01/13/2014 04:29 pm ET Updated Mar 15, 2014

Gut Reaction: New Predictor of Cardiovascular Disease Trumps Cholesterol

Cardiovascular disease (CVD) is the No. 1 killer of both men and women in the United States and consumes $312.6 billion in health care costs annually. Understanding what causes this illness could allow one to predict who will develop CVD, an essential step in reducing this disease burden through preventive measures. Despite significant advances in such understanding and prognostication, our ability to identify those who will have a cardiac event often fails. Dr. Hazen and his research team at the Cleveland Clinic recently discovered something that may revolutionize this arena.

Medicine has intermittently acknowledged the profound influence of diet on health since antiquity. Hippocrates, the father of Western medicine, put it succinctly: "Let food be thy medicine and medicine be thy food."

Although often not thought of in this way, diet represents one of the most important environmental factors effecting health. Recent research indicates that there is a third party in our relationship with food that dramatically influences a myriad of processes including digestion, energy extraction and metabolism. This is the bacterial population that colonizes our gut.

But there's more to this story than a peaceable symbiosis. These intestinal colonists that coevolved with us appear to have a central role in both health and disease. Different types of gut bacteria have been shown to promote obesity, metabolic syndrome and Type 2 diabetes.

Hazen's group has now demonstrated that gut microbes are accomplices in the development of yet another illness, our No. 1 killer, CVD.

Lecithin (phosphatidylcholine) provides the primary dietary source of choline, a nutrient that is part of the B-complex vitamins. Choline plays an important role in fat metabolism, cell wall integrity, and production of the neurotransmitter acetylcholine. Previously Hazen's team had found that when gut microbes metabolized lecithin in animal models, they produced trimethylamine-N-oxide (TMAO). a compound associated with CVD.

In an elegant series of experiments, he set out to see if the same metabolic pathway existed when intestinal bacteria break down dietary lecithin in humans. The researchers fed healthy subjects labeled lecithin before and after suppressing intestinal bacteria with antibiotics. They observed an increase in TMAO after eating labeled lecithin before antibiotic administration, but not after. This proved that TMAO production was dependent on the gut bacteria.

The team then analyzed the relationship between fasting blood TMAO levels and major adverse cardiovascular events over three years of follow-up in 4,007 subjects. Indeed, they found that elevated TMAO levels were associated with a significantly increased risk of these events.

Most importantly, the TMAO level predicted cardiovascular risk independent of traditional risk factors. In other words, TMAO levels identified CVD risk in subjects who looked good on traditional tests such as blood cholesterol, triglycerides and angiographic reading.

These findings have game-changing implications. TMAO blood levels may soon overshadow cholesterol and other traditional markers as the most sensitive indicators of CVD risk. From a therapeutic standpoint, probiotics that suppress the growth of those bacterial populations that have been implicated in TMAO production may define the next generation of cardiac medications.

However the significance of this research extends beyond CVD, reframing models of both health and disease. We now realize there is a complex ecology in both our internal and external worlds. Both possess sensitive balances that affect our biology. The focus of medicine will shift to a new meta-organism defined by resident bacterial populations and their human host.

The concept of diet has also been forever changed. We do not dine alone. Bacterial guests, constant companions at our communal meals, co-author our physiology. Future diets will recommend foods that promote the growth of healthy bacterial populations.

The story of symbiosis, a sort of biological mergers and acquisitions, has a long history. In fact the origin of more complex cells (eukaryotic) that have their own energy source (mitochondria) began with symbiosis. Over a billion years ago one type of bacteria ate another type. Rather than digesting this other bacteria, a new combined entity emerged that had adaptive advantages for both. This allowed life to move out of the ocean onto land, ushering in a new era on earth. These new improved cells were the ancestors of all multicellular organisms including our own species.

Like the cell, we are the products of a kind of symbiosis. In this way we recapitulate the evolution of our own building blocks.