New Discovery in Gut Molecules May Revolutionize Atherosclerosis Treatment, Previously Thought to be Cholesterol-Driven
In a groundbreaking study published in the prestigious journal Nature, researchers from the Carlos III National Center for Cardiovascular Research (CNIC) in Madrid, Spain, have identified a significant contributor to atherosclerosis and metabolic disorders – a molecule called imidazol propionate (ImP).
Produced by intestinal microbiota, ImP acts as a microbial metabolite driver in the development of atherosclerosis by activating the imidazoline receptor I1R, which is broadly expressed on immune cells. This receptor senses ImP and triggers downstream inflammatory signaling pathways critical for atherogenesis. Upon binding to I1R, ImP stimulates the mTOR pathway, evidenced by phosphorylation of ribosomal protein S6 (p-S6), and promotes secretion of pro-inflammatory cytokines, especially tumor necrosis factor (TNF). These inflammatory processes facilitate the progression of vascular inflammation and plaque formation in arteries, hallmark features of atherosclerosis.
Besides atherosclerosis, ImP impairs insulin signaling through the activation of mTORC1, contributing to metabolic dysfunctions such as those seen in type 2 diabetes. Mechanistically, ImP activates p38 MAPK and phosphorylation of p62, further enhancing mTOR activity, which negatively impacts insulin receptor signaling and promotes systemic insulin resistance. Elevated ImP levels correlate with unhealthy dietary patterns and a dysbiotic gut microbiota, which together shift microbial metabolism toward higher production of ImP.
The study combined research on mice and the observation of two large groups of human volunteers, including people with advanced heart disease and a cohort of healthy individuals, in whom atherosclerosis was detected only through advanced imaging studies. The researchers managed to block the I1R receptor in mice, stopping the development of atherosclerosis induced by ImP and a high-cholesterol diet.
The study highlights the role of intestinal microbiota in the development of atherosclerosis and suggests that cholesterol may not be the only mechanism that causes atherosclerosis, as ImP was able to induce the disease without altering blood cholesterol levels. The findings could be crucial for the change of paradigm in prevention and seeking new treatments for atherosclerosis.
The paper's title is 'Imidazol propionate is a driver and a therapeutic target in atherosclerosis'. The study's conclusions emphasise that ImP is a crucial microbial metabolite that links gut microbiota dysbiosis to systemic inflammation, metabolic disease, and cardiovascular pathology. Its role in activating immune receptors and intracellular signaling cascades positions it as both a biomarker and a therapeutic target in atherosclerosis and metabolic disorders.
References: [1] Imidazole propionate drives atherosclerosis via I1R and mTOR pathways (2025-07-16) [2] ImP impairs insulin signaling and relates to diet and microbiota in diabetes (2025-07-01) [3] ImP activates p38 MAPK/p62 and mTOR, worsening insulin resistance (2025-07-09) [4] ImP levels increased in diabetes, linked to microbial ecology and diet (2025-07-06)
In light of the study, ImP, a microbial metabolite identified as a contributor to both atherosclerosis and metabolic disorders, may require attention in health-and-wellness discussions, particularly regarding cardiovascular health. The activation of immune receptors and intracellular signaling cascades by ImP suggests it could be a promising biomarker and therapeutic target for these conditions.
