Distinct microbial and metabolic shifts characterize acute coronary syndrome and recovery

Early identification of patients at risk of acute coronary syndrome (ACS) remains a major unmet need, particularly among those with stable coronary artery disease (sCAD), where timely intervention could markedly improve outcomes. The gut microbiota has been implicated in coronary artery disease (CAD), but its ability to distinguish ACS from sCAD is not well defined. Here, we performed cross‐sectional multi‐omics profiling of fecal microbiota and plasma metabolites in 548 individuals, including participants with normal coronary arteries ( N = 175), primary sCAD ( N = 161), and ACS ( N = 212). To assess whether disease‐associated changes resolve with treatment, we further analyzed an independent cohort of ACS patients ( N = 52) who transitioned to sCAD following standard therapy. We identified profound ACS‐associated alterations in gut microbial composition and systemic metabolism, marked by enrichment of pro‐inflammatory taxa such as Streptococcus spp. and elevated circulating levels of 3‐hydroxybutyrate (3‐HB). Strikingly, many of these ACS‐specific microbial and metabolic signatures, including 3‐HB and related microbial functional pathways, were restored toward sCAD‐like levels after clinical recovery. Integrative models combining microbial taxa, metabolites, and clinical biomarkers robustly discriminated ACS from healthy controls (AUC = 0.91) and from sCAD (AUC = 0.83), significantly outperforming clinical markers alone (AUC = 0.69 for NCA vs. ACS; 0.59 for sCAD vs. ACS). These findings establish the gut microbiome and its metabolic outputs as key discriminators of ACS, reveal their dynamic resolution during disease recovery, and highlight their potential as biomarkers and therapeutic targets for cardiovascular risk stratification and management.