Summary of Study ST003929

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR002461. The data can be accessed directly via it's Project DOI: 10.21228/M8J25F This work is supported by NIH grant, U2C- DK119886.

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This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST003929
Study TitleImidazole propionate is a driver and therapeutic target in atherosclerosis (study 1)
Study SummaryAtherosclerosis (AT) is the leading underlying cause of cardiovascular diseases (CVDs). While current preventive strategies focus on identifying and managing traditional cardiovascular risk factors, they often fail to detect individuals at risk of early-stage vascular disease. Recent studies have uncovered novel contributors to the pathophysiology of atherosclerosis, underscoring the need for alternative biomarkers and therapeutic targets to enhance early diagnosis and treatment. In this study, we identified a strong association between the microbial metabolite imidazole propionate (ImP) and atherosclerosis burden in mice. To explore the translational relevance of these findings in humans, we quantified ImP and its biosynthetic precursors (histidine and urocanic acid)in plasma samples from a subcohort of the PESA study (N = 400). Our analysis revealed a significant relationship between circulating ImP levels and the presence of subclinical atherosclerosis, supporting its potential role as a novel biomarker for early atherosclerotic disease.
Institute
Centro Nacional de Investigaciones Cardiovasculares Carlos III
Last NameMastrangelo
First NameAnnalaura
AddressCalle de Melchor Fernández Almagro, 3 – 28029, Madrid (Spain)
Emailamastrangelo@cnic.es
Phone+34914531202
Submit Date2025-05-23
Raw Data AvailableYes
Raw Data File Type(s)mzML
Analysis Type DetailLC-MS
Release Date2025-06-17
Release Version1
Annalaura Mastrangelo Annalaura Mastrangelo
https://dx.doi.org/10.21228/M8J25F
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:

Project:

Project ID:PR002461
Project DOI:doi: 10.21228/M8J25F
Project Title:Imidazole propionate is a driver and therapeutic target in atherosclerosis
Project Type:Original research
Project Summary:Atherosclerosis (AT) is the main underlying cause of cardiovascular diseases (CVDs). Its prevention is based on the detection and treatment of traditional cardiovascular risk factors (PMID:34120177) but often fails to identify individuals at risk for early vascular disease (PMID:25882487). Recent research has suggested new players in the pathophysiology of atherosclerosis (PMID: 33883728), highlighting the need for alternative disease biomarkers and therapeutic targets to improve early diagnosis and therapy efficacy. Here, we identified that microbially produced imidazole propionate (ImP) is associated with the extent of atherosclerosis in mice and in two independent human cohorts. Furthermore, ImP administration to atherosclerosis-prone mice fed chow diet was sufficient to induce atherosclerosis without altering the lipid profile, and it was linked to activation of both systemic and local innate and adaptive immunity and inflammation. Specifically, we found that ImP caused atherosclerosis through Imidazoline-1 receptor (I1R) expressed in myeloid cells. Blocking this ImP/I1R axis inhibited the development of atherosclerosis induced by ImP as well as by high cholesterol diet in mice. Identification of the strong association of ImP with active atherosclerosis, along with the discovery of the contribution of the ImP/I1R axis to disease progression opens new avenues for improving the early diagnosis and personalized therapy of atherosclerosis.
Institute:Centro Nacional de Investigaciones Cardiovasculares Carlos III
Last Name:Mastrangelo
First Name:Annalaura
Address:Calle de Melchor Fernández Almagro, 3 – 28029, Madrid (Spain)
Email:amastrangelo@cnic.es
Phone:(+34) 914531202

Subject:

Subject ID:SU004065
Subject Type:Human
Subject Species:Homo sapiens
Taxonomy ID:9606
Gender:Male and female

Factors:

