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Serving up health and fitness insights (daily, of course) with a side of irreverence.
10 Apr

Does Red Meat Clog Your Arteries After All?

t boneI’ve been asked to comment on the latest media deluge to suggest that red meat is again the primary cause of atherosclerosis, heart disease, and your impending doom. At least this time they’re targeting something other than cholesterol: this time it’s carnitine.

Carnitine is found in red meat, mostly, as well as dairy, tempeh, and some other meats, and it performs a number of important roles in the human body, foremost of which is the transportation of fatty acids into the mitochondria for breakdown into useable energy. It’s so important to basic function that we make endogenous carnitine by synthesizing it from the amino acids lysine and methionine. Vegans and vegetarians, who tend to run deficient in carnitine, benefit greatly from supplementation (or a nice steak). It’s even been used to reduce atherosclerosis (albeit in rabbits), improve arterial function, and help heart failure patients recover. Carnitine is not some evil compound.

Oh, the study. Let’s get into it. It consisted of several sections, actually.

First, they fed humans eight ounce steaks (amounting to roughly 180 mg carnitine) with a side of 250 mg carnitine tabs. Omnivores showed increased blood and urine levels of Trimethylamine oxide (TMAO), a compound associated with cardiovascular disease, while vegetarians and vegans (who were somehow able to get the steak down) showed far lower levels of TMAO in their blood and urine.

Next, they tested what was producing the TMAO by administering antibiotics. Eliminating gut flora populations with antibiotics also eliminated the food-induced increase in TMAO, showing that the intestinal microbiota were metabolizing carnitine into TMAO. After allowing the subjects’ guts to repopulate, they ate more steak. The increase in TMAO after eating steak reappeared, confirming that gut flora metabolism of carnitine was responsible. Subjects with higher levels of Prevotella bacteria in their guts saw the biggest increases in TMAO.

(As it turns out, gut flora convert carnitine to TMA, which the liver then converts to TMAO using a hepatic enzyme called FMO3, but it’s easier to just say carnitine converts to TMAO.)

They also tested ApoE-deficient mice and got similar results. Feeding mice carnitine increased TMAO levels in serum and doubled arterial plaque formation over control, while giving antibiotics abolished this effect. So, in a certain strain of mice, dietary carnitine increases TMAO levels, which accelerates atherosclerosis. If you recall from this week’s Dear Mark, ApoE status is strongly associated with cardiovascular disease risk, and these mice were totally deficient in it. They were bred to be extremely sensitive to atherosclerosis in order to facilitate research. It’s a common and useful tool – it’s not like they’re trying to pull a fast one – but we should be aware of it.

They also examined how TMAO increases atherosclerosis in mice: by reducing reverse cholesterol transport. In other words, it impaired the mouse’s ability to remove cholesterol from the arterial wall without decreasing cholesterol uptake or synthesis to the same degree, creating a net surplus of cholesterol in the wall and speeding up atherosclerosis.

Now, before you unplug your chest freezer full of grass-fed beef and start buying wheat futures, keep reading.

The initial association between TMAO and cardiovascular disease in humans is just that – an association. Causation is not established, and it may even be that cardiovascular disease or some other common event increases TMAO as a response to injury or disease. An increase in serum TMAO is, for example, a marker of certain kidney injuries (PDF). It could merely be correlation or even reverse causation. We simply don’t know.

We don’t know if the experimental results in rodents apply to humans. Sure, the omnivorous people who ate steak and took supplements saw an increase in serum TMAO, but atherosclerosis was not measured. The same mechanisms that affect ApoE-deficient mice may not apply to humans.

It was the gut flora, not the carnitine. While subjects who typically ate meat saw the biggest increases in TMAO – which the researchers saw as evidence of the gut flora adapting to the host diet – and were characterized as having Prevotella-dominant guts, most evidence suggests that Prevotella bacteria are associated with carbohydrate-rich diets. That said, accumulating evidence suggests that the hundreds of species living in our guts can’t be quite so easily and neatly cataloged or categorized.

You know what else raises TMAO? Fish. That’s right – heart attack-inducing, artery-clogging, linked-to-every-disease-state-known-to-man fish actually contains TMA, the metabolite that converts to TMAO in the body. TMA is what gives fish the “fishy smell,” and when people eat fish, urine TMAO increases. Strangely, the latest research shows that fish is consistently associated with better cardiovascular health, not worse (despite the TMA content and effect on TMAO levels).

