Top: Aortas from mice treated with the bacterial metabolite imidazole propionate (ImP) and a drug that blocks its pro-atherogenic effect. Atherosclerotic plaques are stained red. Bottom: Aortas from mice fed a high-cholesterol diet to induce atherosclerosis over 8 weeks and treated with the ImP-blocking drug during the final 4 weeks. Atherosclerotic plaques are stained red. Credit: CNIC

Cardiovascular disease is the leading cause of death worldwide and often originates in atherosclerosis, a chronic condition in which inflammation and fat deposits cause arteries to harden and narrow. Although clinical practice already targets causal factors like cholesterol, hypertension, and smoking, detecting atherosclerosis in its early stages remains challenging.

A new study led by the Centro Nacional de Investigaciones Cardiovasculares (CNIC) and published in Nature has identified a gut microbiota–derived metabolite, imidazole propionate (ImP), that appears in the blood during the early stages of active atherosclerosis.

"This metabolite is uniquely produced by intestinal bacteria, " explains CNIC researcher Annalaura Mastrangelo, one of the study's two first authors. "Our study shows that its presence in the bloodstream is associated with the development of active atherosclerosis in people who otherwise appear healthy."

Mastrangelo emphasizes that the discovery has important clinical implications. "Detecting this blood marker offers a major advantage because current diagnostic tools rely on advanced imaging techniques that are complex, expensive, and not covered by public health systems. Blood levels of ImP provide a diagnostic marker that could help identify apparently healthy individuals with active atherosclerosis, and thus enable earlier treatment."

But the discovery goes even further. Co–first author Iñaki Robles-Vera explains, "We not only observed elevated ImP levels in people with atherosclerosis, but also showed that ImP itself is a causal agent of the disease. In animal models of atherosclerosis, ImP administration led to the formation of arterial plaques. It does this by activating the imidazoline receptor type 1 (I1R), which increases systemic inflammation and promotes atherosclerosis development."

David Sancho, head of the CNIC Immunobiology Laboratory and lead author on the study, notes that "this discovery is important because it opens the way to a completely new line of treatment."

The study shows that blocking the I1R receptor prevents ImP-induced atherosclerosis and slows disease progression in mouse models fed a high-cholesterol diet. "This suggests that future treatment could combine I1R blockade with cholesterol-lowering drugs to produce a synergistic effect that prevents atherosclerosis development, " explains Sancho.

"These findings open new possibilities for the early detection and personalized treatment of atherosclerosis, " he continues. "Instead of focusing solely on cholesterol and other classic risk factors, we may soon be able to analyze blood for ImP as an early warning signal. At the CNIC, we are also working to develop drugs that block the detrimental effects of ImP."

More information: David Sancho, Imidazole propionate is a driver and therapeutic target in atherosclerosis, Nature (2025). DOI: 10.1038/s41586-025-09263-w. www.nature.com/articles/s41586-025-09263-w  Journal information: Nature