg/day) made ‘my smell’ disappear. Taurine self-sacrifices ankd stands-in at the final stage of amino acid reduction. Not only are mercaptans and amonia never produced, but the taurine breaks into two innert compounds.

  16. Thank you Chris, Very well argued debunking the imaginary fish. I hope all understand to take the red meat daily and real herring weekly, all with greens and a pinch of salt for best health of bone, body and brain function.

  17. Chris, pretty good rebuttal. I’d have liked to see more of a direct point-by-point analysis of the study itself, but that’s just me. Incidentally, the study you cited (3) PMC2885952, also happens to be the second reference in the TMAO study.

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