Article Impact Level: HIGH Data Quality: STRONG Summary of Nature, 1–8. https://doi.org/10.1038/s41586-025-09263-w Dr. Annalaura Mastrangelo et al.
Points
- A gut microbiota-produced metabolite, imidazole propionate, is strongly associated with the extent of atherosclerosis in both humans and mice, serving as a potential new disease biomarker.
- Administering imidazole propionate to atherosclerosis-prone mice was sufficient to induce the disease without altering cholesterol levels, demonstrating a direct causal relationship with plaque formation.
- The metabolite promotes atherosclerosis by activating the imidazoline-1 receptor on myeloid cells, which in turn triggers both systemic and local inflammation and detrimental immune responses.
- Blocking the interaction between imidazole propionate and its I1R receptor successfully inhibited atherosclerosis development in mouse models, suggesting a novel therapeutic strategy for human patients.
- This discovery could lead to a new blood test for early atherosclerosis diagnosis and personalized therapies that target the ImP–I1R pathway to prevent disease progression.
Summary
A recent study has identified the gut microbiota-derived metabolite imidazole propionate (ImP) as a novel biomarker and causal agent in the pathophysiology of atherosclerosis. While prevention typically relies on addressing traditional risk factors¹, many individuals at risk remain unidentified². This research demonstrated a strong association between circulating ImP levels and the extent of atherosclerosis in both mouse models and two independent human cohorts. The findings suggest that ImP could serve as a valuable biomarker for detecting active, early-stage vascular disease, offering a potential advantage over complex and costly imaging techniques for identifying individuals who appear healthy but have subclinical atherosclerosis.
The study established a direct causal role for ImP in disease progression. In atherosclerosis-prone mice fed a standard chow diet, administration of ImP was sufficient to induce atherosclerosis development without altering the lipid profile. This effect was found to be mediated through the activation of both systemic and local innate and adaptive immunity. The specific mechanism involves ImP binding to the imidazoline-1 receptor (I1R, also known as nischarin) on myeloid cells. This activation of the ImP–I1R axis triggers an inflammatory cascade that directly contributes to the formation of atherosclerotic plaques.
These findings present a new therapeutic target for cardiovascular disease. In preclinical models, blocking the ImP–I1R axis successfully inhibited the development of atherosclerosis induced by both ImP administration and a high-cholesterol diet. This suggests that future therapeutic strategies could involve I1R antagonists, potentially in combination with current cholesterol-lowering drugs, to achieve a synergistic effect in preventing or slowing disease progression. The identification of this pathway opens new avenues for improving the early diagnosis and personalized treatment of atherosclerosis beyond traditional risk factor management.
Link to the article: https://www.nature.com/articles/s41586-025-09263-w
References Mastrangelo, A., Robles-Vera, I., Mañanes, D., Galán, M., Femenía-Muiña, M., Redondo-Urzainqui, A., Barrero-Rodríguez, R., Papaioannou, E., Amores-Iniesta, J., Devesa, A., Lobo-González, M., Carreras, A., Beck, K. R., Ivarsson, S., Gummesson, A., Georgiopoulos, G., Rodrigo-Tapias, M., Martínez-Cano, S., Fernández-López, I., … Sancho, D. (2025). Imidazole propionate is a driver and therapeutic target in atherosclerosis. Nature, 1–8. https://doi.org/10.1038/s41586-025-09263-w
