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Paper cited: Mastrangelo, A., Robles-Vera, I., Mañanes, D. et al. Imidazole propionate is a driver and therapeutic target in atherosclerosis. Nature 645, 254–261 (2025). https://doi.org/10.1038/s41586-025-09263-w

Transcript for the Podcast

Transcript: Introduction for our podcast: Welcome to Mirroring Medicine with Kodi and Isabel! In this episode of Mirroring Medicine, we will be going over our first journal club together from an article called “Imidazole propionate is a driver and therapeutic target in atherosclerosis” found in Nature Journal Articles by Mastrangelo et al. We will review this article in depth, its implications, and give you the tools to go over articles. If you have any medical questions about healthcare, please contact your nearest doctor. As we have stated in previous episodes, we are just touching the tip of the iceberg when it comes to this information, and this podcast does not constitute medical advice. If you would like to learn more, we encourage you to explore the diverse journal articles with your scientific curiosity. 

Background Information: 

Defining Key Terms: 

Going into Key terms, I wanted to go over some complicated diction and vocabulary that might need elaboration to understand this article. Firstly, I will go over atherosclerosis. Atherosclerosis, according to the NIH (https://www.nhlbi.nih.gov/health/atherosclerosis), is a common disease that manifests when a plaque (substance made up of fat, cholesterol, calcium, and other substances in the blood which commonly hardens up in the arteries, reducing blood flow in the process and makes it more likely to block oxygen delivery to key organs) builds up in the arteries. For example, think of a dam for water. The more sticks that are put in place for the dam, the more blockage of water and water flow. For this metaphor, the dam is the plaque and the water is the blood flow.  

What is a metabolite and what is the definition of it? A metabolite is a substance formed as a result of metabolism or necessary for metabolism. Metabolism is a complex series of biochemical reactions happening within the organism to convert small molecules into energy. Metabolomics is the comprehensive study of metabolites. 

What does pathophysiology mean? This means the abnormal processes in the body that pertains to disease and/or injury

TMAO, trimethylamine N-oxide is a host-microbial metabolite which is significant due to its association with cardiovascular disease. 

What is a control: A control is a subject or thing that is not altered by scientists. For example, if you wanted to tell if a drink is sweet and its base is water, we can use a control of water to compare with the other drink to determine if it is sweet. 

Methods that they used is RNA-seq, the purpose of RNA seq is to sequence RNA and determine the transcriptome or the quantification of RNA molecules, to determine transcription levels. They first extract RNA from molecules, convert to cDNA, fragment, and sequence through mapping. Kind of think of it as putting puzzle pieces together for find and understand the whole picture. 

What is Imidazole propionate: Imidazole propionate is microbially produced and is derived from histidine. The amino acid histadine is characterized by an imidazole which is a carbon ring containing two nitrogen atoms. To further understand this description it would be best to refer to an image of histidine. The metabolite of imidazole propionate (ImP) is a by product of the microbiota and interestingly contributes to not only atherosclerosis but type 2 diabetes (Nageswaran et al & Mastrangelo et al.)

How to Look Through an Article: 

Abstract: 

First sentence: Atherosclerosis is the main underlying cause of cardiovascular diseases.

Claim: ​​ 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.

Claim specific: 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.

Background: 

Previous research has linked the microbiota and the development of CVD. This article is expanding on that as they frame it: We sought to identify microbial metabolites associated with early stages of atherosclerotic vascular disease that could contrib-

ute to atherosclerosis progression.

Thor experiment: To screen for microbial metabolites that could affect atherosclero-

sis progression, we fed atherosclerosis-prone Apoe−/− mice different

diets with or without antibiotic treatment to deplete the microbiota13

(Extended Data Fig. 1a). 

Group HC = High cholesterol

HC/HC=HC diet supplemented with choline (HC/HC)

 ImP, a microbiota-dependent

metabolite15, to be highly associated with atherosclerosis upon HC

feeding (Fig. 1f,g and Extended Data Fig. 1e). 

ImP (Imidazole propionate) linked to subclincial atherosclerosis in humans 

Study: 400 asymptomatic volunteers from the Progression of Early

Subclinical Atherosclerosis (PESA)-Centro Nacional de Investigaciones

Cardiovasculares (CNIC)-Santander prospective cohort (hereafter

the PESA cohort) study2 (Supplementary Table 1a,b). 

we classified 295

participants with subclinical atherosclerosis and 105 controls without

atherosclerosis.

Targeted metabolomics was used to quantify ImP and its

related metabolites (histidine and urocanic acid)15 in plasma samples.

Plasma concentrations of ImP, but not histidine or urocanic acid, were

selectively increased in individuals with subclinical atherosclerosis

compared with controls (Fig. 2a and Extended Data Fig. 2a).

