Early Studies Linking Gut Bacteria to Atherosclerosis, Offer Tantalizing Glimpse at New Drug Target

Researchers have identified a small molecule that inhibits the metabolism of microbiota previously linked to heart disease and atherosclerosis, lending hope that selectively targeting the pathway could reduce the cardiovascular risks believed associated with bacteria in the gut.

“This is the first time whereby specifically inhibiting a bacterial pathway, we’re inhibiting the development or progression of atherosclerotic heart disease,” said Stanley Hazen, MD, PhD, Cleveland Clinic. “An analogy is where Helicobacter pylori was discovered to be linked to the development of ulcers. We now actually treat ulcers in patients who are Helicobacter pylori-positive with an antibiotic cocktail to kill the Helicobacter pylori.”

Unlike H. pylori and ulcers, the researchers say the newly identified compound does not kill the gut microbes but rather blocks a specific microbial pathway that generates a metabolite known as trimethylamine-N-oxide (TMAO).

Speaking with TCTMD, Hazen explained that animal products in general, including red meat and high-fat dairy products, are rich in choline and carnitine and their previous research showed that microbes in the gut convert these nutrients into a compound known as trimethylamine (TMA). With the help of a liver enzyme, TMA is converted into TMAO. In 2011, the group,  including lead author Zeneng Wang, PhD, Cleveland Clinic, showed, in a mouse model, that a diet rich in TMAO increased atherosclerosis. The TMAO story progressed further with additional research groups showing in multiple cohorts that serum TMAO levels were predictive of cardiovascular disease and major adverse cardiac events.

Given the established role of TMAO, researchers have attempted to block the enzyme that converts TMA to TMAO. They found that this successfully inhibits atherosclerosis but that inhibiting the enzyme also has several adverse side effects, including liver inflammation. The buildup of TMA also results in a noxious fish odor.

“More recently, as were done with the obesity and diabetes studies, the atherosclerosis studies were able to show that if you transplant microbes that have different capabilities for making TMA, which is the precursor for TMAO, you can transplant the capability of making TMAO and atherosclerosis susceptibility into a recipient,” said Hazen. “The higher the TMAO, the more extensive the atherosclerotic plaque development.”

Identifying a Compound

In the present study, which is published December 17, 2015 in Cell,  instead of targeting the conversion of TMA to TMAO, the researchers targeted the microbial pathway with a small molecule known as 3,3-dimethyl-1-butanol (DMB), a compound similar in structure to choline. DMB is present in some cold-pressed extra virgin olive oils, grapeseed oils, and to a lesser extent, red wine and some balsamic vinegars, said Hazen.

In a series of experiments, the researchers showed that DMB is a potent inhibitor of TMA lyases, the enzymes that mediate the metabolism of choline to TMA in the gut. DMB inhibited the formation of TMA in cultured microbes and also inhibited TMA production from cultures obtained from the intestine and human feces. In animal models, they showed DMB reduced TMAO levels in mice fed a diet rich in choline or carnitine. In the mice, DMB inhibited the formation of cholesterol-laden macrophage foam cells, a hallmark of atherosclerosis, resulting from the choline-rich diet without affecting circulating cholesterol levels. Importantly, they also showed DMB inhibited atherosclerosis development in animal models.

“The novel part here is that we’re trying to inhibit just the pathway and not the lifespan of the bug,” said Hazen. “In a nutrient-rich environment, like inside the gut, we find that when we give the inhibitor, we can block TMA production without affecting the growth and replication of the microbes.”

Annika Lindskog Jonsson, PhD, and Fredrik Bäckhed, from the University of Gothenburg, Sweden, point out that the normal gut microbiota is a major regulator of host metabolism and has been causally linked not only to atherosclerosis but also to fat gain and impaired glucose metabolism. “Direct targeting of the gut microbiome could represent a novel and attractive platform to treat cardiometabolic disease,” they write in an accompanying editorial.

Like Hazen, they agree that targeting the choline-to-TMAO pathway “seems to be an effective target for treating atherosclerotic disease” without depleting the entire gut microbial community. Given that the drug blocked the pathway without killing the microbe means there should be “less selective pressure” of resistance against a potential drug therapy targeting the gut’s TMAO-formation pathway than with an antibiotic, added Hazen.

Hazen also noted that a recent study looking at adherence to the Mediterranean diet that urinary TMAO concentrations decrease in a dose-dependent manner in individuals with better adherence to the Mediterranean diet. This piece of the puzzle makes sense given the presence of DMB in extra virgin olive oil and grapeseed oil, he said.