FMO3, which as you’ll recall from the parenthetical above is responsible for the conversion of TMA to TMAO, does things other than produce heart disease. It is also involved in the metabolism of selenium (an important cardioprotective, thyroid-protective, and cancer-protective nutrient).

TMAO itself may not be “all bad.” It’s an osmolyte – a protein stabilizer. It’s even been used to prevent cataract formation in mammalian eye lenses.

Choline, another important nutrient found in eggs, meat, dairy, and offal with a similar structure to carnitine, was shown a couple years ago to convert to TMAO after exposure to certain types of gut flora, causing researchers to suggest it too promotes atherosclerosis (see Chris Masterjohn’s take on it). And yet eggs have been vindicated over and over again for their beneficial or neutral effects on heart health, including the most recent one I mentioned this past Sunday.

It’s complicated, in other words.

That’s not to discredit the results of this latest study; sufficient amounts of TMAO do appear to accelerate atherosclerosis in rodents. Impaired reverse cholesterol transport, which TMAO produces (again, in rodents), probably accelerates atherosclerosis regardless of species, all else being equal. We should definitely keep an eye on this and any other future research. I’m particularly interested in what this means for research into the effects of gut flora on human health.

Ultimately, this admittedly interesting research is all very preliminary. Rodents bred to be especially sensitive to cardiovascular disease (ApoE-knockouts) develop atherosclerosis at twice the normal rate when exposed to TMAO in the diet and/or serum. That’s all that they’ve established. Humans with the right (wrong?) gut flora composition also generate serum TMAO in response to dietary carnitine, but increased atherosclerosis has not been shown. And, contrary to their assumptions, a relationship between red meat (not processed meat) and cardiovascular disease has not been established in the literature. Quite the contrary: recent epidemiological evidence seems to exonerate the fresher, redder stuff.

If anything, this serves to underline (not undermine) the basic gist of the Primal eating philosophy. Eat a variety of foods. Don’t just eat steak. Eat fish, and eggs, and chicken liver, and pork chops. Don’t just eat meat. Eat vegetables. Eat probiotic-rich foods (probiotics have already been used to lower TMAO levels, while kimchi consumption was said to account for the inter-individual differences in TMAO production in another study). Eat prebiotic-rich foods, so as to provide food for your gut and diversify the population.

That last bit is key. We have to realize that it’s the gut flora modulating the effects of carnitine and TMAO – not the carnitine (or red meat) itself. It may be that we Primal eaters (as if you could categorize us so easily) have the absolute worst kind of gut flora, the kind that produces TMA by the truckload to be carted off to the liver for conversion into TMAO, and we’re about to start dropping off like flies. But I doubt it. I think the way we eat is more likely to diversify our guts and give us a floral profile associated with better health, rather than worse. But we’ll see. We still have a lot to learn about what lurks – and lives – inside us.

I’m sure you’ll be inundated with other writers giving their thoughts today and in the near future, but these are my initial ones. Hope it helps!

You want comments? We got comments:

Imagine you’re George Clooney. Take a moment to admire your grooming and wit. Okay, now imagine someone walks up to you and asks, “What’s your name?” You say, “I’m George Clooney.” Or maybe you say, “I’m the Clooninator!” You don’t say “I’m George of George Clooney Sells Movies Blog” and you certainly don’t say, “I’m Clooney Weight Loss Plan”. So while spam is technically meat, it ain’t anywhere near Primal. Please nickname yourself something your friends would call you.

  1. Don’t base your life on mice studies would be my take-home message from this study.

    Bjarni wrote on April 10th, 2013
  2. Mark, within your 3rd & 4th paragraphs, I thought, how is this silly study relevant? What threw me was the supplementation of 250 mg carnitine in addition to actually eating a steak PLUS administering of antibiotics. Long before I had ever heard of eating primal, I knew all too well how detrimental antibiotics are to our gut flora. Mess with the flora = mess of troubles in the body. But as you said, we’re fine as long as we eat red meat (grass fed & hormone free) in moderation and also a variety of other good foods. Too much of any one good thing can be bad.

    Rose wrote on April 10th, 2013
  3. I’m thinking yet again, confounding variable(s). Every time we try to laser in on a really bad or really good thing, there’s always more to the story.

