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BACKGROUNDGut microbiota have been implicated in atherosclerotic disease, but their relation with subclinical coronary atherosclerosis is unclear. This study aimed to identify associations between the gut microbiome and computed tomography-based measures of coronary atherosclerosis, and to explore relevant clinical correlates.METHODSWe conducted a cross-sectional study of 8973 participants aged 50 to 65 without overt atherosclerotic disease from the population-based Swedish Cardiopulmonary BioImage Study (SCAPIS). Coronary atherosclerosis was measured using coronary artery calcium score (CACS) and coronary computed tomography angiography (CCTA). Gut microbiota species abundance and functional potential were assessed with shotgun metagenomics sequencing of stool samples, and their association with coronary atherosclerosis was evaluated with multivariable regression models adjusted for cardiovascular risk factors. Associated species were evaluated for association with inflammatory markers, metabolites, and corresponding species in saliva.RESULTSThe mean age of the study sample was 57.4 years, and 53.7% were female. Coronary artery calcification was detected in 40.3% of participants, and 5.4% had at least one stenosis with more than 50% occlusion. Sixty-four species were associated with CACS independent of cardiovascular risk factors, with the strongest associations observed forStreptococcus anginosusandS. oralissubsp. oralis(P-5). Associations were largely similar across CCTA-based measurements. Out of the 64 species, 19 species, including streptococci and other species commonly found in the oral cavity, were associated with high-sensitivity C-reactive protein plasma concentrations and 16 with neutrophil counts. Oral species in the gut were negatively associated with plasma indole propionate and positively associated with plasma secondary bile acids and imidazole propionate. Five species correlated with the same species in saliva and were associated with worse dental health in the Malmö Offspring Dental Study. Microbial functional potential of dissimilatory nitrate reduction, anaerobic fatty acid beta-oxidation and amino acid degradation was associated with CACS.CONCLUSIONSThis study provides evidence of an association of a gut microbiota composition characterized by increased abundance ofStreptococcusspp. and other species commonly found in the oral cavity with coronary atherosclerosis and systemic inflammation. Further longitudinal and experimental studies are warranted to explore the potential implication of a bacterial component in atherogenesis.CLINICAL PERSPECTIVEWHAT IS NEW?Shotgun metagenomics identified associations between gut species and subclinical atherosclerosis assessed with computed tomography-derived coronary artery calcium score (CACS) in 8973 participants, with an overrepresentation of theStreptococcusandOscillobactergenera.The relative abundance of CACS-associated oral species detected in fecal samples was negatively associated with indole propionate, while positively associated with secondary bile acids and imidazole propionate.GutStreptococcusspp. were positively associated with circulating biomarkers of systemic inflammation and infection response, and with the same species located in the mouth, which were in turn associated with oral pathologies.WHAT ARE THE CLINICAL IMPLICATIONS?We describe the link between gut microbiota composition, especially species commonly found in the mouth, with subclinical coronary atherosclerosis and biomarkers of inflammation in the largest cardiovascular and metagenomics study to date.The effects of gut and oralStreptococcusspp. on risk for coronary artery disease merit further longitudinal and experimental studies.