Subject type: Human; Subject species: Homo sapiens (Factor headings shown in green)

mb_sample_id local_sample_id AT FDG Sample source
SA445852R4_F9_10 1 plasma
SA445853R4_E12_10 1 plasma
SA445854R4_E8_10 1 plasma
SA445855R4_E9_10 1 plasma
SA445856R4_F10_10 1 plasma
SA445857R4_F11_10 1 plasma
SA445858R4_F12_10 1 plasma
SA445859R1_H5_10 1 plasma
SA445860R4_F3_10 1 plasma
SA445861R1_H11_10 1 plasma
SA445862R4_F8_10 1 plasma
SA445863R4_G11_10 1 plasma
SA445864R4_E10_10 1 plasma
SA445865R4_G12_10 1 plasma
SA445866R4_G8_10 1 plasma
SA445867R4_G9_10 1 plasma
SA445868R4_H10_10 1 plasma
SA445869R4_H11_10 1 plasma
SA445870R1_G1_10 1 plasma
SA445871R4_H12_10 1 plasma
SA445872R4_H8_10 1 plasma
SA445873R4_H9_10 1 plasma
SA445874R5_A1_10 1 plasma
SA445875R5_A2_10 1 plasma
SA445876R4_E11_10 1 plasma
SA445877R4_D9_10 1 plasma
SA445878R5_B1_10 1 plasma
SA445879R4_A12_10 1 plasma
SA445880R3_A8_10 1 plasma
SA445881R3_B3_10 1 plasma
SA445882R2_D4_10 1 plasma
SA445883R3_D2_10 1 plasma
SA445884R3_F10_10 1 plasma
SA445885R3_F2_10 1 plasma
SA445886R3_F9_10 1 plasma
SA445887R2_C4_10 1 plasma
SA445888R3_G8_10 1 plasma
SA445889R4_A10_10 1 plasma
SA445890R4_A11_10 1 plasma
SA445891R4_A9_10 1 plasma
SA445892R4_D8_10 1 plasma
SA445893R4_B10_10 1 plasma
SA445894R4_B11_10 1 plasma
SA445895R4_B9_10 1 plasma
SA445896R4_C10_10 1 plasma
SA445897R4_C11_10 1 plasma
SA445898R4_C12_10 1 plasma
SA445899R4_C8_10 1 plasma
SA445900R4_C9_10 1 plasma
SA445901R4_D10_10 1 plasma
SA445902R4_D11_10 1 plasma
SA445903R4_D12_10 1 plasma
SA445904R5_A3_10 1 plasma
SA445905R4_G10_10 1 plasma
SA445906R5_B2_10 1 plasma
SA445907R1_B2_10 1 plasma
SA445908R7_C2_10 1 plasma
SA445909R7_C3_10 1 plasma
SA445910R7_C4_10 1 plasma
SA445911R7_C5_10 1 plasma
SA445912R7_D1_10 1 plasma
SA445913R7_D2_10 1 plasma
SA445914R1_C1_10 1 plasma
SA445915R1_B9_10 1 plasma
SA445916R7_D3_10 1 plasma
SA445917R7_D4_10 1 plasma
SA445918R5_C1_10 1 plasma
SA445919R7_E1_10 1 plasma
SA445920R7_E2_10 1 plasma
SA445921R7_B5_10 1 plasma
SA445922R7_E3_10 1 plasma
SA445923R7_E4_10 1 plasma
SA445924R7_F1_10 1 plasma
SA445925R7_F2_10 1 plasma
SA445926R7_F3_10 1 plasma
SA445927R7_G2_10 1 plasma
SA445928R7_G3_10 1 plasma
SA445929R7_G4_10 1 plasma
SA445930R7_H1_10 1 plasma
SA445931R7_H2_10 1 plasma
SA445932R7_H3_10 1 plasma
SA445933R7_H4_10 1 plasma
SA445934R7_C1_10 1 plasma
SA445935R7_D5_10 1 plasma
SA445936R5_E1_10 1 plasma
SA445937R1_D5_10 1 plasma
SA445938R5_D1_10 1 plasma
SA445939R1_E3_10 1 plasma
SA445940R5_E2_10 1 plasma
SA445941R5_C2_10 1 plasma
SA445942R5_F1_10 1 plasma
SA445943R5_F2_10 1 plasma
SA445944R5_G1_10 1 plasma
SA445945R5_D2_10 1 plasma
SA445946R5_H1_10 1 plasma
SA445947R5_H2_10 1 plasma
SA445948R5_G2_10 1 plasma
SA445949R7_B2_10 1 plasma
SA445950R7_A3_10 1 plasma
SA445951R7_A4_10 1 plasma
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Collection:

