Department of Integrated PharmacoMetrics, PharmacoGenomics and PharmacoKinetics, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
Microbiome. 2023 Jul 6;11(1):138. doi: 10.1186/s40168-023-01578-y.
Following solid organ transplantation, tacrolimus (TAC) is an essential drug in the immunosuppressive strategy. Its use constitutes a challenge due to its narrow therapeutic index and its high inter- and intra-pharmacokinetic (PK) variability. As the contribution of the gut microbiota to drug metabolism is now emerging, it might be explored as one of the factors explaining TAC PK variability. Herein, we explored the consequences of TAC administration on the gut microbiota composition. Reciprocally, we studied the contribution of the gut microbiota to TAC PK, using a combination of in vivo and in vitro models.
TAC oral administration in mice resulted in compositional alterations of the gut microbiota, namely lower evenness and disturbance in the relative abundance of specific bacterial taxa. Compared to controls, mice with a lower intestinal microbial load due to antibiotics administration exhibit a 33% reduction in TAC whole blood exposure and a lower inter-individual variability. This reduction in TAC levels was strongly correlated with higher expression of the efflux transporter ABCB1 (also known as the p-glycoprotein (P-gp) or the multidrug resistance protein 1 (MDR1)) in the small intestine. Conventionalization of germ-free mice confirmed the ability of the gut microbiota to downregulate ABCB1 expression in a site-specific fashion. The functional inhibition of ABCB1 in vivo by zosuquidar formally established the implication of this efflux transporter in the modulation of TAC PK by the gut microbiota. Furthermore, we showed that polar bacterial metabolites could recapitulate the transcriptional regulation of ABCB1 by the gut microbiota, without affecting its functionality. Finally, whole transcriptome analyses pinpointed, among others, the Constitutive Androstane Receptor (CAR) as a transcription factor likely to mediate the impact of the gut microbiota on ABCB1 transcriptional regulation.
We highlight for the first time how the modulation of ABCB1 expression by bacterial metabolites results in changes in TAC PK, affecting not only blood levels but also the inter-individual variability. More broadly, considering the high number of drugs with unexplained PK variability transported by ABCB1, our work is of clinical importance and paves the way for incorporating the gut microbiota in prediction algorithms for dosage of such drugs. Video Abstract.
在实体器官移植后，他克莫司（TAC）是免疫抑制策略中必不可少的药物。由于其治疗指数较窄以及其高体内和体内药代动力学（PK）变异性，其使用构成了挑战。由于肠道微生物群对药物代谢的贡献现在正在出现，因此它可能被探索为解释 TAC PK 变异性的因素之一。在此，我们探讨了 TAC 给药对肠道微生物群落组成的影响。反过来，我们使用体内和体外模型的组合来研究肠道微生物群对 TAC PK 的贡献。
TAC 在小鼠中的口服给药导致肠道微生物群落的组成改变，即均匀度降低和特定细菌分类群的相对丰度紊乱。与对照组相比，由于抗生素给药导致肠道微生物负荷降低的小鼠，TAC 全血暴露降低 33%，个体间变异性降低。TAC 水平的这种降低与小肠中 ABCB1（也称为 p-糖蛋白（P-gp）或多药耐药蛋白 1（MDR1））的表达更高强烈相关。无菌小鼠的常规化证实了肠道微生物群能够以特定于部位的方式下调 ABCB1 的表达。体内 ABCB1 的功能性抑制通过 zosuquidar 正式确立了该外排转运蛋白在肠道微生物群调节 TAC PK 中的作用。此外，我们表明，极性细菌代谢物可以再现肠道微生物群对 ABCB1 的转录调节，而不影响其功能。最后，全转录组分析指出，其中包括组成型雄烷受体（CAR）作为可能介导肠道微生物群对 ABCB1 转录调节影响的转录因子。
我们首次强调了细菌代谢物如何调节 ABCB1 的表达导致 TAC PK 的变化，这不仅影响血液水平，还影响个体间的变异性。更广泛地说，考虑到有许多药物的 PK 变异性无法解释，这些药物由 ABCB1 转运，我们的工作具有临床意义，并为将肠道微生物群纳入此类药物剂量预测算法铺平了道路。
