Carnitine, the Culprit in Red Meat and the Heart? Think Again.

by Dallas L. Clouatre, PhD

A chemical found in red meat helps explain why eating too much steak….is bad for the heart, say US scientists.  (BBC News 7 April 2013) 

A media blitz the first weekend of April based on an article in NatureMedicine (2013) announced that the nutrient L-carnitine, found in red meat and nutritional supplements, promotes atherosclerosis as a result of bacterial action in the gut.  These same bacteria do not stop with carnitine.  They similarly transform choline and phosphatidylcholine found in eggs, soybeans and even many vegetables into the same proatherogenic toxin.

The culprit is a compound associated with the smell of rancid fish, trimethylamine (TMA), which is further metabolized to trimethylamine-N-oxide (TMAO) by particular bacteria common in the gut of meat eaters, but not vegetarians.  It is the TMAO that does the damage.  Or so the story goes.  On closer inspection, the facts do not add up.  

L-Carnitine, a Well-Studied Heart Protectant

On its face, the thesis that ingesting L-carintine damages the heart would appear to be dubious.  As much as 95 percent of all the L-carnitine in the body is found in the heart and skeletal muscles, in part because the heart receives 60 percent or more of its energy as fatty acids and requires L-carnitine to be able to metabolize fatty acids for fuel.  On their face, these facts suggest that L-carnitine is heart protective.  Decades of research come to the same conclusion. 

PubMed, which is an Internet portal for the US National Library of Medicine, lists 2,172 entries matching the search terms “carnitine” and “heart.”  If L-carnitine, not just from meat, but also from supplements, were a cause of cardiovascular disease, this fact surely would have emerged from the hundreds of human trials involving L-carnitine.  However, just the opposite is the normal finding.  For instance, a randomized, double-blind, placebo-controlled trial of L-carnitine in suspected acute myocardial infarction found that total cardiac events in the carnitine-supplemented group (2 grams/day for 28 days) were 15.6% versus 26.0% in the non-supplemented group.

Similarly, 2 grams/day oral L-carnitine dramatically improved the three-year survival rate of patients with heart failure caused by dilated cardiomyopathy.

In yet another study,L-carnitine was randomly administered to 81 patients at an oral dose of g 4/die for 12 months, in addition to the pharmacological treatment generally used. For the whole period of 12 months, these patients showed, in comparison with the controls, an improvement in heart rate (p < 0.005), systolic arterial pressure (p < 0.005) and diastolic arterial pressure (NS); a decrease of anginal attacks (p < 0.005), of rhythm disorders (NS) and of clinical signs of impaired myocardial contractility (NS), and a clear improvement in the lipid pattern (p < 0.005). The above changes were accompanied by a lower mortality in the treated group (1.2%, p < 0.005), while in the control group there was a mortality of 12.5%"

In other words, in clinical studies using as much as 4 grams L-carnitine per day and lasting as long as 12 months, not only did blood lipidsimprove –– the opposite of the prediction of the 2013 carnitine/TMAO study –– but also life expectancy was significantly enhanced.  A 2013 meta-analysis of L-carnitine studies confirms this positive view of the benefits of L-carnitine for the heart.  Its authors conclude, “[c]ompared with placebo or control, L-carnitine is associated with a 27% reduction in all-cause mortality, a 65% reduction in Vas [ventricular arrhythmias], and a 40% reduction in anginal symptoms in patients experiencing an acute myocardial infarction.”

Food Sources of TMA / TMAO

The 2013 Nature Medicine publication makes much of red meat as a food source of L-carnitine and then L-carnitine’s as a substance that can be transformed by intestinal bacteria to TMA and TMAO.  Other foodstuffs that, likewise, can be converted are betaine, choline, creatinine, phsophatidylcholine and lecithin.  Gut enterobacteria accomplish the conversion.  Notably, from the discussion in the 2013 article, one would never realize that the primary dietary sources of TMA and TMAO are foods that are heart-healthy, meaning fish.  Indeed, a diet without fish is associated with a 10-fold lower turnover of TMA/TMAO than is a fish-heavy diet.  More surprising still, a serving even of many common vegetables is associated with greater 8 hours TMA/TMAO excretion than is beef. 

The simple truth is that humans produce very little TMA/TMAO from any source other than fish.  Whereas a serving of red meat might cause the release of 77 µmol TMA/TMAO in 8 hours, a 227 gram portion of halibut might lead to the excretion of more than 100 hundred times that amount, which is to say, 8230 µmol (>600 mg) and most fish fall into the 3000 – 5000 µmol range.

