Mastrangelo, AnnalauraRobles-Vera, IñakiMañanes, DiegoGalán, MiguelFemenía-Muiña, MarcosRedondo-Urzainqui, AnaBarrero-Rodríguez, RafaelPapaioannou, EleftheriaAmores-Iniesta, JoaquínDevesa, AnaLobo-González, ManuelCarreras, AlbaBeck, Katharina RIvarsson, SophieGummesson, AndersGeorgiopoulos, GeorgiosRodrigo-Tapias, ManuelMartínez-Cano, SaraiFernández-López, IvanNuñez, VanessaFerrarini, AlessiaInohara, NaohiroStamatelopoulos, KimonBenguría, AlbertoCibrian, DanaySánchez-Madrid, FranciscoAlonso-Herranz, VanesaDopazo, AnaBarbas, CoralVázquez, JesúsLópez, Juan AntonioGonzález-Martín, AliciaNuñez, GabrielStellos, KonstantinosBergström, GöranBäckhed, FredrikFuster, ValentínIbañez, BorjaSancho, David2025-07-302025-07-302025-07-16Nature. 2025 Jul 16.https://hdl.handle.net/20.500.12105/26847Atherosclerosis is the main underlying cause of cardiovascular diseases. Its prevention is based on the detection and treatment of traditional cardiovascular risk factors. However, individuals at risk for early vascular disease often remain unidentified. Recent research has identified new molecules in the pathophysiology of atherosclerosis, highlighting the need for alternative disease biomarkers and therapeutic targets to improve early diagnosis and therapy efficacy. Here, we observed that imidazole propionate (ImP), produced by microorganisms, is associated with the extent of atherosclerosis in mice and in two independent human cohorts. Furthermore, ImP administration to atherosclerosis-prone mice fed with chow diet was sufficient to induce atherosclerosis without altering the lipid profile, and was linked to activation of both systemic and local innate and adaptive immunity and inflammation. Specifically, we found that ImP caused atherosclerosis through the imidazoline-1 receptor (I1R, also known as nischarin) in myeloid cells. Blocking this ImP-I1R axis inhibited the development of atherosclerosis induced by ImP or high-cholesterol diet in mice. Identification of the strong association of ImP with active atherosclerosis and the contribution of the ImP-I1R axis to disease progression opens new avenues for improving the early diagnosis and personalized therapy of atherosclerosis.The authors thank M. C. Collado for mouse gut microbiota analysis; M. O. Garmendia for assistance with the metadata from volunteers; members of the D.S. laboratory for help with discussions and critical reading of the manuscript; and the CNIC facilities, foremost the animal, cellomics, histology, metabolomics, genomics, microscopy, clinical trial and bioinformatics facilities, and personnel for assistance. I.R.-V. is funded by FJC2021-048099-I funded by MCIN/AEI/10.13039/501100011033 and European Union NextGenerationEU/PRTR. D.M. is funded by grant PRE2020-092578 MCIN/AEI/10.13039/501100011033. M.G. is funded by beca de formación de profesorado Universitario fellowship 20/01418. M.F.-M. is funded by INPhINIT Retaining 2024 from Caixa Foundation LCF/BQ/DR24/12080010. A.R.-U. is supported by Community of Madrid (PIPF-2022/SALGL-24581). R.B.-R. is funded by Beca de Formación de Profesorado Universitario Fellowship 20/03365. A. Devesa is scientifically supported by the Thrasher Research Fund and acknowledges the support of Sociedad Española de Cardiología (grant SEC/PRS-MOV-INT20/002). Work in the D.S. laboratory is funded by the CNIC; the European Union’s Horizon 2020 Research and Innovation Program under grant agreement ERC-2016-Consolidator Grant 725091; Ministerio de Ciencia, Innovación y Universidades (MICIU) PID2022-137712OB-I00, CPP2021-008310 and CPP2022-009762 MICIU/AEI/10.13039/501100011033 Agencia Estatal de Investigación, Unión Europea NextGenerationEU/PRTR; Comunidad de Madrid (P2022/BMD-7333 INMUNOVAR-CM); Scientific Foundation of the Spanish Association Against Cancer (AECC- PRYGN246642SANC); Worldwide Cancer Research WWCR-25-0080; European Union ERC-2023-PoC; a research agreement with Inmunotek S.L.; and la Caixa Foundation (LCF/PR/HR23/52430012 and LCF/PR/HR22/52420019). Work in the B.I. laboratory is supported by the European Commission (H2020-HEALTH 945118 and ERC-CoG 819775); the PID2022-140176OB-I00, PID2019-107332RB-I00 MCIN/AEI /10.13039/501100011033; and the Comunidad de Madrid RENIM P2022/BMD-7403. F.B. is funded by grants from the Swedish Heart Lung Foundation (20240882) and is a Wallenberg Fellow and recipient of an ERC-Advanced grant 2022 (101096705-IMPACT). K. Stellos was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation — Project ID 394046768 — SFB1366 ‘Vascular control of organ function’ C07), the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (MODVASC, grant agreement 759248), the German Centre for Cardiovascular Research (DZHK) and the Helmholtz-Institute for Translational AngioCardioScience (HI-TAC) of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) at Heidelberg University, Heidelberg, Germany. Metabolomics Workbench is supported by NIH grant U2C-DK119886 and OT2-OD030544 grants. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the MICIU and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (CEX2020-001041-S funded by MICIU/AEI /10.13039/501100011033). The PESA study is funded by the CNIC and Santander Bank. This study was partially funded by an intramural grant CNIC-Severo Ochoa to B.I. and D.S.engVoR40670786Natureopen access