It turns out that even if you eat your fiber, your genes might be working against you when it comes to heart health. New research suggests that rare genetic variations can prevent the body from benefiting from the cardiovascular protection offered by gut microbes, potentially increasing the risk of high blood pressure and heart disease.
This groundbreaking study from Monash University, which looked at nearly 400,000 people, is the first to demonstrate in humans that the signaling of short-chain fatty acids (SCFAs)—substances produced when gut bacteria break down dietary fiber—can significantly protect against cardiovascular disease and hypertension. The findings, published in the journal Cardiovascular Research, indicate that this protection can be reduced by up to 20 percent if certain genetic variants are present.
The Gut-Heart Connection: More Than Just Digestion
The gut microbiome, a bustling community of trillions of microorganisms residing in our intestines, plays a surprisingly vital role in our overall health, including the health of our hearts. When we consume dietary fiber, which our bodies can’t digest, these gut bacteria get to work. They ferment the fiber, producing beneficial by-products known as short-chain fatty acids (SCFAs).
These SCFAs are more than just waste products; they are powerful signaling molecules that interact with our bodies. Previous studies, particularly in mice, have suggested that SCFAs help lower blood pressure and protect against issues like enlargement of the heart muscle and scarring of heart tissue. The proposed mechanism involves SCFAs binding to specific “receptor” proteins on our cells, which then activate anti-inflammatory signals.
When Genes Get in the Way: A Hidden Risk
This new study zeroed in on these SCFA-sensing “receptor” genes. The researchers hypothesized that if rare, faulty versions of these genes existed, they could disrupt the critical way our gut communicates with our body, thereby increasing the risk of heart disease. It’s like having a faulty receiver that can’t pick up the beneficial signals from your gut.
To explore this, the Monash team leveraged the vast resources of the UK Biobank, a comprehensive database containing health, lifestyle, and genetic information from nearly 400,000 participants. This enormous sample size allowed them to identify rare genetic variations that were predicted to negatively affect how these receptors work.
Dr. Leticia Camargo Tavares, the study’s lead author, highlighted the impact of these disruptions: “The study found that disruption in these receptors is associated with up to 20 percent increased prevalence of hypertension and heart disease or stroke – even after accounting for other risk factors like body weight and smoking.” Professor Marques added that “these rare genetic variants occur in less than 1 percent of individuals.”
How the Study Was Conducted: Digging Deep into Data
The researchers carefully analyzed the UK Biobank data. They identified individuals with high blood pressure and those who had experienced major adverse cardiac events, such as heart attacks, heart failure, and strokes, using various medical records.
They then used advanced statistical methods to see if there was a significant difference in the number of individuals carrying these rare genetic variations between those with health issues and healthy individuals.
To ensure their findings were accurate, they adjusted for various other factors that could influence heart health, such as age, sex, body mass, and even lifestyle choices like smoking. This careful process allowed them to pinpoint the specific effect of these genetic variations, confirming that the increased risk for heart problems among those with these genetic variations was independent of other well-known risk factors.
Key Findings: Fiber’s Benefit Undermined by Genetics
The results were compelling. The presence of these rare genetic variations was significantly higher in participants with high blood pressure and major heart events compared to those without these issues. Carrying these genetic variations in specific genes was strongly linked to an increased risk of heart failure and high blood pressure. These connections remained significant even after extensive statistical checks.
One of the most intriguing aspects of the study involved dietary fiber intake. Since beneficial SCFAs are primarily produced by gut bacteria when we eat fiber, the researchers investigated whether carrying these genetic variations increased the risk of high blood pressure and heart problems even in individuals who ate enough fiber.
They found that high blood pressure was significantly more common among individuals with these genetic variations, even when they consumed an adequate amount of fiber. This observation strongly indicates that the heart-protective benefits typically associated with fiber intake are lessened when there are genetic problems in the pathways that receive signals from SCFAs.
This research paves the way for new treatment options. The Monash team is already working on developing products to deliver SCFAs directly, and also aims to create drugs that can activate these specific receptors. Such developments could offer novel approaches to managing blood pressure and preventing heart disease.
Paper Summary
Methodology
The study analyzed health, lifestyle, and genetic data from nearly 400,000 individuals of white-European ancestry from the UK Biobank. Researchers identified rare genetic variations in specific genes (FFAR3, FFAR2, and HCAR2) that are involved in how our bodies use beneficial substances from gut bacteria. They then compared the prevalence of these genetic variations in people with high blood pressure and major heart events (like heart attacks, heart failure, and stroke) against healthy individuals. To ensure accuracy, they statistically adjusted for other factors that could influence heart health, such as age, sex, body mass, and lifestyle. The study also examined how these genetic variations interacted with dietary fiber intake.
Results
The study found that individuals with these rare genetic variations had a significantly higher risk of high blood pressure and major heart problems. This risk persisted even after accounting for other known risk factors. Specifically, genetic variations in HCAR2 were linked to an increased risk of heart failure, and variations in FFAR2 were associated with a higher risk of high blood pressure. Crucially, the research revealed that individuals with these genetic variations did not get the full heart-protective benefits from consuming enough dietary fiber, suggesting that their genes hindered the body’s ability to utilize beneficial signals from gut bacteria.
Limitations
The study primarily used data from individuals of white-European descent, meaning the findings might not apply equally to people of other ethnic backgrounds. The data on fiber intake relied on self-reported dietary recalls, which can sometimes be inaccurate. Because the genetic variations studied are rare, these findings apply to a small percentage of the population. The study shows a strong association, but it does not definitively prove that these genetic variations directly cause the heart conditions, although previous research supports the underlying mechanisms.
Funding and Disclosures
The research received funding from various sources, including a Senior Medical Research Fellowship and National Heart Foundation Fellowships. The authors stated they have no conflicts of interest. The data used was from the UK Biobank.
Publication Information
This research paper is titled “Rare pathogenic variants in G-protein coupled receptor genes involved in gut-to-host communication are associated with cardiovascular disease risk” and was authored by Leticia Camargo Tavares, Rikeish R. Muralitharan, Matthew Snelson, and Francine Z. Marques. It was posted as a preprint on medRxiv on January 29, 2025 (doi: https://doi.org/10.1101/2024.10.01.24314734). As a preprint, it has not yet undergone formal peer review.