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The gut microbiota has emerged as a metabolically active endocrine-like organ with a crucial role in coronary artery disease (CAD), yet its contribution to adverse clinical outcomes remains incompletely understood. In this prospective cohort of 319 participants, we integrated metagenomic and metabolomic profiling with longitudinal follow-up over a median of 1.85 years. Fecal microbiota transplantation from patients with CAD transmitted susceptibility to atherosclerosis in antibiotic-treated ApoE ^-/- mice, accompanied by microbiota-induced vascular inflammation mediated through LPS-TLR4 signaling. Gut microbiota-derived aromatic amino acid metabolism was associated with thrombotic risk and major adverse cardiac events (MACE). Machine learning identified gut microbial features that improved prospective prediction of MACE. Together, these findings implicate the gut microbiome in CAD progression and support the development of microbiome-based strategies for cardiovascular risk prediction and prevention.