Gut-heart axis: Scientists link bacterial metabolites to coronary disease risk

A new large-scale study involving participants from the US and China reveals eight specific metabolites — byproducts produced by gut bacteria — that are statistically associated with the risk of coronary heart disease. 

While the identified metabolites appear to be universal markers for heart disease across different ages and ethnicities, researchers noted that the baseline levels of these substances — and the intensity of their impact — can vary between US and Asian populations.

The human digestive tract naturally harbors a diverse array of microbes. The researchers highlight that people have different proportions of various gut microbes, which produce different molecules through their normal metabolic reactions.

These metabolites can enter the bloodstream and exert a broad range of effects, both beneficial and harmful, on human health. Certain gut microbe metabolites may be linked with a person’s risk of coronary heart disease, which is the world’s leading cause of death.

“These metabolites enter the bloodstream through the intestinal lining and influence heart health via modulating cardiometabolic risk factors, including systemic inflammation, blood lipids, blood pressure, glycemic control, liver function, and renal function,” lead author Danxia Yu of Vanderbilt University Medical Center, US, tells Nutrition Insight.

Yu believes these metabolites may eventually serve as biomarkers to help predict cardiovascular disease risk. “There is a high potential, as most of these metabolites are associated with disease risk beyond established cardiovascular risk factors.”

“They may serve as novel biomarkers to inform future mechanistic and interventional studies.”

Eight metabolites associated with risk

In the study published in PLOS Medicine, Yu and colleagues reported findings on the gut-heart axis and analyzed blood samples from several thousand Black, White, and Asian adults across the US and Shanghai, China.

Looking at data from nearly 2,000 of the participants, the researchers focused on nine gut microbe metabolites associated with the risk of developing coronary heart disease.

“Eight of these substances were associated with an increased risk,” says Yu. “For instance, 3-hydroxybutyrate and imidazole-propionate showed the strongest correlation, with each significant increase in their levels raising the likelihood of heart disease by roughly 27% and 26%, respectively.”

Future studies, including those based on animal models, could broaden the scope of identified gut microbes that impact heart health.

Other compounds, such as the gut-health marker trimethylamine N-oxide (TMAO) and 4-hydroxyhippuric acid, similarly posed higher risk. TMAO is formed when bacteria break down nutrients like choline and L-carnitine — abundant in red meat, eggs, and dairy — into trimethylamine, which the liver oxidizes into TMAO. 

Conversely, indolepropionate stood out as the lone protective factor in the group, with higher levels actually correlating to a roughly 11% reduction in heart disease risk.

Consistent link across ethnicities

Most of the links between metabolites and heart disease remained consistent across participants when taking into account lifestyle or family history. However, the researchers observed some differences when individuals were stratified by race or age.

“We did observe that some metabolite concentrations differ between US and Asian individuals, and some metabolites show varied associations across ethnic groups,” Yu explains.

“For example, 4-hydroxyphenylacetate and phenylacetyl-L-glutamine showed numerically stronger associations among Black than White or Asian participants; 1-methyl-4-imidazoleacetate was significant only among White participants; TMAO was significant only among US participants, not among Asian participants. We also found potential effect modification by age and obesity status.”

Based on their findings, the researchers call for follow-up research on the nine identified metabolites to determine whether they represent promising avenues for developing new ways to treat or prevent coronary heart disease.

“Although our findings provide comprehensive epidemiological evidence through a rigorous multi-stage study, the causal role of the highlighted microbial metabolites in coronary heart disease etiology and therapeutics remains to be investigated,” says Yu.

Future studies, including those based on animal models, could broaden the scope of identified gut microbes and the metabolic byproducts they produce. 

Previous research also found that certain metabolites can have a conversely positive effect on heart health. In February, researchers discovered that bacterial metabolites in the gut may affect the heart by interacting with specific neurons — illuminating new pathways connected to the brain.