Finding between ImP and diet: Among the five main principal com-

ponent analysis (PCA)-derived dietary patterns in the PESA cohort

(Extended Data Fig. 2b), ImP was inversely correlated with a Breakfast1

and a Mediterranean dietary pattern (Fig. 2e), consistent with previous

findings17. 16S ribosomal DNA (rDNA) sequencing of faecal samples

detected a direct correlation of ImP with the relative abundance of

Veillonella and Acidaminococcus, and inverse correlation with Erysipel-

otrichaceae and Coriobacteriaceae families (Fig. 2e), which are altered

in individuals with CVD18,19

Plasma ImP and related efforts: In both cohorts, ImP directly

correlated with fasting glucose and an adverse cardiometabolic pro-

file, including increased high-sensitivity C-reactive protein (hs-CRP),

body mass index (BMI), visceral fat, dyslipidaemia and hypertension,

and lower high-density lipoprotein (HDL)-cholesterol (Fig. 2e,f and

Supplementary Tables 1b and 2b). 

ImP also showed additive value when

added to established blood-derived atherosclerosis biomarkers such as low-density lipoprotein (LDL)-cholesterol and hs-CRP in discriminating

atherosclerosis prevalence in both cohorts (Extended Data Fig. 2c,d).

Group: active atherosclerosis (FDG+) Increased ImP plasma

concentration was observed in the FDG+ group, following a non-linear

association with the outcome (Fig. 2h,i). 

Additionally, ImP demonstrated additive

discriminative ability for active atherosclerosis over LDL-cholesterol

and hs-CRP alone (Extended Data Fig. 2c,d). These findings reveal a

strong association between ImP and atherosclerosis, particularly active

atherosclerosis, suggesting its potential use as an indicator of early

active atherosclerosis before other comorbidities become confound-

ing factors.

Mice - explore further: administered ImP in the drinking water of

atherosclerosis-prone mice, including chow-fed Ldlr−/− mice, which we

treated with ImP for 12 weeks (Fig. 3a and Extended Data Fig. 3a,b) and

chow-fed Apoe−/− mice, which we treated with ImP for 8 weeks (Fig. 3b

 Result: In both models, ImP supplementation

increased atherosclerosis development in the aorta and aortic root

without affecting circulating cholesterol or glucose concentration

(Fig. 3a,b and Extended Data Fig. 3a–e). 

Additional ImP supplementation did

not significantly exacerbate atherosclerosis in HC-fed Apoe−/− mice,

although it further increased atherosclerotic lesions in Ldlr−/− mice

(Extended Data Fig. 3f,g). 

Further exploration: Notably, Apoe−/− mice treated

with ImP for eight weeks showed an expansion of proinflammatory

Ly6Chi monocytes, and T helper 1 TH1 and T helper 17 (TH17) cells

(Fig. 3c,d and Extended Data Fig. 4a) in the blood, which are associ-

ated with a proatherogenic environment22.

To further understand the specific changes induced by ImP in the

aorta, we performed single-cell RNA-sequencing (scRNA-seq) analy-

sis of the whole aorta from chow-fed Apoe−/− mice that were admin-

istered ImP for four or eight weeks (Extended Data Fig. 4b–e).

Mice

treated with ImP for four weeks showed a mild increase in aortic arch

atherosclerosis (Extended Data Fig. 4f), and some local changes in

cell population frequency in the aorta (Extended Data Fig. 4e), with-

out changes in circulating immune cells (Extended Data Fig. 4g,h)

scRNA-seq of aortas from mice treated with ImP for eight

weeks revealed an increase in the relative number of fibroblasts,

endothelial cells and immune cells (Fig. 3e). 

Reclustering of each cell type in independent analyses

identified four macrophage, five fibroblast and three endothelial cell

subclusters (Extended Data Fig. 5a–c). Analysis of the ImP effect in these

subclusters (including four- and eight-week data) showed a reduction in

the MF1 cluster associated with homeostatic genes23, and an increase in

the MF3 cluster expressing genes associated with lipid metabolism,

inflammation and macrophage activation24–26 (Extended Data Fig. 5d,g).

Other areas of commonality: ImP has been related to type 2 diabetes,

cardiometabolic disease in people with HIV, coronary artery disease

and heart failure15,38,40–43. 

Here, we demonstrate that ImP is associated

with atherosclerosis progression in mice and with subclinical active ath-

erosclerosis in an otherwise healthy cohort, in whom atherosclerosis is

detected solely through advanced imaging studies that are unavailable

in the clinical practice for large population screenings44.

we demonstrate that ImP induces

atherosclerosis without influencing blood cholesterol concentration.

Proatherogenic effects of ImP can be pleiotropic and act on multiple

cell types45,46. We observed that administration of ImP induced local

increase in transcriptional activity in macrophages, fibroblasts and—to

a lesser extent—endothelial cells. 

Citations

Citations: Mastrangelo, A., Robles-Vera, I., Mañanes, D. et al. Imidazole propionate is a driver and therapeutic target in atherosclerosis. Nature 645, 254–261 (2025). https://doi.org/10.1038/s41586-025-09263-w