Gut Metabolite Imidazole Propionate Identified as Novel Atherosclerosis Driver and Therapeutic Target
核心洞察
Researchers identified imidazole propionate (搜索) (ImP), a gut microbiota-derived metabolite, as both a biomarker and therapeutic target for atherosclerosis (搜索) through activation of the imidazoline-1 receptor (搜索) on immune cells.
ImP administration to mice induced atherosclerotic lesions independently of cholesterol levels, while selective receptor blockade completely prevented disease progression in multiple mouse models.
Plasma ImP levels were significantly elevated in two human cohorts with subclinical atherosclerosis (搜索) and improved cardiovascular risk stratification beyond traditional biomarkers like LDL cholesterol and C-reactive protein.
A groundbreaking study published in Nature has identified imidazole propionate (搜索) (ImP), a metabolite produced by gut bacteria, as a novel driver of atherosclerosis (搜索) that operates independently of traditional cholesterol pathways. The research by Mastrangelo et al. reveals ImP as both a potential biomarker for early cardiovascular disease (搜索) detection and a promising therapeutic target.
Gut-Heart Connection Reveals New Pathway
ImP is produced by intestinal bacteria through histidine metabolism, an essential amino acid obtained from diet. While previously linked to metabolic disorders including type 2 diabetes (搜索) and insulin resistance (搜索), its role in cardiovascular disease (搜索) remained unclear until this comprehensive investigation.
The researchers combined mouse models with human studies across two major cohorts. Using untargeted metabolomics in atherosclerosis (搜索)-prone mice, they identified a strong link between ImP and disease progression. Remarkably, ImP administration to mice on a normal diet induced atherosclerotic lesions independently of cholesterol levels, challenging traditional lipid-centric paradigms of cardiovascular disease (搜索).
Human Validation Across Multiple Cohorts
The findings were validated in two human cohorts: the PESA (Progression of Early Subclinical Atherosclerosis (搜索)) study with 400 participants and the IGT (Impaired Glucose Tolerance) cohort with over 1,800 participants. Plasma ImP levels were significantly higher in individuals with subclinical atherosclerosis compared to controls.
ImP demonstrated strong association with metabolically active atherosclerosis (搜索), as detected by 18F-fluorodeoxyglucose PET imaging, indicating early-stage disease. Plasma ImP levels directly correlated with numerous cardiovascular risk factors, including fasting glucose levels, body mass index, and blood pressure. After adjusting for traditional cardiovascular risk factors, elevated ImP levels remained independently linked with atherosclerotic outcomes.
Critically, ImP improved risk stratification when added to conventional cardiovascular biomarkers such as LDL cholesterol and high-sensitivity C-reactive protein, offering diagnostic value beyond existing markers.
Mechanistic Insights and Therapeutic Target
Mechanistic studies revealed that ImP binds the imidazoline-1 receptor (搜索) (I1R (搜索) or nischarin (搜索)) on myeloid cells, activating the mTOR (搜索) (mechanistic target of rapamycin) signaling pathway. The research demonstrated that mTORC1 (搜索) activation promotes atherosclerosis (搜索) while mTORC2 (搜索) remains protective.
Selective deletion of I1R (搜索) in myeloid cells completely prevented ImP-induced atherosclerosis (搜索). Similarly, mice lacking the mTORC1 (搜索) component Raptor in myeloid cells resisted the proatherogenic effects of ImP, confirming the critical I1R–mTORC1 axis.
Pharmacological blockade using a selective I1R (搜索) antagonist (AGN192403) recapitulated these protective effects, reducing immune activation, plaque complexity, necrotic cores, and atherosclerosis (搜索) progression in multiple mouse models without altering cholesterol levels. Treatment also reduced pro-inflammatory Ly6Chi monocytes and T helper 1 cells in the bloodstream, accompanied by decreased systemic cytokines such as TNF and interferon gamma.
Clinical Implications and Precision Medicine
The discovery represents a significant advance toward precision cardiovascular medicine. Current early detection methods rely on costly, limited-access imaging, whereas a simple blood test for ImP could enable earlier identification of at-risk individuals and timely intervention.
ImP represents the first immune-metabolism-mediated biomarker operating independently of traditional lipid pathways, offering distinct mechanistic approaches beyond existing markers. Notably, ImP levels were lower in individuals following Mediterranean-style diets rich in fish, vegetables, and whole grains, while higher levels correlated with increased abundance of bacterial genera such as Veillonella and Acidaminococcus.
Challenges and Future Directions
Translation to clinical practice requires several key developments. Standardized assays for ImP measurement must be developed and validated across diverse populations, particularly in Asian and African populations where distinct gut microbiota could alter predictive accuracy. Preliminary analysis reveals inter-cohort variation in ImP concentrations, with median levels of approximately 29 nM in PESA versus 7 nM in IGT cohorts.
Clinical trials will be needed to evaluate I1R (搜索) antagonists as therapeutic agents, with comprehensive safety profiling important given that chronic mTORC1 (搜索) modulation may carry metabolic side effects. ImP biomarker utility in patients with gastrointestinal disorders presents complexity, as inflammatory bowel disease (搜索) may artificially alter ImP levels.
The research adds to a growing understanding of gut microbiome-derived metabolites in cardiovascular disease (搜索), alongside compounds like trimethylamine N-oxide (搜索) (TMAO) and short-chain fatty acids. Unlike TMAO, ImP appears to act primarily through immune activation and inflammatory signaling, expanding understanding of the gut-aorta axis in disease pathogenesis.
This discovery opens new avenues for both early diagnosis and personalized cardiovascular treatment, potentially advancing precision cardiometabolic care through targeting of gut microbial metabolites.