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

## TL;DR

This study shows that a gut bacterium called Olsenella scatoligenes produces skatole, which worsens atherosclerosis by promoting smooth muscle cell activity.

## Contribution

The study identifies skatole as a microbial effector linking Olsenella scatoligenes to atherosclerosis through the aryl hydrocarbon receptor-calponin 1 pathway.

## Key findings

- Olsenella scatoligenes abundance is 4.7-fold higher in CAD patients and correlates with disease severity.
- Skatole supplementation increases aortic plaque area by promoting vascular smooth muscle cell proliferation and migration.
- Skatole activates the aryl hydrocarbon receptor, enhancing its binding to calponin 1's promoter region.

## Abstract

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.