RPVs in SCFA-sensing GPCR genes are associated with poor cardiovascular outcomes. Credit: Cardiovascular Research (2025). DOI: 10.1093/cvr/cvaf070

A Monash University study of almost 400, 000 people, published in the journal Cardiovascular Research, is the first to indicate, in humans, that the signaling of substances called short-chain fatty acids or SCFAs, released when gut bacteria break down dietary fiber, significantly protects against cardiovascular disease and hypertension by up to 20%.

A previous clinical trial by the Monash team, led by Professor Francine Marques, has shown that these SCFAs—when provided as a supplement—lead to lowered blood pressure. Another trial is underway.

The current study used data from the UK Biobank database and found rare genetic variants that profoundly impact the function of receptors that bind to SCFAs essentially prevent people from utilizing the cardiovascular protection offered by their own gut microbes.

"We wanted to determine whether people with these genetic modifications had an increased risk of hypertension and major adverse cardiac events, including acute coronary syndrome, heart failure, and ischemic stroke, " said Professor Marques.

For this, the researchers compared individuals with these genetic variants and their cardiovascular medical history to controls, finding that this affected cohort had a significantly higher incidence of hypertension and long-term risk of cardiovascular disease, including heart attacks, heart failure and stroke.

Dr. Leticia Camargo Tavares was the leading author of the study.

"The study found that disruption in these receptors is associated with up to 20% increased prevalence of hypertension and heart disease or stroke—even after accounting for other risk factors like body weight and smoking, " Dr. Tavares said.

"However, it is worth mentioning these rare genetic variants occur in less than 1% of individuals, " Professor Marques said.

Importantly, the researchers also looked into what happened to this affected cohort—without the cardioprotective capacity—when fiber intake followed dietary guidelines.

"If they consumed adequate dietary fiber, but were unable to turn this into protection against heart disease, then this would prove the importance of short-chain fatty acids signaling in cardio-protection, " Professor Marques said.

"Consistent with our hypothesis, the prevalence of hypertension was significantly higher in this cohort, even among those who ate a diet rich in fiber, " Dr. Tavares added.

The research team is currently in the process of developing a commercially available product that can deliver SCFAs orally. In addition, the team aims to develop drugs that activate these receptors, which may provide a novel way to lower blood pressure and prevent heart disease.

More information: Leticia Camargo Tavares et al, Rare pathogenic variants in G-protein-coupled receptor genes involved in gut-to-host communication are associated with cardiovascular disease risk, Cardiovascular Research (2025). DOI: 10.1093/cvr/cvaf070  Journal information: Cardiovascular Research