Mediterranean Diet Impacts Microbiome’s Influence on Heart Disease

This image depicts how drugging the gut microbiota with a nonlethal inhibitor that blocks production of the metabolite trimethylamine reduces the formation of atherosclerotic lesions and represents the first step toward treatment of cardiometabolic diseases by targeting the microbiome. [Wang et al./Cell 2015]

For several years now, scientists and physicians have extolled the benefits of the Mediterranean diet, which emphasizes eating more fruits, nuts, veggies, and healthy oils, while limiting red meat and high-fat dairy consumption. However, uncovering the precise molecular mechanisms for benefits of this diet regimen has remained elusive.

Now, researchers at the Cleveland Clinic have identified a novel compound that is naturally abundant in some cold-pressed extra virgin olive oils, balsamic vinegars, and grape seed oils, which interfere with the metabolic activity of gut microbes, preventing them from turning unhealthy foods into metabolic byproducts linked to atherosclerosis.

The findings from this study—which was done in mice—suggest that a Mediterranean diet exerts its beneficial health effects by altering the activity of gut microbes. If replicated in humans, the study could lead to a new strategy for treating and possibly preventing heart disease and stroke—the top two causes of death worldwide.   

“Many chronic diseases like atherosclerosis, obesity, and diabetes are linked to gut microbes,” explained senior study author Stanley Hazen, M.D., Ph.D., chairman of the department of cellular and molecular medicine at the Cleveland Clinic. “This study shows for the first time that one can target a gut microbial pathway to inhibit atherosclerosis and also demonstrates the exciting possibility that we can prevent or retard the progression of diet-induced heart diseases starting in the gut. This opens the door to the future for new types of therapies for atherosclerosis, as well as other metabolic diseases.”

The findings from this study were published recently in Cell through an article entitled “Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis.”

The gut microbiota converts compounds such as choline and carnitine—abundant  in meat, egg yolk, and high-fat dairy products—into a compound called trimethylamine (TMA), which in turn is converted by host enzymes into a metabolite called trimethylamine N-oxide (TMAO)—accelerating atherosclerosis in animal models and has been shown to increase the risk for heart disease in humans.

Previously, efforts to target this pathway for therapeutic benefit have focused on inhibiting the host enzymes that convert TMA into TMAO. However, this approach causes liver damage as well as an unhealthy build-up of TMA. The Cleveland team hypothesized that a better approach would be to target the gut microbes directly and prevent the formation of TMA in the first place.

Dr. Hazen and his team went to work, screening for inhibitors of TMA production. They identified a compound called 3,3-dimethyl-1-butanol (DMB), found naturally in many Mediterranean diet foods. When the researchers gave the compound to mice that were on a choline-rich diet and genetically predisposed to atherosclerosis, the DMB treatment substantially lowered TMAO levels and inhibited the formation of arterial plaques without producing toxic effects.   

“We were able to show that 'drugging the microbiome' is an effective way to block this type of diet-induced heart disease. The inhibitor prevents formation of a waste product produced by gut microbes, leading to lowering of TMAO levels and prevention of diet-dependent atherosclerosis.” said Dr. Hazen. “This is much like how we use statins to inhibit cholesterol synthesis in human cells.

Interestingly, the investigators found that DMB did not kill the gut microbes, but it did reduce the proportions of some bacteria associated with high levels of TMA, TMAO, and atherosclerosis.

“It was especially nice to see that the drug blocked the pathway without killing the microbe,” Hazen says. “There should be less selective pressure for the development of resistance against a nonlethal drug than an antibiotic.”

Dr. Hazen and his team were excited by the results from their study, but urge caution in over interpretation as the studies were performed in mice, which have a much different gut microbiome than humans.    

“If we replicate our findings in upcoming human studies, this could be a whole new approach to the treatment of cardiovascular and metabolic diseases,” Hazen says. “In the meantime, our findings suggest that it might not be a bad idea to consume a Mediterranean diet to help stave off heart disease and other health problems.”