image: This visual abstract 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. view more
Credit: Wang et al./<i>Cell</i> 2015
A first-of-a-kind drug that interferes with the metabolic activity of gut microbes could one day treat heart disease in humans, according to a mouse study published December 17 in Cell. Dietary supplementation with a compound that is naturally abundant in red wine and olive oil prevented gut microbes from turning unhealthy foods into metabolic byproducts that clog arteries.
The findings 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.
"This study shows for the first time that one can target a gut microbial pathway to inhibit atherosclerosis," says senior study author Stanley Hazen of the Cleveland Clinic. "This new approach opens the door to the concept of drugging the microbiome to affect a therapeutic benefit in the host."
Atherosclerosis, commonly known as hardening of the arteries, has been linked to the consumption of high amounts of nutrients such as choline and carnitine, which are abundant in foods such as meat, egg yolks, and high-fat dairy products. Gut microbes convert these nutrients into a compound called trimethylamine (TMA), which in turn is converted by host enzymes into a metabolite called trimethylamine N-oxide (TMAO), which accelerates atherosclerosis in animal models and is associated with an increased risk for heart disease in humans.
Until now, 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. Hazen and his team figured that a more promising approach would be to directly target gut microbes to prevent the formation of TMA in the first place.
Toward this goal, Hazen and first author Zeneng Wang of the Cleveland Clinic screened for inhibitors of microbial TMA production from choline. They identified a compound called 3,3-dimethyl-1-butanol (DMB), which is naturally abundant in some cold-pressed extra virgin olive oils, balsamic vinegars, and grape seed oils. In mice that were on a choline-rich diet and genetically predisposed to atherosclerosis, DMB treatment substantially lowered TMAO levels and inhibited the formation of arterial plaques without producing toxic effects.
Additional experiments suggested that DMB exerted its beneficial effects by inhibiting TMA formation. Moreover, 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 non-lethal drug than an antibiotic."
DMB treatment would also differ from cholesterol-lowering drugs such as Lipitor because it targets molecular pathways in gut microbes, not in human cells. "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."
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This research was supported by the National Institutes of Health and the Office of Dietary Supplement. Additional funding was received by the American Heart Association and the Leonard Krieger fund. Studies were performed on instrumentation housed within a facility partially supported by AB SCIEX. Three authors are co-inventors on patents held by the Cleveland Clinic relating to cardiovascular diagnostics and/or therapeutics. Stanley Hazen reports having been paid as a consultant and receiving research funds from several pharmaceuticals.
Cell, Wang et al.: "Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis" http://dx.doi.org/10.1016/j.cell.2015.11.055
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