L-Carnitine in Red Meat May Up CVD Risk via Altered Gut Flora

Marlene Busko

April 09, 2013

CLEVELAND, OH — Research in mice and human volunteers has suggested a mechanism that may contribute to an association between eating red meat and increased risk of cardiovascular disease[1]. It involves microbes in the gut.

People who regularly eat red meat have an increased colonization of intestinal bacteria that break down the carnitine in red meat into a metabolite that promotes increased cholesterol deposition in the artery wall, the researchers report. Their study was published online April 7, 2013 in Nature Medicine.

Energy drinks are another major source of carnitine, senior author Dr Stanley L Hazen (Cleveland Clinic, OH) told heartwire . If someone regularly eats red meat or drinks energy drinks, "microbes that like carnitine become more abundant [in the gut], and now you are much more capable of making this metabolite . . . trimethylamine-N-oxide (TMAO)," he said. "This paper showed [that TMAO] . . . essentially leads to an enhanced capacity to deposit cholesterol on the cells of your artery wall."

Previously, the researchers showed that dietary choline and phosphatidylcholine (lecithin) are metabolized in mice and humans by intestinal microbes to produce trimethylamine, which is rapidly metabolized to TMAO, which is linked to accelerated atherosclerosis. Hypothesizing that carnitine, which has a similar molecular structure to choline, behaves this way, the researchers performed a series of experiments.

Carnitine Linked to TMAO Levels

First, they showed, for what they believe is the first time, that humans need gut microbes to form TMAO from dietary carnitine. After an overnight fast, volunteer omnivores were given a carnitine challenge--they were fed a capsule of carnitine plus an 8-oz sirloin steak--and their TMAO plasma and urine levels were measured. The volunteers were then given oral, broad-spectrum antibiotics for a week to suppress their gut microbes, after which they received a second carnitine challenge. Then after three weeks to allow their gut organisms to repopulate, they received a third carnitine challenge. Their TMAO levels were almost undetectable after the antibiotic regimen, but the levels rebounded after their gut flora repopulated.

The researchers also showed that after ingesting carnitine capsules, vegans and vegetarians produced markedly lower levels of TMAO than omnivores.

TMAO, Not Carnitine, Drives CVD

Next, in a cohort of 2595 subjects undergoing elective cardiovascular evaluation, the researchers determined that increased plasma carnitine was associated with increased risk of having or soon developing CAD, peripheral artery disease (PAD), or other CVD. However, after adjustment for traditional cardiovascular risk factors, an elevated carnitine concentration predicted a higher three-year risk of MI, stroke, or death only in subjects with high plasma TMAO levels. Thus TMAO, not carnitine, drives the cardiovascular outcomes, the researchers conclude.

Their mouse studies suggest a possible, multifaceted mechanism for the development of atherosclerosis. In mice, dietary carnitine promoted cholesterol buildup in the artery wall, which was completely inhibited after treatment with an antibiotic cocktail. In other mice with intact intestinal microbes, receiving TMAO and carnitine or lecithin led to inhibition of the reverse cholesterol transport pathway.

For Now, Eat Well; in Future, Also Take a Pill?

Does this mean that physicians should advise all their patients to become vegetarians and avoid drinking energy drinks? Hazen says that people need to be aware that "a can of an energy drink can have more carnitine than a porterhouse steak." Carnitine is obtained from many sources, since it is derived from lysine, the most abundant amino acid in animal and vegetable protein in the diet, he noted.

For now, "it makes sense to adhere to a lower-cholesterol, lower-saturated-fat diet [that will be] more heart healthy in terms of decreasing the nutrients that give rise to forming TMAO, [since] this may be one of the hidden contributors to heart disease."

In the future, there might be a TMAO test and a drug that targets TMAO, Hazen speculated. "Measuring TMAO can be a very strong predictor of cardiovascular risk, and it will become a test that is available for clinical use in the future," he hypothesized. "Down the road, we think we are going to be able to go after this, just like we take a statin . . . to decrease the [risk of] development of heart disease."

Hazen is named as coinventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics. He has been paid as a consultant or speaker by the following companies: Cleveland Heart Lab, Esperion, Liposciences, Merck, and Pfizer. He has received research funds from Abbott, Cleveland Heart Lab, Esperion, and Liposciences and has the right to receive royalty payments for inventions or discoveries related to cardiovascular diagnostics from Abbott Laboratories, Cleveland Heart Lab, Frantz Biomarkers, Liposciences, and Siemens. Disclosures for the coauthors are listed in the online version of the paper.

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