Combinatorial, additive and dose-dependent drug-microbiome associations

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(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.

Automated summary

The study reveals that drugs have a greater explanatory power for variability in host and gut microbiome features than diseases during the transition from a healthy state to cardiometabolic disease. The effects of single medications, their combinations, and additive effects can shift the metabolome and microbiome towards a healthier state. The study also shows a quantitative relationship between the number of antibiotic courses prescribed and progression towards a microbiome state associated with the severity of cardiometabolic disease, providing new hypotheses for drug-host-microbiome interactions.