To treat the heart, start with the gut

Potential drug targeting intestinal bacteria stops chain reaction that leads to artery plaque

mouse arteries

GUT CHECK  Mice predisposed to heart disease and fed a diet high in choline — a compound found in meat and eggs — had plaque buildup in their arteries (left: plaques, red; artery, blue). Mice also given a drug to prevent their gut microbes from breaking down the choline had much less artery clogging (right). 

Z. Wang et al/Cell 2015 

Blocking gut reactions could help defend against heart disease.

Intestinal microbes break down the essential nutrient choline, abundant in meat and eggs, into a compound that leads to hardening of the arteries. A drug candidate that prevents the microbes from making this chemical conversion can reduce both the amount of this compound and the extent of artery damage in mice, researchers report online December 17 in Cell.

Manipulating gut bacteria to treat various diseases has clinical promise, says physician and microbiologist Martin Blaser of the New York University Langone Medical Center. “It’s a very exciting idea that may change the future therapies that are available for doctors.” He notes that this study addresses a particularly important and common disease: atherosclerosis, in which fatty plaques build up inside arteries, increasing the risk of heart attack and stroke.

Some bacteria found in both mouse and human guts turn choline into trimethylamine, or TMA. In the liver, TMA is transformed into an artery-clogging compound that study coauthor Stanley Hazen and his colleagues previously linked to atherosclerosis risk in humans (SN: 5/18/13, p. 14).

Now the researchers have discovered that a cholinelike compound could be used as a drug to block TMA production. Instead of fueling bacteria’s TMA-making activity, the potential drug suppresses some of the enzymes that microbes use to turn choline into TMA. This drug, nicknamed DMB, limits how much TMA mouse and human gut bacteria produce. In mice fed a diet high in choline or another TMA precursor, those given the drug in their drinking water developed less plaque-forming chemicals in their blood than those not given the drug. A high-choline diet caused plaques to build up in the arteries of mice genetically predisposed to atherosclerosis. But treating these mice with DMB completely prevented this artery clogging, Hazen says.

The drug compound — which the researchers found occurs naturally in some olive oils and red wines — didn’t cause any harmful effects in the mice after four months of treatment, and was quickly broken down and cleared out of the mice’s bodies. The compound was also nontoxic to the gut bacteria. Manipulating gut microbes without killing them could minimize the risk of developing drug-resistant bacteria, says Hazen, a physician scientist at the Cleveland Clinic.

But there’s no guarantee that the gut microbes wouldn’t develop drug resistance, Blaser says. TMA is an energy source for some microbes, and certain bacteria could evolve new ways of making the compound, he says. The team did find that the drug treatment changed the relative numbers of certain bacterial species in mouse intestines, increasing the presence of some and decreasing that of others. This change was small, Hazen says, but indicates that the drug does lead to selection of some bacteria over others. “I was actually surprised at that, but then again, the microbial community is incredibly dynamic,” he says.

Blaser says that more research is needed to determine if the experimental drug will work in people. Future work may also uncover other compounds that are even more effective at shutting down bacterial production of artery-clogging chemicals, Hazen says. “On the one hand, we want to move this [drug] into humans. On the other hand, we want to move it along in terms of making newer, better, more potent versions,” he says. “There’s lots more to do.” 

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