    Sadly, I don’t see Veggie | Paleo | SAD control groups coming to a rigorous study any time soon, so we’re left to our own devices and this does give us a bit to think about.

    As usual, we need to approach the system, not the constituent parts and as usual, Mark is doling out pragmatic, practical advice.

    Greg wrote on April 10th, 2013
  4. So… any scientific study showing the dangers of sugar or carbs is the gospel truth, but a study showing a correlation between red meat and heart disease warrants a LMAO? The lack of objectivity and critical thinking on this forum is laughable.

    Eric wrote on April 10th, 2013
  5. I remember getting my test results back from my doctor after eating low carb/clean protein (grass-fed/finished beef, lamb, pork, chicken), clean veggies/fruits (organic/local grown) and having the occasional goody (dark chocolate or other) if I wanted it. No “exercise” regime as we have a farm and I can walk up and down some steep inclines, haul feed bags, etc. I ate this way for about 6 months before the blood work tests. Her note to me? “Whatever you are doing, keep it up! These numbers are PERFECT! And you’ve lost 25 lbs.” The proof for me is in my own body :)

    Kathleen wrote on April 10th, 2013
  6. One of the concerns about the lead author was that many energy drinks contain carnitine as a supplement, and that many teenagers drink a lot of that crap. Might be useful to know if this is a bad idea for developing children.

    Also, the NY Times write up indicated that the association between TMAO levels and CVD risk had previously been established by a study which had examined blood from 10,000 people who had come though the Cleveland Clinic system. They were then followed for several years to monitor the subsequent development CVD. The point was to look for associations between trace chemicals in the blood that might be associated with increased risk of CVD. Such associations are useful for formulating mechanistic hypotheses for further testing.

    Why did they bother to do this? Well, apparently, lots of people still die of heart disease. And unlike the experts here who seem to know everything there is to know about the cause and prevention of heart disease, most medical professionals still aren’t sure that they have all the answers.

    Craig wrote on April 10th, 2013
  7. I think you do not have to be so careful if you are eating a small plate only and well balanced with many types of food. Too much of anything is a bad thing of course!

    Leevin Sheftin wrote on April 11th, 2013
  8. Another useless study, that doesn’t contribute any insights into the broad picture.

    Margit wrote on April 11th, 2013
  9. As well as the ‘quality’ of the mice used for testing, the ‘quality’ of the human would be just as critical. Its like saying ‘meat is bad for you’, because in many trials vegetarians have lower levels of cancer/cardiovascular disease. This in no way implies that meat is bad for you. Perhaps the vegetarians eat far more vegetables, or predominantly eat organically, and are avoiding pollutant-rich processed meats. The cause is not so discernible.

    In this case, the carnivores chosen for the test may have had poor gut flora balances or a host of other digestive disorders, and are therefore converting far more TMAO than a healthier individual might. An unhealthy test group is no way to test health….

    Barnaby wrote on April 11th, 2013
  10. What bothers me in this study is, that 69% of participants were smokers and all were suffering from some kind of cardiac disease. 70% were men age 54-71. Their blood carnitine levels correlated with smoking, male gender, triglycerides as well as use of ACE-inhibitors (hypertension med). Correlation of these were in the same ballpark as ingested carnitine. So, makes one wonder, if high levels of carnitine in blood are result of deficient metabolism due to those other correlating factors?

    Ariel wrote on April 11th, 2013
  11. See also Paul Jaminet’ excellent post on this topic on perfecthealth.com Or did someone already mention this?

    Dutch Digitalis wrote on April 11th, 2013
  12. Our tax dollars hard at work.

    Matt wrote on April 11th, 2013
  13. I think what we forget with these studies is that yes although they test theories on humans, but they also test them (mostly) on mice and other rodents. We are omnivores, mice are herbivores, so wouldn’t it make sense that a mouse we respond much more aggressive to this type of thing, because their digestive track is much less used to digesting these substances then we are? It’s like us, we have started developing all sorts illnesses since we started incorporating grains in our diet, so who says the same thing doesn’t happen to a herbivore mouse who usually eats seeds, grains and fruit….???? Maybe I am seeing this too simplistic, who knows, but I won’t give up the Paleo lifestyle, as I feel the best I have ever felt since I’ve stopped eating the SAD/SBD (stands for standard british diet :-))

    Eva wrote on April 11th, 2013
  14. Thanks for the article Mark. Grok didn’t have the benefit of these studies and somehow he made out fine. All things in moderation and variety sounds good.

