Wednesday, April 10, 2013

Red Meat and trimethylamine N-oxide - Kresser

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

By on April 10, 2013 
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 intern 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.
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 a single “representative” meat-eater. A single person in each group is not an adequate sample size, and is hardly convincing given the wide variation in the response to carnitine (see next bullet) among meat-eaters.

  • 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)


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.


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.

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 is working on a detailed analysis of the data from this paper, which should be ready soon. 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!).
Read the complete article here.
Also read more here.

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