Collection ID:CO004058
Collection Summary:This study was conducted in a subset of participants (n=400) from the PESA study (Progression of Early Subclinical Atherosclerosis) (PMID: 34238438). The PESA-CNIC-Santander (NCT01410318) is an ongoing observational prospective cohort study of 4,184 asymptomatic employees of the Santander Bank in Madrid (subjects from 40 to 54 years of age and free of known CVD at baseline in 2009). In addition to the exclusion criteria followed in the main study (PMID: 25882487), subjects taking antibiotics in the three months prior to the sample collection, with known Type 2 diabetes or treated for diabetes and/or intestinal disorders were excluded from our study. This allowed removing possible confounding effects due to the role of ImP in diabetes and insulin resistance (PMID: 30401435) and to the modification of gut microbiota possibly affecting the production of ImP. Subclinical atherosclerosis was assessed by imaging studies including 2D and 3D vascular ultrasonography of carotid and iliofemoral arteries and presence of coronary artery calcium assessed by CT scan, as previously described (PMID: 24268213). Subjects with subclinical atherosclerosis underwent a whole body 18F-FDG PET/MRI study to characterize arterial 18F-FDG uptake and bone marrow metabolic activity, as described (PMID: 30922468 and PMID: 35567559). This information was used to further stratify subjects with subclinical atherosclerosis in: inactive atherosclerosis (FDGneg, n=74), arterial 18 F-FDG uptake (FDG+_A, n=57), bone marrow activation (FDG+_BM, n=40), and both arterial uptake and bone marrow activation (FDG+_SYS, n=124) as indicatives of metabolically active atherosclerosis (FDG+, n=221). For the metabolomic analysis, peripheral blood samples collected after overnight fasting were centrifuged at 2,750 x g at RT for 10 minutes to obtain plasma that was further aliquoted and stored at -80°C. The institutional ethics committee approved the study protocol, and all participants were provided with written informed consent.
Sample Type:Blood (plasma)

Treatment:

Treatment ID:TR004074
Treatment Summary:No therapeutic interventions were applied to participants. The study was observational.

Sample Preparation:

Sampleprep ID:SP004071
Sampleprep Summary:For the PESA cohort, individual 1000PPM stock solutions of ImP (Sigma-Aldrich 77951), urocanic acid (Urocanic acid-1,2,3-13C3, Sigma-Aldrich: 709638) and histidine (L-Histidine-d3 hydrochloride monohydrate, Sigma-Aldrich:791318) were prepared in ultrapure water and stored at -20ºC. Their respective dilutions were then prepared in MeOH/EtOH (1:1, v/v) and stored at 4ºC. For the PESA cohort, 65 μL of MeOH/EtOH (1:1, v/v) were added to 50 μL of plasma sample and 35 μL of isotopic labeled internal standards in MeOH/EtOH (IS) (urocanic acid and histidine). Samples were vortex-mixed for 10 seconds and then centrifuged at 13,000 rpm for 20 minutes at 4ºC. 100 μL of supernatant were taken and transferred to LC vials for the analysis

Chromatography:

Chromatography ID:CH004898
Instrument Name:Agilent 1290 Infinity
Column Name:InfinityLab Poroshell 120 HILIC-Z column (150 x 2.1 mm, 2.7 μm)
Column Temperature:25ºC
Flow Gradient:The initial conditions at time 0 were 100 % B, decreasing to 70 % at 11.5 min. The gradient was then increased to 100 % B at time 12.0 min and held until the total run time of 15 min.
Flow Rate:0.50 mL/min
Solvent A:100% Water; 20 mM Ammonium formate (pH 3)
Solvent B:90% Acetonitrile/10% Water; 20 mM aqueous Ammonium formate (pH 3)
Chromatography Type:HILIC

Analysis:

Analysis ID:AN006452
Analysis Type:MS
Chromatography ID:CH004898
Num Factors:5
Num Metabolites:3
Rt Units:Minutes
Units:nMol
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