    Gord, Vancouver wrote on April 11th, 2013
  15. Research into gut flora is pretty exciting!

    I agree with previous comments that it’s media reports on science that trigger the misinformation cascade. For example, it was media reporting that said “red meat kills” when the studies implicated “red and processed meat” together. Sure, the study could have been designed better to separate whole and manufactured foods, and other confounding variables (since these types of studies are usually just meta-analyses of other questionnaire-type studies, so you’re getting two layers of “oops”) but it wasn’t the study itself that said “Oh my God, put down your fork!” That was sensationalism and cherry-picking on the part of whichever media outlet reported on it in order to increase viewership by feeding on the fear of food we already have.

    Kristina wrote on April 11th, 2013
  16. Annabelle is so correct. I’d like to see people here respect the tremendous work of researchers in journals like Nature instead of bashing a negative result.

    An emotional litmus test – If the study concluded that TMAO was REDUCED with meat consumption, would you question the study/ study title/ journal with the same vigour?

    +1 on the need for long term Paleo Primal data. I’ve been transitioning to the Primal diet slowly, 60/40 since January and experienced great results. After 1 month on the 80/20 rule, and taking good notes on what I eat, I am scheduling a full lipid and triglyceride profile – at my own expense. I will share the results with this community.

    Others have done this and putting together the results can be beneficial (Mark Sisson et. al?). It will NOT constitute a rigorous scientific study; however, it WILL provide nutritional scientists a grouping of anecdotal evidence. This is often the first step in designing a proper scientific study.

    Look for my blood work results in June.

    For all future studies – Be critical or supportive, but steer clear of douchebaggery! We are all self-experimenting here, with mostly good results.

    George wrote on April 11th, 2013
  17. Especially for men, steak is very healthy for us. It’s got a chock full of vitamins and minerals that we need to eat.

    It is funny the media portrays steak as unhealthy. There is a certain tribe in Nigeria that is known for their physical prowess. They eat everything on the animal including the liver (said to be the most healthiest part) and even the blood is given to the little kids!

    It is the same with the egg yolk having “bad cholesterol”. Egg yolk is a GREAT testosterone boost. It pains me to see how bad the media is influencing our society.

    Chest Coach wrote on April 11th, 2013
  18. I have always heard that eating red meat was bad for you and your cholesterol levels. I never would have thought that fish contains the same TMA and that’s what gives it it’s fishy odor.

    I wonder if the more fishy it smells the more tma it has?

    Christina wrote on April 12th, 2013
  19. I have to laugh myself, not at the study but at everyone who continues to sluff off all the actual medical research and science that has proven over and over again exactly how a diet focused so heavily on meat and dairy is killing us. Its nice to have folks tell you good things about your bad habits but lets be real. As tasty as bacon and hamburger are, grassfed or not, I think on some level intellectual level we all know its just not healthy for us.

    I wish it were so, I really do because I love bacon and I love deliciously grilled meat, but having switched the focus of my diet to more plant based (whole plants) I can’t denie the obvious benefits, improved elimination, more stable weight, and my cholesterol which has been chronically high my whole life is finally starting to come down.

    I doubt I will ever be able to completely eliminate animal based foods from my life but I have no doubt that if I could the true health benefits possible would continue to make themselves evident.

    I would encourage everyone to start looking at the real medical research, not what the media reports and certainly not what all these self proclaimed expert AKA Bloggers say. Plants are where its at folks but again I think when we get passed what we all WANT to be true and accept what we really know is true, we all know that.

    Rob wrote on April 12th, 2013
  20. I shared this study with both of my cats, who by the way are unable to synthesize carnitine. They both pointed out if I eliminated carnitine from their diet, they would die of dilated cardiomyopathy. I told them I understood but that I would keep it from them because I didn’t want them to die from atherosclerosis.

    Ed Terry wrote on April 12th, 2013
  21. Study shows that we need to go back at creation in the garden of Eden. Before sin entered the world, they were vegetarians. They only eat fruits, nuts, and herbs. After the fall, that’s the time they experience death. Adam and Eve realized the penalty of sin when Cain killed his brother Abel. I believed that vegetarian diet is more safer that the flesh eating diet. We will live more longer.

