TMAO: A New 'Gut' Player in Heart Disease

A look at gut bacteria's role in cardiovascular health

Gut bacteria and heart health
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Most doctors used to advise watching how often you eat meat, eggs, and high-fat dairy products due to the elevated levels of saturated fat and cholesterol they contain. Consuming saturated fat can raise levels of low-density lipoprotein (LDL) cholesterol, the "bad" cholesterol and the type implicated in increasing one's risk of cardiovascular disease and its outcomes, like heart attack and stroke.

But the degree of the connection between dietary fats and cholesterol and heart disease has recently been questioned. Today, we know that most cholesterol is produced by the liver and only 15 to 20 percent comes from your diet.

This finding is not a license to feast on bacon, eggs, and buttered toast, however. Experts still recommend you eat these foods in moderation. Although these foods may not raise your cholesterol as much as previously thought, they wreak havoc on your cardiovascular health in a different way.

Studies have found a direct link between the chemical products created in the gut when these foods—which are common in a Western diet—are eaten and the occurrence of heart attack, stroke, heart failure, and death, the major adverse outcomes of cardiovascular disease.

Digestion Is Key

Our gut is swarming with bacteria that serve as a filter for our largest environmental exposure—the food we eat.

“What we feed these bacteria over time influences what happens throughout our bodies,” says Stanley Hazen, MD, PhD, Section Head of Preventive Cardiology at Cleveland Clinic, who has led the institution’s research in this area.

Dr. Hazen’s laboratory conducted key studies discovering a mechanistic link between gut microbes and heart disease via a substance called trimethylamine-N-oxide (TMAO).

TMAO is formed from nutrients commonly found in animal products.

These studies, and subsequent key findings, showed how certain bacteria in the intestines turn choline—a byproduct of lecithin found in meat, egg yolks, and high-fat dairy products—into trimethylamine (TMA), which is absorbed into the bloodstream and metabolized by the liver. There, TMA is transformed into TMAO, which appears to be a key player in a number of disease processes linked to the heart and blood vessel walls.

Moreover, these studies revealed a clear link between higher TMAO levels and higher rates of heart attack, stroke, and death within three years in humans, as well as accelerated heart disease in animal models.

Dr. Hazen’s lab also showed that the same gut microbe-based process plays a role in accelerated heart disease following ingestion of L-carnitine, a compound that is found naturally in most red meats but is also a frequent additive to energy drinks. The study found that the gut also turns L-carnitine into TMA (and then TMAO) and that TMAO contributes to heart disease in part by changing how the body uses cholesterol. TMAO also was shown to trigger inflammation in blood vessels and to create unstable plaques in artery walls, thereby raising the risk of heart attack.

Heart Failure

Further studies by Dr. Hazen’s team have shown a link between the TMAO pathway and heart failure. When they examined the role of TMAO in patients with stable heart failure, they found that the higher the TMAO level, the greater the risk of cardiovascular death.

“This risk held true regardless of other traditional risk factors and regardless of kidney function or blood markers indicating heart strain,” notes Dr. Hazen. In this study, higher TMAO levels more than tripled the risk of death.

Kidney Disease

Traditional risk factors don’t account for the increased cardiovascular risk in patients with impaired kidney function (conditions called chronic kidney disease and end-stage kidney disease).

Dr. Hazen’s team found a connection between the TMAO pathway, kidney disease, and the heightened cardiovascular risks observed in people with diminished kidney function. In addition to showing a link between TMAO and elevated cardiovascular risk in subjects with impaired kidney function, they found (in animal models) that consuming increased levels of choline via diet and exposure to high levels of TMAO over time triggers scar tissue formation (fibrosis) in the kidneys. This can cause kidney function to deteriorate.

In one study, Dr. Hazen observed people with and without kidney disease for five years. He found that those with high TMAO levels when the study began were more likely to have an accelerated decline in kidney function, a heart attack, a stroke, or die—compared to those with lower TMAO levels.

Furthermore, as kidney function declines, TMAO levels rise because TMAO is excreted by the kidneys. “The higher TMAO levels observed may explain why people with serious kidney disease tend to have increased risk of dying from heart disease,” Dr. Hazen reports.

More Research & Findings

Dr. Hazen’s lab continues to investigate TMAO’s role in other disease processes. Studies to date confirm that gut microbes, through generation of TMAO, are a major player in cardiovascular health. Most recently, studies from the Hazen lab point to TMAO's role in peripheral arterial disease—a disease of the leg arteries—and in the formation of blood clots that can lead to heart attack and stroke.

The discovery that gut microbes and the TMAO pathway are linked to cardiovascular health opens the door for many potential advances. Improvements in dietary recommendations and nutrition are one obvious action. Another is that the recognition of this pathway is leading to new diagnostic tests and potential treatments targeting microbe processes that contribute to cardiovascular disease.

The pioneering studies by Dr. Hazen’s team showed that targeting the first step in the creation of TMAO—production of TMA, which gets converted into TMAO by microbes—can help prevent atherosclerosis (hardening of the arteries) in animal models. This new approach holds promise for its eventual use as a preventive treatment for heart attack, stroke, and other manifestations of atherosclerosis.

For example, when mice were fed diets rich in choline or carnitine (similar to a Western diet), they experienced accelerated atherosclerosis. When half the mice on the high-choline diet were given a naturally occurring substance that blocks the microbial pathway leading to TMAO formation, less atherosclerosis occurred. The natural substance used on the mice, found in cold-pressed, extra-virgin olive oil and grape seed oil, was also shown to be very safe, even in high doses.

What This Means for You

New evidence links gut microbes to metabolism and heart health. And diet is the single largest factor that impacts gut microbe composition and function. “The studies, to date, suggest that adopting a diet where one eats less meat and animal products, like a vegetarian or vegan diet as well as a Mediterranean diet, might be particularly beneficial, especially if you have high cardiovascular risk, heart failure, or chronic kidney disease,” says Dr. Hazen.

As for the rest of us, he adds that it’s hard to say whether or not cutting down or cutting out red meat, dairy, and eggs might help us live longer, healthier lives. However, a blood test for TMAO is now available and Dr. Hazen notes that it can help individual patients determine whether his or her TMAO level is too high. “Knowing your TMAO level can give a clearer picture of your cardiovascular risk,” he says.

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