There’s a silent process happening within many of us, even if we’re careful about diet and exercise, that could be setting the stage for serious heart trouble. For a long time, the spotlight has been on familiar culprits like high cholesterol and blood pressure when it comes to heart disease. But what if a tiny, unseen resident in your gut, one you’re likely unaware of, is playing a far more damaging role in a condition affecting millions?
Groundbreaking new research, published in the prestigious journal Nature, points to a surprising new player in the deadly progression of heart disease: a molecule called imidazole propionate, or ImP. Produced by your gut bacteria, this substance isn’t just an innocent bystander; it appears to be a direct cause of atherosclerosis, the stiffening and narrowing of arteries that leads to most heart attacks and strokes. The most compelling discovery? Even in mice on a normal, healthy diet, simply giving them ImP was enough to start the process of artery hardening, without any changes to their cholesterol levels. This indicates that ImP, a compound made exclusively by the microscopic world inside us, could be an independent and previously overlooked trigger for artery disease.
This finding opens up an exciting possibility: what if we could detect this hidden factor, ImP, in your blood long before significant damage occurs, and even stop its harmful effects? This study thoroughly investigates how ImP orchestrates its attack on your arteries and, even more remarkably, suggests a potential method to block its damaging influence.
Uncovering ImP: The Scientific Journey
Scientists began this investigation by studying mice genetically predisposed to developing atherosclerosis. These mice were given different diets, some high in cholesterol, and others also received antibiotics to clear out their gut bacteria. The goal was to see how diet and gut microbes affected artery hardening. They observed that a high-cholesterol diet did cause artery disease, but this was partly prevented when antibiotics were given, hinting at the involvement of gut bacteria.
To pinpoint the specific molecules involved, researchers used a technique called “untargeted metabolomics” to scan the mice’s blood for thousands of different substances. This broad search revealed that ImP, a byproduct of gut microbes, was strongly connected to atherosclerosis in mice on high-cholesterol diets. They also noticed that higher ImP levels were linked to changes in certain gut bacteria, particularly an increase in Escherichia and Shigella.
Would these findings apply to humans? To answer this crucial question, the research team then studied two large, independent groups of people. The first was the PESA cohort, consisting of 400 asymptomatic volunteers, aged 40 to 54, from a bank in Madrid, Spain. These participants underwent detailed imaging tests, such as ultrasound and CT scans, to check for early, “subclinical” atherosclerosis (meaning it hadn’t yet caused symptoms). Of this group, 295 showed signs of subclinical atherosclerosis, while 105 did not. Researchers carefully excluded anyone who had recently taken antibiotics or had known type 2 diabetes or intestinal disorders, to ensure the results weren’t skewed.
A second independent group, the IGT cohort, further confirmed these findings. This group included 529 healthy individuals and 1,315 with subclinical atherosclerosis. Researchers measured ImP levels in the blood plasma of all these human volunteers using highly precise methods.
The human studies involved comprehensive health assessments, including dietary habits and gut bacteria composition from stool samples. This extensive approach allowed scientists to see if ImP levels correlated with various health markers, dietary patterns, and specific types of gut bacteria. The study was careful to account for traditional risk factors like age, sex, smoking, and cholesterol levels when analyzing ImP’s association with atherosclerosis. This helped confirm that the link between ImP and artery disease was not just a side effect of other known problems.
ImP’s Impact: Inflammation and a New Treatment Path
The findings were remarkable. In both the PESA and IGT human groups, ImP levels were significantly higher in individuals with subclinical atherosclerosis compared to those without. This wasn’t just a small difference; higher ImP levels were independently tied to more severe atherosclerosis, even after accounting for well-known risk factors like age, smoking, and “bad” LDL cholesterol.
How does ImP cause this damage? The study uncovered a fascinating mechanism. When ImP was given to mice, it not only caused artery hardening but also ramped up their immune system, leading to widespread and localized inflammation. Inflammation is a key factor in the development of atherosclerosis. Specifically, researchers discovered that ImP triggers atherosclerosis by interacting with a particular protein called the imidazoline-1 receptor (I1R), found on certain immune cells called myeloid cells. One can consider I1R as a specific lock on these cells, with ImP being the key that fits into it, starting a chain reaction that promotes inflammation and artery damage.
This “ImP-I1R axis,” as the scientists called it, proved incredibly important. When they blocked this interaction in mice—either by genetically removing I1R from myeloid cells or by using a specific drug that inhibits I1R—it prevented the development of atherosclerosis, whether caused by ImP itself or by a high-cholesterol diet. This is a major breakthrough, as it points to a direct way to potentially intervene in the disease process.
The research also found that ImP was associated with an unhealthy “cardiometabolic profile” in humans, including higher blood sugar, increased C-reactive protein (a marker of inflammation), higher body mass index (BMI), more belly fat, unhealthy cholesterol levels, and high blood pressure. This suggests that ImP is involved in a broader range of metabolic issues that contribute to heart disease. Furthermore, the study noted a connection between lower ImP levels and healthier eating habits, such as those associated with “Breakfast” and “Mediterranean” dietary patterns. This indicates that healthy eating might somehow reduce ImP levels or counteract its effects, though more research is needed to confirm this.
What This Means for Your Heart Health
This research marks a significant leap in our understanding of atherosclerosis. The discovery of ImP as a substance from gut bacteria that directly causes artery hardening, even independently of cholesterol, offers a fresh perspective on preventing and treating heart disease. By identifying the specific cellular pathway—the ImP-I1R axis—through which this molecule acts, scientists have found a promising new target for treatment. We might soon see a future where a simple blood test for ImP could identify those at hidden risk, and a targeted treatment could block its harmful effects, protecting countless lives from the devastating impact of cardiovascular disease.
Paper Summary
Methodology
The study utilized atherosclerosis-prone ApoE mice, fed varying diets with or without antibiotics, to identify microbiota-derived metabolites linked to atherosclerosis. For human validation, two independent cohorts (PESA and IGT, total ~2,244 participants) were analyzed. Researchers measured plasma ImP levels and assessed subclinical atherosclerosis using advanced imaging. Gut microbiota composition and dietary patterns were also analyzed, with statistical models adjusting for traditional cardiovascular risk factors.
Results
Imidazole propionate (ImP), a gut microbiota metabolite, was strongly associated with atherosclerosis in both mice and humans. ImP alone induced atherosclerosis in mice, even without lipid changes, by activating immune responses and inflammation via the imidazoline-1 receptor (I1R) on myeloid cells. Blocking the ImP-I1R pathway prevented atherosclerosis in mice. In humans, higher ImP levels independently correlated with subclinical atherosclerosis and an adverse cardiometabolic profile.
Limitations
Further research is needed to identify specific ImP-producing bacterial strains. Establishing direct causation in human observational studies is complex. While numerous confounders were adjusted for, unmeasured factors could still influence associations. Human cohort sample sizes were based on availability.
Funding and Disclosures
Key funding was provided by the ‘la Caixa’ Foundation, Swedish Heart Lung Foundation, European Research Council, German Centre for Cardiovascular Research, Helmholtz-Institute for Translational AngioCardioScience, and NIH grants.
Paper Publication Info
Title: Imidazole propionate is a driver and therapeutic target in atherosclerosis Authors: Annalaura Mastrangelo et al. Journal: Nature DOI: 10.1038/s41586-025-09263-w Received: 1 June 2023 Accepted: 9 June 2025 Published online: 16 July 2025