    Marlyn wrote on April 12th, 2013
  22. This reminds me of an example of causation vs association my high school science teacher told us… “The more ice cream that is consumed in a certain area, the number of car stereos stolen also increases, therefore, we need to eat less ice cream and not just because it’s not primal”.

    The rise in theft is caused by the fact that people leave their car windows down more when it gets hot. People also eat more ice cream wen it gets hot. Association, not causation.

    ryancathey wrote on April 12th, 2013
  23. For the past 33 years, I have looked in the mirror every morning and asked myself: ‘If today were the last day of my life, would I want to do what I am about to do today?’ And whenever the answer has been ‘No’ for too many days in a row, I know I need to change something.

    Marshall wrote on April 12th, 2013
  24. http://www.mindfood.com/?article=health-wellbeing-iron-deficiency-widespread
    Yet another case of less-than-ideal health due to being advised by the powers that be to decrease red meat consumption….

    Amanda wrote on April 17th, 2013
  25. The NY TImes is reporting on a study claiming that lecithin in eggs breaks down into choline and promotes gut bacteria production of TMAO. The study is by the same group as the carnatine study. (including Stanley Hazen)

    http://www.nytimes.com/2013/04/25/health/eggs-too-may-provoke-bacteria-to-raise-heart-risk.html?hp&_r=0

    Mark’s article above comments on an older version of the same finding on choline. This TMAO alarm may take a while to get sorted out. At least I hope it gets sorted out.

    robit wrote on April 25th, 2013
  26. I think there are a bunch of things wrong with this study, although effects of gut flora composition are probably important and worth a lot more study.

    1) There is a huge conflict of interest. The authors filed a patent in 2008 initially (latest http://www.google.com/patents/US20120157397) where they ‘invent’ a protocol for analysis and treatment of TMAO levels. If they can persuade everyone who’s having a questionably effective lipid panel and buying statins to do the same with their test, and a patented probiotic, they’ll be doing very well out of the royalties.

    2) They definitely have drawn the association with meat on purpose – it’s core to their abstract, ignoring the fact that TMA+TMAO levels are elevated to significantly higher levels than beef by fish, beans and other un-demonized food ingredients. It would appear that this story’s been actively marketed to the mainstream media and the hard links to meat in the abstract and conclusions would certainly not hurt that cause.

    3) The parallels between atherosclerosis-prone mice at huge doses, and humans with a normal diet seems pretty flaky

    It’s bad science I think – and it’s an interesting coincidence that TMAO is the compound that gives fish that ‘fishy smell’ – some of it has definitely rubbed off on the study.

    Troy wrote on May 7th, 2013
  27. Indians consume 28 times less meat than Americans and 20-30 less than Europeans and have major problems with heart disease. The patients are getting younger every year. High LDL, low HDL. Lots of refined carbs and a diet increasingly American but with extremely low meat consumption. Their problem with heart disease is a multiple compared to the western world and their meat consumption is a tiny fraction. Funny that nobody is using that correlation to scare people away from carbs. And even funnier that they are blaming meat for heart disease even in India, saying that the meat consumption has “increased”. They are blaming their lack of exercise, their genes, their bad luck, anything except the carbs:)

    India wrote on June 12th, 2013
  28. Meat must be a $100billion market in the states alone. Even a small shift to other types of food is worth billions to the usual suspects.

    India wrote on June 12th, 2013
  29. I think that the major distinction that you need to make is that processed and non-grass fed red meat are going to be the types of red meats that increase your risk of cardiovascular disease. Honestly, if we look at the majority of the population, most people are eating steroid and antibiotic ridden red meat, which is not ideal.

    Brett wrote on April 9th, 2014
  30. Mark, the study you mentioned as having shown that “probiotics have already been used to lower TMAO levels” was (a) in mice, and (b) showed that one of the probiotic supplements had no effect on liver TMAO levels, and the other actually *elevated* liver TMAO levels; either there was no effect on TMAO levels in the plasma, which is the most relevant compartment, or they didn’t measureit there :
    http://msb.embopress.org/content/4/1/157.long

    Another +1 to Annabella, FWIW.

    Michael wrote on July 20th, 2014

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