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“Is the fountain of youth in the gut microbiome?” This provocative question popped up a few months back, not in a dodgy online ad promoting probiotics, but as the headline of a March 2019 perspective article in the Journal of Physiology. Its inspiration: a new study that found when aged mice were given a broad-spectrum antibiotic to suppress their microbiomes, their arterial function bounced back to that of much younger animals. These results along with similar findings from other groups, the authors of the perspective article wrote, indicate that the gut microbiome is a promising therapeutic target for reducing the risk of age-related cardiovascular disease in humans.

In light of what’s now known about the effects of gut bacterial metabolites on the cardiovascular system, the results weren’t surprising, says Vienna Brunt, a physiology researcher at the University of Colorado Boulder and the first author on the mouse study. In human and animal studies, researchers have in recent years uncovered ways in which certain microbial species can modulate disease risk, often via interactions with their hosts’ diets. And, while Brunt cautions that antibiotics were an experimental tool in her study and should not be viewed as a potential way to boost cardiovascular health in humans, some teams are investigating other ways to exploit the crosstalk between the gut and the cardiovascular system to develop new therapeutics.

Stanley Hazen, a physician-researcher at the Cleveland Clinic, likens the emerging awareness of the microbiome’s influence on health to a similar realization “a century ago when we were just learning what hormones were. . . . Now we [know of] hundreds of compounds that are being made by gut microbes that then get absorbed and, we see, have biological effects in the host.”

Good metabolites, bad metabolites

Hazen is a pioneer in mapping microbial contributions to cardiovascular disease risk. In 2011, he and his colleagues reported that levels of metabolites of the dietary lipid phosphatidylcholine were elevated in the plasma of people who went on to experience a heart attack, stroke, or death in the following three years compared with those who did not. The researchers also found that those metabolites led to artery hardening, or atherosclerosis, in mice, and that the deleterious effects of adding one metabolite, choline, to the diet could be suppressed in the animals if they were first given broad-spectrum antibiotics.

In subsequent studies, Hazen and his team have fleshed out the details of that relationship, finding that choline, an essential nutrient present at high levels in animal products, is converted by gut microbes into trimethylamine N-oxide (TMAO) and other trimethylamines (TMA). Those metabolites signal the blood’s platelets to become more reactive and prone to clotting, Hazen says. If blood clots do form—a condition known as thrombosis—they can cause a heart attack or stroke. Hazen and colleagues also found that carnitine, a compound found in high levels in red meat, can, like choline, be converted to TMA by gut microbes.

It’s not going to be a magic solution where you take this pill with this organism and you’re going to be healthy. —Federico Rey, University of Wisconsin-Madison

Other groups have added to, and complicated, the story of how gut microbes work through TMAO to influence cardiovascular health. For example, University of Gothenburg microbiologist Fredrik Bäckhed and colleagues recently reported that germ-free mice were less susceptible to aorta lesions, a signature of atherosclerosis, and had lower cholesterol than wildtype mice. But those differences disappeared when both groups of mice were fed extra choline, suggesting that the microbiome may not be a major driver of atherosclerosis, at least in the strain of mice the researchers used.

Brunt has also investigated connections between TMAO and gut microbes. She and her colleagues recently found that blood TMAO levels increase with age in mice, and are accompanied by changes in microbiome composition. It’s not yet clear why these changes occur, Brunt says. “The theory right now is that it’s the overall process of aging,” she says. “If there’s more inflammation in your body, that can go on to negatively affect the bacteria in your gut as well.” She’s now working on a study comparing people put on a Western-style diet—high in fat and sugar but low in fiber—with another group fed a low-fat, low-sugar, high-fiber diet for a week to see whether the latter diet could ameliorate age-related microbiome changes.

Not all gut microbial influences on cardiovascular health are negative. Recently, Bäckhed, University of Wisconsin-Madison bacteriologist Federico Rey, and other colleagues found an apparently protective role for some species. Atherosclerosis-prone mice colonized by the butyrate-producing Roseburia intestinalis, for example, had fewer aortic lesions than mice lacking the bacterium, the team reported last year. Mice fed a butyrate precursor also had fewer lesions.

Another potentially protective taxon is Bifidobacterium. In a 2017 study, this bacterial genus was found to correlate with better vascular function (including more-pliable vessels and better endothelial function) in mice. “One of the next steps could be to follow up on that and actually administer Bifidobacterium back to the mice to see if it’s protective,” says study coauthor Chris Gentile, a physiology researcher at Colorado State University in Fort Collins.

Tweaking the microbiome

Such findings suggest that probiotics could be developed to deliver protective species to people who lack them, Rey says. But, he cautions, “it’s not going to be a magic solution where you take this pill with this organism and you’re going to be healthy. Many of these organisms . . . require the consumption of specific nutrients, or specific food for these microbes, so that if you don’t consume that you’re going to lose the organism or the organism may not have its full effect.”

Blocking the effects of harmful microbes is also a potential avenue for therapeutics. Last year, Hazen’s group reported that they’d identified a compound, fluoromethylcholine (FMC), that blocks the action of microbial TMA-generating enzymes without killing the bugs. Dosing mice with FMC reduced the levels of TMA and TMAO in the animals’ blood and made their platelets less prone to clotting compared with those of control mice, so the team is continuing preclinical testing on the compound.

Scientists continue to find new connections between the microbiome and cardiovascular health, each with their own therapeutic implications. For example, studies in animals have found that short-chain fatty acids that bacteria churn out when they break down fiber interact with receptors on host cells to regulate blood pressure. And while the microbiome is far from the only mediator of cardiovascular health, researchers in the field suspect there are many more links to discover.

Hazen compares the beginnings of his microbiome-related research, which started in 2007, to the scene in Men in Black II when the main characters discover a whole society of aliens living inside a modest-size locker at Grand Central Terminal. As more findings emerge, he says, “the gut microbiome is going to end up being—and I’m convinced it is—our most important organ.”

Shawna Williams is an associate editor at The Scientist. Email her at swilliams@the-scientist.com.