This study reveals interindividual variability in gut microbial metabolism of immunosuppressive drugs mediated by specific bacterial species and enzymes.. Unraveling interindividual differences and functional consequences of gut microbial metabolism of critical dose immunosuppressants

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.

本研究探讨了人类肠道微生物组在实体器官移植（Solid Organ Transplantation, SOT）所用的关键剂量免疫抑制药物代谢中的作用，旨在解决治疗指数狭窄、患者间药物反应差异巨大的问题。本研究共分析38份粪便菌群样本（其中10份来自肾移植受者），并针对25种药物（含16种关键免疫抑制剂）检测了45种细菌的代谢能力，结果揭示了显著的个体间代谢差异与药物特异性代谢模式。研究发现，几乎所有免疫抑制剂均可被至少一种肠道菌群代谢，同时已鉴定出具备强效代谢能力的特定细菌物种。此外，本研究为每种免疫抑制剂均检测到至少一种独特的微生物源性药物代谢产物，并发现了西罗莫司（sirolimus）和依维莫司（everolimus）的两种新型代谢产物。本研究阐明了肠道微生物组在实体器官移植核心免疫抑制药物代谢过程中的关键作用，揭示了微生物可使他克莫司（tacrolimus）失活，以及吗替麦考酚酯（MMF）被微生物激活并产生毒性代谢产物的现象。此外，研究发现微生物源性药物代谢产物的吸收速率可能与其母体化合物存在差异，这可能会改变药物的药代动力学过程。通过开展肠道细菌的高通量遗传筛选，本研究鉴定出单形拟杆菌（B. uniformis）中的一种酶及其结构特征，该酶可激活前体药物吗替麦考酚酯。本研究利用机器学习基于细菌群落特征构建微生物药物代谢模型后发现，尽管常见物种的丰度特征可较好预测部分药物的生物转化过程，但对于其他药物而言，需借助先验实验信息深入了解相关细菌基因及酶蛋白结构，方能充分阐明酶-底物相互作用的具体细节。本研究凸显了利用肠道微生物组相关研究成果优化实体器官移植患者个体化免疫抑制治疗的潜力，为开展靶向临床试验以鉴定微生物组编码特征、从而更精准预测药物反应铺平了道路。