HealthDay News — Intestinal microbiota appear to play a role in the development of atherosclerosis, results of a two-part experiment and observational study suggest.

Increased levels of atherosclerosis-related trimethylamine-N-oxide (TMAO), which is released when dietary lecithin is metabolized, correlates with the risk for major adverse cardiovascular events. Individuals with the highest plasma TMAO levels had a 2.5-fold higher risk for major adverse cardiovascular events than those with the lowest levels (P<0.001), according to W.H. Wilson Tang, MD, from the Cleveland Clinic, and colleagues.

High TMAO levels predicted myocardial infarction, stroke and death after adjusting for other risk factors, the researchers reported in New England Journal of Medicine.

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It appears the process is dependent on intestinal microbiota, as TMAO levels decreased with flora-supressing antibiotics and increased when the medication was discontinued. However, Tang and colleagues were quick to point out that antibiotics are not the solution, since the microbes would develop drug resistance.

Instead, clinicians should recommend patients avoid excessive consumption of the major sources of lecithin (also called phosphatidylcholine) to keep TMAO levels in check. This includes foods such as eggs, liver, beef and pork.

“A vegetarian or high-fiber diet can reduce total choline intake,” the researchers wrote. However, they noted following standard dietary recommendations should be adequate, as these foods are already recommended in moderation due to high fat and cholesterol content.

It is important that choline not be completely eliminated from the diet, as it is a semi-essential nutrient, and doing so could result in a deficiency state. Probiotics or pharmaceuticals could be other approaches to controlling TMAO levels, the researchers suggested.

In the first study, Tang and colleagues measured TMAO and plasma choline and betaine in 40 healthy adults after they consumed two hard-boiled eggs and radioisotope-labeled phosphatidylcholine. Six participants were then assigned to broad-spectrum antibiotics for one week to suppress intestinal flora. These six patients were asked to return for repeat “phosphatidylcholine challenges” at one week and one month follow-up.

At one week, participants assigned to the antibiotic had almost total suppression of TMAO and radio-labeled TMAO in plasma and urine, but experienced no differences in choline, betaine or trimethylamine levels. At repeat challenge one month later, participants experienced variable recovery to pre-antibiotic TMAO levels and radio-labeled TMAO, as expected with 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 wrote.

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

During three 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 μM among participants who did not experience an event (P<0.001).

Risk for nonfatal myocardial infarction or stroke was 2.13-fold higher among patients with elevated TMAO levels (95% CI: 1.48-3.05), and risk for CVD-related death was 3.37-fold higher (95% CI: 2.39-4.75; P<0.001 for both), the researchers found.

They also assessed the utility of including TMAO levels as a prognostic too with traditional markers of CVD risk like cholesterol, triglyceride, or glucose levels, and found that including TMAO improved risk estimation by a net 8.6% (P<0.001).

Furthermore, the prognostic value of elevated TMAO plasma levels for cardiovascular risk remained significant in various low-risk subgroups, the researchers found. This including those aged younger than 65 years, nonsmokers, women, and participants who did not have a known history of coronary artery disease, as well as those with low lipid and apolipoprotein levels, normal BP, and low levels of other known risk markers, such as C-reactive protein, myeloperoxidase and white-cell count.

In an accompanying editorial, Joseph Loscalzo, MD, PhD, of Harvard and Brigham and Women’s Hospital in Boston, said the study findings “point to a truly novel and potentially modifiable risk factor for atherothrombotic vascular disease.”

However, he noted the study falls short of providing a mechanism of action for how TMAO promotes atherothrombosis. Further studies are needed to determine this, as well as to corroborate the prognostic value of TMAO testing.


  1. Tang WHW et al. N Engl J Med. 2013;368:1575-84.
  2. Loscalzo J et al. N Engl J Med. 2013; 368:1547-49.