The authors of the 2013 Nature Medicine article damning L-carnitine need to explain this paradox in which “healthful” foods, such as fish, lead to great increases of bad TMA/TMAO and “bad” foods, such as beef, lead to trivial rates of excretion.

In short, in humans levels of TMA/TMAO are directly associated with weekly fish consumption.

Aside from the consumption of fish and the consumption of test materials already contaminated with TMA/TMAO, it turns out to be the case that humans just do not produce much of these compounds from ingested food.

Neither L-carnitine-rich foods, such as red meat, nor choline-rich foods, such as liver and eggs, in normal practice lead to significant releases of TMA/TMAO.

TMA / TMAO Blood Levels

In actual fact, individuals with normal kidney function have no difficulty in excreting TMA/TMAO.  Still, Robert Koeth et al., the authors of the 2013 Nature Medicine article insist that blood levels of not just TMA/TMAO, but also L-carnitine and choline are proportionate to cardiovascular failings.  These authors insist on a causal relationship.  They may be correct in asserting that there is a causal relationship, but they have the cause and effect backwards.  For instance, elevated blood levels of choline are found in cases of artery plaque instability as a result of the instability itself.

Similarly, disturbed L-carnitine regulation is associated with poor cardiovascular outcomes.

About Those Mice

L-carnitine typically is given to laboratory animals to improve their metabolic and cardiovascular responses to bad diets.

This means that the negative health effects reported in the 2013 Nature Medicine seem oddly out of place against the background of available scientific data.  In fact, there are problems within the 2013 article itself.  For one thing, there is no evidence that the negative effect reported can be replicated outside of the mouse model used.  Information from the same authors published a year earlier indicated, for instance, a negative effect in female animals, but not in male animals (atherogenic-prone C57BL/6J mice.)

Probiotics to the Rescue?

To demonstrate that gut bacteria can cause the release of TMAO, Koeth et al. (2013) conducted several tests with somewhat surprising results.  In one of these, subjects after a fast were fed steak (eaten in 10 minutes) along with 250 mg L-carnitine, the amount found in 1.5 pounds red meat.  The radiolabeled carnitine tracked blood levels of TMAO that rose about 1.8 parts per million after 24 hours.  The paper points out that the vegetarian subjects did not exhibit the same blood levels of TMAO as did the habitual meat eaters.  Subjects then took antibiotics and repeated the test, which led to no TMAO being present after 24 hours.  These trials demonstrated a gut bacteria connection to the formation of TMAO and, likewise, that the bacteria responsible are associated with the habitual consumption of meat.  Nevertheless, objectively, the rise in TMAO blood levels even under conditions intended to elicit such an elevation simply was not of great moment.  

The objectively impressive finding was very interesting, indeed.  After antibiotics were used to kill off gut bacteria, if the bacteria were allowed to regrow for three weeks, the replacement bacteria upon challenge with steak and L-carnitine as before yielded 7 times the TMAO levels found previously.  Killing off the normal bacteria with antibiotics and then adding lots of meat and carnitine to the diet apparently leads to an overgrowth of bacteria specialized to feed on meat and carnitine.  

Also interesting is the finding in the Koeth et al. paper that 70 percent of omnivores had TMAO levels that were in the same range as 90% of the vegetarians.  Put differently, 25 percent of the omnivores and 10 percent of the vegetarians exhibited elevated TMAO levels.  The cause is not meat eating per se, but rather bacteria that convert L-carnitine to yield TMAO.  It is the gut flora that are predictive, not meat eating.  Subjects with high Prevotella and low Bacteroides averaged about triple the TMAO levels of those with low Prevotella and high Bacteroides flora.  In other words, subjects with high bacteria-linked TMAO levels probably were those subjects who ate diets poor in fermentable fiber and it was the absence of the proper support for healthful gut flora rather than the presence of meat in the diet that was determining.

Conclusions

1. Neither L-carnitine found in red meat nor choline and phosphatidylcholine found in eggs, soybeans and other foods, under normal circumstances, contributes much to blood levels of TMAO.


2. Fish appears to be the primary source of TMAO in the diet.


3. Gut bacteria can contribute to the formation of TMAO; this seems to reflect not so much routine meat consumption as it does a diet poor in fiber and other components that support normal gut bacterial balance.


4. Moderation is the key 




1. moderation in terms of a diet with reasonable amounts of fiber and other foods that support gut health 


2. avoidance sugar, refined flours and similar foods that damage gut health


3. avoidance of antibiotics when possible and reestablishment of proper gut flora after a course of antibiotics


4. moderation in consumption of red and processed meats