Olsenella scatoligenes-derived Skatole Promotes Smooth Muscle Cell Proliferation and Migration to Aggravate...

Coronary artery disease remains the leading cause of mortality and morbidity globally. The gut microbiota has been implicated in the development of coronary artery disease through unclear mechanisms. Here, we demonstrate that the abundance and inter-species interactions of Olsenella scatoligenes are 4.7-fold and 1.6-fold higher in patients with coronary artery disease, respectively, and positively associated with disease severity. Furthermore, integrative metagenomic and metabolomic analyses identify skatole as the key microbial effector mediating the pro-atherogenic effect of Olsenella scatoligenes. Consistently, supplementation with Olsenella scatoligenes or skatole results in 1.26- and 1.23-fold increases in aortic plaque area, respectively, by promoting vascular smooth muscle cell proliferation and migration to the intima. Mechanistically, Olsenella scatoligenes -derived skatole facilitates nuclear translocation of the aryl hydrocarbon receptor, and enhances its binding to the promoter region of calponin 1. Silencing either aryl hydrocarbon receptor or calponin 1 attenuates approximately 40% of the vascular smooth muscle cell proliferation and migration induced by skatole. Collectively, our study identifies increased skatole production as the principal microbial effector linking Olsenella scatoligenes to aggravated atherosclerosis through activation of aryl hydrocarbon receptor -calponin 1 axis and underscores the therapeutic potential of targeting skatole production for the management of coronary artery disease.