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BACKGROUND: How gut microbiota alterations may contribute to host inflammation and metabolomic profiles affecting atherosclerosis is not fully elucidated, especially in the context of HIV.METHODS: We examined associations between gut microbial features (measured by shotgun metagenomics) and subclinical carotid atherosclerosis, as assessed by high-resolution B-mode ultrasound, in 359 men from the MACS/WIHS Combined Cohort Study. We measured 822 plasma metabolites using LC-MS/MS, and up to 2866 circulating proteins by the Olink Explore 3072/384 platform (with a primary focus on 617 proteins related to inflammation and immune function).FINDINGS: Carotid artery plaque was detected in 115/359 men (32%). Adlercreutzia equolifaciens and Eubacterium sp3131 were associated with lower odds of plaque (OR [95% CI] = 0.57 [0.43, 0.77], 0.84 [0.76, 0.93], respectively), while Coprococcus sp13142 was associated with higher odds of plaque (OR [95% CI] = 1.14 [1.06, 1.23]). Results were consistent in men both with and without HIV. A. equolifaciens was positively correlated with HDL cholesterol and inversely correlated with systolic blood pressure. These plaque-associated microbial species were also associated with a range of circulating metabolites and inflammatory proteins. For example, A. equolifaciens positively correlated with the metabolites palmitoyl-EA and mesobilirubinogen, and inversely correlated with the pro-inflammatory chemokine CXCL9, the immune regulator CD160, and IL-24.INTERPRETATION: We identified gut microbial features associated with carotid artery atherosclerosis, consistent across HIV status; these associations were partially explained by specific microbiota-related metabolites and inflammatory markers. If validated, these findings suggest gut microbiota-related targets for CVD prevention.FUNDING: The study was funded by the National Heart, Lung, and Blood Institute (U01HL146204-04S1, K01HL169019).