The specific chemical isn’t the important part of this discovery. “There have been many compounds that block atherosclerosis in rodents. So, in and of itself, that’s not super exciting,” says Hazen. What matters here is the team’s approach: If there’s a chemical that can prevent heart disease in mice by targeting their microbes, it may be possible to make a drug for humans that works the same way.
To be clear, the researchers aren’t trying to kill the microbes. Their substance isn’t an antibiotic; it just nudges the microbes’ behavior away from certain actions that negatively affect our health. “It’s a new approach to treating not just the individual Homo sapiens but also the microbes that live with us, and collectively contribute to disease,” says Hazen.
It takes two to TMAO: Bacteria first transform choline into TMA, before an enzyme from the host animal changes TMA into TMAO. At first, Hazen’s team tried to prevent the second part of this chain by blocking the animal enzyme. They succeeded, lowering TMAO levels in mice and making them resistant to atherosclerosis. But there was just one problem: Disabling the enzyme leads to a build-up of TMA, which doesn’t harm the heart but does smell of rotting fish.
So Wang went after the microbes instead. He identified a substance called DMB that looks a little like choline, and acts as a gobstopper. It gums up the enzymes that the bacteria normally use to digest choline, which prevents them from producing TMA.
When Wang laced his lab rodents’ drinking water with DMB, he found that the mice produced far less TMAO, even when they ate choline-rich food. And their arteries benefited: Even though these mice were genetically bred to be prone to atherosclerosis, they developed fewer signs of the disease.
“This study is of potentially groundbreaking significance,” says Marius Troseid from Oslo University Hospital, who also studies TMAO. “So far, interventions targeting gut microbes, including probiotics, antibiotics, and fecal transplantaion, have been non-specific,” taking a broader approach to manipulating the microbiome. By contrast, Wang and Hazen’s technique seems to target one particular bacterial process.
The usual caveat applies: The team have only looked at mice, so it’s not clear if DMB would work in the same way in humans. But Hazen argues that there’s good reason to think it would. His work on TMAO started in people—he was searching for chemicals that predicted the risk of heart disease. Since then, he has bounced back and forth between mice and humans, checking that the same microbial processes are at work in both species. And they are.
If DMB, or some other chemical like it, works in humans, it would carry several advantages. It seems safe—it’s naturally found in foods like balsamic vinegar, extra-virgin olive oil, and some red wine. It might also help to prevent diseases others than atherosclerosis, since TMAO has been linked to chronic kidney disease.