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During the transition from a healthy state to cardiometabolic disease, patients become heavily medicated, which leads to an increasingly aberrant gut microbiome and serum metabolome, and complicates biomarker discovery.sup.1-5. Here, through integrated multi-omics analyses of 2,173 European residents from the MetaCardis cohort, we show that the explanatory power of drugs for the variability in both host and gut microbiome features exceeds that of disease. We quantify inferred effects of single medications, their combinations as well as additive effects, and show that the latter shift the metabolome and microbiome towards a healthier state, exemplified in synergistic reduction in serum atherogenic lipoproteins by statins combined with aspirin, or enrichment of intestinal Roseburia by diuretic agents combined with beta-blockers. Several antibiotics exhibit a quantitative relationship between the number of courses prescribed and progression towards a microbiome state that is associated with the severity of cardiometabolic disease. We also report a relationship between cardiometabolic drug dosage, improvement in clinical markers and microbiome composition, supporting direct drug effects. Taken together, our computational framework and resulting resources enable the disentanglement of the effects of drugs and disease on host and microbiome features in multimedicated individuals. Furthermore, the robust signatures identified using our framework provide new hypotheses for drug-host-microbiome interactions in cardiometabolic disease. An analysis of 2,173 individuals from the MetaCardis cohort quantifies the individual and combinatorial effects of a range of drugs on host health, metabolome and gut microbiome in cardiometabolic disease., Author(s): Sofia K. Forslund [sup.1] [sup.2] [sup.3] [sup.4] [sup.5] [sup.6] , Rima Chakaroun [sup.7] , Maria Zimmermann-Kogadeeva [sup.1] , Lajos Markó [sup.2] [sup.4] [sup.5] , Judith Aron-Wisnewsky [sup.8] [sup.9] , [...]