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Red meat consumption tracks closely with levels of trimethylamine N-oxide (TMAO), a byproduct of red meat digestion linked to increased heart disease risk, a randomized trial affirmed.

One month on a heavy red-meat diet (equivalent to 8 oz steak a day) increased plasma and urine TMAO levels more than twofold compared with either a diet high in white meat or in non-meat proteins (P<0.0001).

Conversely, swapping out red meat for white meat or non-meat protein reduced blood and urine TMAO back to baseline levels within 4 weeks, Stanley Hazen, MD, PhD, of Cleveland Clinic, and colleagues reported online in .

TMAO is an atherosclerosis- and thrombosis-promoting metabolite transformed by gut microbiota from carnitine and choline, two compounds abundant in meats like beef and pork.

"The study provides further, but still preliminary, evidence for the health benefits of diets reduced in red meat," commented Marion Nestle, PhD, MPH, of New York University in New York, who said that this and other microbiome studies make up "an exciting area of research from which it is too soon to draw firm conclusions."

While observational studies have demonstrated an association of TMAO with cardiovascular risk and animal studies demonstrated benefits from reduced TMAO levels, proving an impact of intervention to reduce TMAO on hard clinical endpoints in humans would be hard to do, and very expensive, she told 乌鸦传媒 in an email.

Hazen's group also showed that red meat reduced fractional renal excretion of TMAO (P<0.05) while increasing the excretion of carnitine and two of its alternative metabolites (P<0.05).

"This is the first study of our knowledge to show that the kidneys can change how effectively they expel different compounds depending on the diet that one eats – other than salts and water," Hazen said in a press release. "We know lifestyle factors are critical for cardiovascular health, and these findings build upon our previous research on TMAO's link with heart disease. They provide further evidence for how dietary interventions may be an effective treatment strategy to reduce TMAO levels and lower subsequent risk of heart disease."

The crossover study randomized participants to three 4-week diets of the same caloric value in different orders, the main difference among the diets being the protein source: red meat, white meat (poultry), or no meat (legumes, nuts, grains, soy). A washout period separated each diet.

Stratifying groups into high- versus low-saturated fat arms showed that dietary fat intake had no impact on TMAO or its metabolites.

From a subset of 13 individuals out of the total 113 healthy volunteers who were randomized to a heavy isotope tracer study, red meat and white meat turned out to boost TMAO production from carnitine (P<0.05 for both) but not choline.

Commenting to 乌鸦传媒, C. Noel Bairey Merz, MD, of Cedars-Sinai Medical Center in Los Angeles called the study design "rigorous" in implicating the three pathways of a red meat diet, gut microbiota, and renal excretion in blood TMAO levels.

"Of note, data to support TMAO contributing to CVD remains uncertain, so while this study is extremely useful to understand mechanistic pathways for any biomarker, causal risk factor or risk predictor, continued investigation is needed to determine causality, as well as utility for risk prediction, as well as treatment target," she said.

In a separate study in the , Hazen's team discovered that carnitine gets converted to TMAO in a two-step pathway.

The first step done by one set of gut bacteria was the same for both vegans or vegetarians and for those who eat meat. But the second step by other bacteria formed TMAO faster in those who eat meat.

After just 1 month of daily carnitine supplementation, however, vegans and vegetarians in the CARNIVAL study started making more TMAO.

By uncovering this new pathway, we can potentially develop new treatments to interrupt this process before both the development and progression of cardiovascular disease," Hazen said in a statement.

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