This study reveals interindividual variability in gut microbial metabolism of immunosuppressive drugs mediated by specific bacterial species and enzymes.
This study explores the role of the human gut microbiome in the metabolism of critical dose immunosuppressive drugs used in solid organ transplantation (SOT), addressing the issue of narrow therapeutic index and large interpatient variability. Analyzing 38 fecal  communities, including 10 from kidney transplant recipients, and 45 bacterial species against 25 drugs, including 16 critical immunosuppressants, revealed significant interindividual differences and drug-specific metabolic patterns. Almost all immunosuppressants were metabolized by at least one gut microbial community, with specific bacterial species identified as potent metabolizers. Moreover, we detected at least one distinct microbial drug metabolite for each immunosuppressant, uncovering two novel metabolites of sirolimus and everolimus. Our study highlights the role of the gut microbiome in processing cornerstone immunosuppressants used in SOT, revealing microbial deactivation of tacrolimus and activation and toxification of MMF. Additionally, we discovered that the absorption rates of microbial drug metabolites may differ from their parent compound, potentially leading to altered pharmacokinetics. Using a high-throughput genetic screen in gut bacteria, we identified an enzyme in B. uniformis and its structural features that activate the prodrug MMF. Using machine learning to model microbial drug metabolism based on bacterial community features, we found that while species abundance features of prevalent species predict biotransformation ofmay be sufficient for some drugs well, for others a priori experimental information require a deeper understanding of the responsible on bacterial genes and enzyme protein structures may beal details of enzyme-substrate interactions is  necessary. Our research highlights the potential of using gut microbiome insights to optimize personalized immunosuppression in SOT, paving the way for targeted clinical trials to identify microbiome-encoded signatures to better predict drug response.