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The gut microbiota appears to play a role in atherosclerosis through a complex metabolic pathway that involves dietary lecithin, a two-part experiment and observational study determined.

Levels of atherosclerosis-related trimethylamine-N-oxide (TMAO) released by the process were dependent on gut bacteria, as evidenced by the fact that the levels fell with flora-suppressing antibiotics and rose afterward, Stanley L. Hazen, MD, PhD, of the Cleveland Clinic and colleagues found.

TMAO levels predicted myocardial infarction, stroke, or death after adjustment for other risk factors, the group reported in the April 25 issue of the New England Journal of Medicine.

Individuals with the highest plasma levels of TMAO had a 2.5-fold higher risk of major adverse cardiovascular events than those with the lowest levels (P<0.001).

Long-term antibiotics aren't the solution, since the microbes would become resistant, Hazen's group noted. But avoiding excessive consumption of the major sources of lecithin (also known as phosphatidylcholine) -- eggs, liver, beef, and pork -- should help keep TMAO levels down, they suggested.

"A vegetarian or high-fiber diet can reduce total choline intake," they wrote, but added that following standard dietary recommendations should be enough, since those foods are typically recommended in moderation anyway due to their high fat and cholesterol content.

"It should also be noted that choline is a semi-essential nutrient and should not be completely eliminated from the diet, since this can result in a deficiency state."

Other strategies could be probiotics or pharmaceuticals to suppress synthesis of TMAO.

There are larger implications too, Joseph Loscalzo, MD, PhD, of Harvard and Brigham and Women's Hospital, noted in an accompanying editorial. "The meta-organism comprising humans and their microbiota must be viewed as a self-contained unit of complex molecular mediators interacting with its environment to yield a functional phenotype or, in cases of dysfunction, a pathophenotype," they wrote.

"In light of this new model, disease can never be viewed in quite the same way, nor should it."

The first study included 40 healthy adults whose plasma and urinary levels of the metabolites of phosphatidylcholine -- TMAO and plasma choline and betaine -- were measured after they were given two hard-boiled eggs and radioisotope-labeled phosphatidylcholine.

Six of the participants then took oral broad-spectrum antibiotics to suppress intestinal flora for a week and came back in for another phosphatidylcholine challenge, which showed almost total suppression of TMAO and radio-labeled TMAO in plasma and urine but no difference in choline, betaine, or trimethylamine.

Repeat challenge at 1 month showed variable recovery to pre-antibiotic levels in TMAO and radio-labeled TMAO, as expected from variable recovery of intestinal microbiota.

"The ability of oral broad-spectrum antibiotics to temporarily suppress the production of TMAO is a direct demonstration that intestinal microorganisms play an obligatory role in the production of TMAO from phosphatidylcholine in humans," the researchers explained.

"Intestinal microbiota convert the choline moiety of dietary phosphatidylcholine into trimethylamine, which is subsequently converted into TMAO by hepatic flavin-containing monooxygenases."

To show the clinical impact of TMAO, the researchers measured fasting levels in 4,007 patients undergoing elective diagnostic coronary angiography.

During 3 years of follow-up, incident major adverse cardiovascular events were associated with higher baseline TMAO levels, with an average 5.0 μM compared with 3.5 in those who didn't have an event (P<0.001).

Elevated TMAO levels were associated with (P<0.001):

• 3.37-fold higher risk of death (95% confidence interval 2.39 to 4.75)
• 2.13-fold higher risk of nonfatal myocardial infarction or stroke (95% CI 1.48 to 3.05)

Including TMAO improved risk estimation by a net 8.6% over traditional risk factors (P<0.001). That result might also suggest monitoring TMAO levels in the clinic, Hazen noted in a statement.

"More studies are needed to confirm that TMAO testing, like cholesterol, triglyceride, or glucose levels, might help guide physicians in providing individualized nutritional recommendations for preventing cardiovascular disease," he said.

Notably, the prognostic value of elevated TMAO plasma levels held across subgroups, including low-risk groups like those under age 65, women, and those without a known history of coronary artery disease, low lipid and apolipoprotein levels, normal blood pressure, no smoking, and low levels of C-reactive protein and other risk markers.

One limitation of the study was that it couldn't provide a mechanism for how TMAO promotes atherothrombosis, Loscalzo noted. He suggested a possible role in promoting vascular injury via its action as an oxidant that consumes thiol-reducing equivalents, including glutathione.

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