Abstract Aims Despite treatment advancements, cardiovascular disease remains a leading cause of death worldwide. Identifying new targets is crucial for enhancing preventive and therapeutic strategies. The gut microbiome has been associated with coronary artery disease (CAD), however our understanding of specific changes during CAD development remains limited. We aimed to investigate microbiome changes in participants without clinically manifest CAD with different cardiovascular risk levels and in patients with ST-elevation myocardial infarction (STEMI). Methods and results In this cross-sectional study, we characterized the gut microbiome using metagenomics of 411 faecal samples from individuals with low (n = 130), intermediate (n = 130), and high (n = 125) cardiovascular risk based on the Framingham score, and STEMI patients (n = 26). We analysed diversity, and differential abundance of species and functional pathways while accounting for confounders including medication and technical covariates. Collinsella stercoris, Flavonifractor plautii, and Ruthenibacterium lactatiformans showed increased abundances with cardiovascular risk, while Streptococcus thermophilus was negatively associated. Differential abundance analysis revealed eight species and 49 predicted metabolic pathways that were differently abundant among the groups. In the gut microbiome of STEMI patients, there was a depletion of pathways linked to vitamin, lipid, and amino acid biosynthesis. Conclusion We identified four microbial species showing a gradual trend in abundance from low-risk individuals to those with STEMI, and observed differential abundant species and pathways in STEMI patients compared to those without clinically manifest CAD. Further investigation is warranted to gain deeper understanding of their precise role in CAD progression and potential implications, with the ultimate goal of identifying novel therapeutic targets.