Olsenella scatoligenes -derived skatole promotes smooth muscle cell proliferation and migration to aggravate atherosclerosis

作者：Yawen Zhao, Jiarui Chen, Shanshan Zhu, Yingxi Xu, Jiangyuan Zhu, Jialu Yang, Weibin Zhou, Ying Yang, Maohuan Lin, Qian Chen, Min Xia, Yangxin Chen, Yan Liu · 发表于：The ISME Journal · 年份：2025 · DOI：10.1093/ismejo/wraf238 · 被引用次数：2 · 研究领域：Epigenetics and DNA Methylation、Pancreatic and Hepatic Oncology Research、Connective tissue disorders research

Coronary artery disease (CAD) remains the leading cause of mortality and morbidity globally. The gut microbiota has been implicated in the development of CAD through unclear mechanisms. Here, we demonstrate that the abundance and interspecies interactions of Olsenella scatoligenes are 4.7- and 1.6-fold higher in patients with CAD, 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 O. scatoligenes. Consistently, supplementation with O. 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, O. 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 ~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 O. scatoligenes to aggravated atherosclerosis through activation of the aryl hydrocarbon receptor-calponin 1 axis and underscores the therapeutic potential of targeting skatole production for the management of CAD.