Targeting gut bacteria to reduce heart disease

A new drug that blocks the production of one chemical by gut bacteria significantly reduces cardiovascular risk factors.

Gut bacteria are intrinsically linked with the health of our entire body. Be it the gut, the brain, or the heart, our microbiome is involved.

One important way in which they influence our health is through the chemicals that they produce and release.

Some of these can leach into our blood, and, once in the circulatory system, travel far and wide.

Although we are very far from understanding the full range of influences that our bacterial residents have on cardiovascular health, researchers from the Cleveland Clinic in Ohio are focusing on one in particular.

Gut bacteria and the heart

Led by Dr. Stanley Hazen, Ph.D., the Cleveland researchers are interested in a particular chemical called atrimethylamine N-oxide (TMAO), which gut bacteria produce.

When gut bacteria break down choline, lechithin, and carnitine — compounds found in particularly high levels in high-fat dairy producs, egg yolk, liver, and red meat — the process produces TMAO.

Previous studies by Dr. Hazen and team demonstrated that TMAO levels are powerful predictors of future cardiovascular disease, including stroke and heart attack.

They showed that this increase in risk is due to TMAO's ability to increase platelet reactivity, or how "sticky" platelets are, and thrombosis, or clotting potential.

The researchers wanted to see whether they could interfere with the bacteria to prevent or reduce TMAO production in a mouse model. They published their findings in the journal Nature Medicine.

To influence TMAO levels, they used a choline analog — a compound structurally similar to choline, which is an essential chemical in the manufacture of TMAO. Because bacteria use choline as an energy source, they absorb the analog readily.

Once the analog enters the bacteria, it blocks the production of TMAO by inhibiting the enzyme choline utilization protein C. As expected, this reduced circulating TMAO levels significantly.

In fact, one oral dose of the inhibitor reduced TMAO levels for 3 days. It also lowered platelet responsiveness and excessive clot formation following arterial injury.

Commonly, drugs that reduce clot formation also increase the risk of excessive bleeding. With this inhibitor, that was not the case.

A novel approach

Importantly, this experimental approach does not kill gut bacteria; it simply removes their ability to produce TMAO. Compared with antibiotics that indiscriminately destroy potentially useful gut bacteria, this novel technique could be a game-changer.

"To our knowledge, this is the most potent therapy to date for 'drugging' the microbiome to alter a disease process. In addition, gut bacteria are altered but not killed by this drug, and there were no observable toxic side effects."

Dr. Stanley Hazen, Ph.D.

This is an entirely new way of interacting with the microbiome and the team plans to continue traveling down this exploratory road; Dr. Hazen believes that eventually, with some tweaks, it "could potentially be used to target other gut microbial pathways."

The path will be a long one, but the team is looking forward "to advancing this novel therapeutic strategy into humans."

With so many boxes ticked — the drug is not toxic, has no side effects, and does not add to antibiotic resistance — this new methodology is likely to receive a great deal of interest. We eagerly await the results of clinical trials.