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Biological systems are exposed to a complex environment in which pollutants can interact through synergistic or antagonistic mechanisms, but limited information is available on the combined effects. To this end, conventional and antibiotic-treated (Abx) mice models were fed regular rodent or selenium (Se) supplemented diets and exposed to a "chemical cocktail" (CC) including metals and pharmaceuticals. Metallomics, metabolomics, and metataxomics were combined to delve into the impact on gut microbiota, plasma selenoproteome, metabolome, and arsenic metabolization. At the molecular level, Se decreased the concentration of the antioxidant glutathione peroxidase in plasma and increased the arsenic methylation rate, possibly favoring its excretion, but not in the Abx and also plasma metabolomes of Abx, and Abx-Se were not differentiated. Moreover, numerous associations were obtained between plasma selenoproteins and gut microbes. Se-supplementation partially antagonizes the gut microbiota alteration caused by Abx, and slightly by CC, but strongly altered profiles were observed in CC-Abx-Se, suggesting synergistic deleterious effects between pollutants, Abx and Se. Moreover, although CC and Abx changed gut microbiota, several common taxa were enriched in CC-Abx and control mice, indicating possible synergistic effects. Our results suggest a potential beneficial impact of supplementation, but mediated by gut microbes being reversed in their absence.