Gut microbiota-derived trimethylamine-N-oxide inhibits SIRT1 to regulate SM22α-mediated smooth muscle cell inflammation and promote atherosclerosis progression

Atherosclerosis (AS) is a prevalent cardiovascular disease, and emerging evidence highlights the critical role of gut microbiota in its development. Trimethylamine-N-oxide (TMAO), a metabolite derived from gut microbiota, is thought to promote AS progression by regulating smooth muscle protein 22-alpha (SM22α)-mediated inflammation in vascular smooth muscle cells. This study aims to explore the molecular mechanisms of TMAO in AS through multi-omics analysis, particularly its effects on SIRT1 inhibition and SM22α modulation. 16S ribosomal RNA sequencing revealed an altered gut microbiota composition in AS mice, characterized by increased Bacteroides and decreased Firmicutes. Metabolomics analysis indicated elevated levels of TMAO in AS mice. Transcriptomic data and cell experiments further confirmed that TMAO promotes AS by regulating SM22α-mediated inflammation via SIRT1 regulation. These findings suggest that TMAO accelerates progression through the SIRT1 and SM22α-related pathways, offering novel therapeutic targets for AS intervention.