Faecalibacterium prausnitzii (F. prausnitzii) shows potential as an antiatherosclerotic microbe. This study identified key biomarkers using metagenomics and untargeted metabolomics to assess their association with atherosclerosis. A total of 371 participants, including individuals with various coronary artery disease (CAD) types and CAD-free controls, were analyzed. F. prausnitzii was found to be a robust, independent predictor of CAD, with higher presence correlating with lower CAD incidence. The gut microbiota and metabolites may predict CAD occurrence and progression, influencing amino acid and vitamin metabolism. In vivo and in vitro experiments showed that F. prausnitzii reduced intestinal LPS synthesis, strengthened mechanical and mucosal barriers, and decreased plasma LPS levels, leading to antiatherosclerotic effects in ApoE-/- mice. The study also revealed that F. prausnitzii mitigated inflammation and improved intestinal barrier function, reducing endotoxaemia and atherosclerosis. Metagenomic and metabolomic analyses identified significant differences in microbial composition and metabolite profiles among CAD groups. F. prausnitzii was found to be highly important in predicting CAD, with better diagnostic efficacy compared to controls. The antiatherosclerotic effect of F. prausnitzii was independent of blood lipids and glucose levels. The study highlights the potential of F. prausnitzii in preventing atherosclerosis through mechanisms involving reduced LPS synthesis, enhanced intestinal barrier function, and anti-inflammatory effects. These findings suggest that F. prausnitzii could be a promising therapeutic target for CAD prevention.Faecalibacterium prausnitzii (F. prausnitzii) shows potential as an antiatherosclerotic microbe. This study identified key biomarkers using metagenomics and untargeted metabolomics to assess their association with atherosclerosis. A total of 371 participants, including individuals with various coronary artery disease (CAD) types and CAD-free controls, were analyzed. F. prausnitzii was found to be a robust, independent predictor of CAD, with higher presence correlating with lower CAD incidence. The gut microbiota and metabolites may predict CAD occurrence and progression, influencing amino acid and vitamin metabolism. In vivo and in vitro experiments showed that F. prausnitzii reduced intestinal LPS synthesis, strengthened mechanical and mucosal barriers, and decreased plasma LPS levels, leading to antiatherosclerotic effects in ApoE-/- mice. The study also revealed that F. prausnitzii mitigated inflammation and improved intestinal barrier function, reducing endotoxaemia and atherosclerosis. Metagenomic and metabolomic analyses identified significant differences in microbial composition and metabolite profiles among CAD groups. F. prausnitzii was found to be highly important in predicting CAD, with better diagnostic efficacy compared to controls. The antiatherosclerotic effect of F. prausnitzii was independent of blood lipids and glucose levels. The study highlights the potential of F. prausnitzii in preventing atherosclerosis through mechanisms involving reduced LPS synthesis, enhanced intestinal barrier function, and anti-inflammatory effects. These findings suggest that F. prausnitzii could be a promising therapeutic target for CAD prevention.