Imidazole propionate: a novel driver of atherosclerosis and biomarker of subclinical diseases

Cardiovascular disease remains the leading cause of death worldwide, but its pathogenesis is not yet fully understood, hampering the development of effective early diagnostics and treatments. Despite regular treatments that target traditional risk factors such as cholesterol levels, many patients face cardiovascular events. Emerging evidence suggests that chronic inflammation and the gut microbiome contribute to the development of atherosclerosis, identifying early markers of the condition in asymptomatic individuals.

Recent findings published in Nature¹ show that the gut microbiota-derived metabolite imidazole propionate contributes to atherosclerosis and could be a useful marker of early active atherosclerosis.

Using an unbiased metabolomics approach, the authors first screened atherosclerosis-prone ApoE knockout (ApoE^–/–) mice, the most commonly used mouse model for the development of atherosclerosis and are characterized by elevated total plasma cholesterol levels, for microbial metabolites involved in early atherosclerosis. The gut microbiota-derived metabolite ImP was associated with early-stage disease. ImP is a metabolite resulting from microbial histidine metabolism that has been associated with type 2 diabetes, coronary artery disease, and heart failure².

Plasma levels of ImP were also increased in two separate cohorts of Spanish and Swedish individuals with subclinical atherosclerosis compared with healthy volunteers and correlated with early-stage atherosclerosis, even after adjustment for classical risk factors including body mass index, fasting glucose and blood pressure. Moreover, plasma IMP levels were increased in subjects with subclinical metabolically active atherosclerosisas evidenced by increased arterial uptake of 18F-fluorodeoxyglucose, and ImP improved risk stratification when added to conventional cardiovascular markers. As David Sancho, the study’s corresponding author, notes in an accompanying research highlight Nature Cardiovascular Research³“What makes this finding clinically significant is that ImP appears to act early in the disease process. This opens the door to earlier detection strategies, especially in individuals otherwise considered low risk by traditional metrics.”

To investigate whether ImP was causally involved in the development of atherosclerosis, ImP was administered orally into atherosclerosis-prone ApoE.^–/– and LDL receptor knockout (Ldr^–/–) mice. ImP induced the development of plaque buildup in the aorta and aortic root in both mouse models without altering cholesterol and glucose blood levels. It was found that ImP supplementation activated pro-inflammatory pathways in macrophages and fibroblasts, which was associated with increased T cell infiltration and expansion of pro-inflammatory monocytes, with the mTOR pathway being a key downstream effector of ImP-induced atherogenic activity. However, blocking the ubiquitously expressed imidazoline receptor I1R with I1R antagonist AGN192403 prevented plaque formation and slowed disease progression, even when mice were fed a high-cholesterol diet. As discussed by the authorsThese findings suggest a novel therapeutic potential by combining I1R blockade with cholesterol-lowering drugs to produce a synergistic effect that prevents the development of atherosclerosis, further advancing the potential role of precision medicine in targeting the microbiome for the treatment of cardiovascular disease, especially in apparently healthy individuals with subclinical inflammation and atherosclerosis.

These findings highlight that ImP may act as both a marker for early active atherosclerosis and an active driver of atherosclerosis. They also support the potential role of ImP in disease risk assessment and stratification, adding diagnostic value beyond traditional cardiovascular risk factors such as LDL cholesterol, and the potential role of targeting the imidazole propionate-I1R axis in the treatment of atherosclerosis.

References:

1. Mastrangelo A, Robles-Vera I, Mañanes D, et al. Imidazole propionate is a driver and therapeutic target in atherosclerosis. Nature. 2025; 645(8079):254-261. doi:10.1038/s41586-025-09263-w.
2. Molinaro A, Lassen PB, Henry M, and to the. Imidazole propionate is increased in diabetes and is associated with dietary patterns and altered microbial ecology. Wet Common. 2020; 11(1):5881. doi:10.1038/s41467-020-19589-w.
3. Martini E. Imidazole propionate promotes the formation of atherosclerotic plaques. Nat Cardiovasc Res. 2025; 4(9):1035. two: 10.1038/s44161-025-00706-1.