Unraveling interindividual differences and functional consequences of gut microbial metabolism of immunosuppressants

A major challenge in kidney transplantation (KT) is the large interpatient variability in the pharmacokinetics of immunosuppressive drugs. Here, we explored the role of the gut microbiome in interindividual variation in immunosuppressive drug metabolism. Analysis of 38 fecal communities, including 10 from KT recipients, and 45 bacterial species against 25 drugs, revealed significant interindividual and drug-specific differences in metabolism. Notably, 15 of 16 immunosuppressants tested were metabolized by at least one microbial community, and we found specific bacterial species, such as Bacteroides uniformis, to be potent metabolizers. We identified 18 different metabolites for 16 drugs, including two previously undescribed metabolites for sirolimus and everolimus. Our study reveals the functional impact of microbial metabolism on key immunosuppressants, including inactivation of tacrolimus, activation and potential increase in toxicity of mycophenolate mofetil (MMF), and shows that the microbial metabolite of methylprednisolone exhibits a 2.6-fold increase in epithelial permeability compared to the parent drug. Through a gain-of-function genetic screen we identified the B. uniformis enzyme BACUNI_RS05305 to be responsible for MMF activation. Using machine learning to model microbial community drug metabolism, abundance features of prevalent species predicted the biotransformation of some drugs well, while for others, a priori experimental information on bacterial genes and enzyme protein structures led to improved predictions. Our research highlights the potential of gut microbiome features to explain interindividual variability in immunosuppressive therapies and sets the stage for clinical trials to identify microbiome-encoded signatures predictive of drug metabolism in KT patients. One Sentence SummaryThis study reveals interindividual variability in gut microbial metabolism of immunosuppressive drugs mediated by specific bacterial species and enzymes.