Gut Microbiota and Tacrolimus Trough Variability in Kidney Transplant Recipients

项目总结 肾移植是终末期肾病患者的救命手段。使用他克莫司 预防肾移植排斥反应，但亚治疗他克莫司的治疗窗口很窄 与急性排斥反应相关的水平和与肾毒性相关的超治疗水平 神经毒性。重要的是，肾移植受者具有他克莫司谷变异性，即显著的患者内 他克莫司谷值的变化，增加了急性排斥反应和肾移植失败的风险。这个 然而，预测患者内他克莫司波谷变异性的因素还不是很清楚。我们的预赛 研究支持他克莫司肠道细菌代谢与他克莫司谷变异性之间的关系。 这项研究的总体目标是确定肠道微生物区系和他克莫司之间的关系 肾移植受者的谷型变异性。我们的中心假设是特定的肠道微生物种类 与他克莫司的代谢和患者体内他克莫司谷的变异性有关。假设是 基于我们的初步研究并受到其启发：(1)粪便杆菌、布鲁氏菌和其他共生生物 他克莫司直接代谢成M1，一种活性较低的他克莫司代谢物(2)M1的产生存在于 肾移植受者的粪便标本(3)肾移植受者口服后血M1的检测 他克莫司的管理(Guo等人，Drug Metabo Dispos 47(3)：194-202,2019；Guo等人，移植直接 6(10)：E601,2020)。 在这项研究中，我们将招募80名肾移植受者在第一阶段连续收集粪便标本。 移植后3个月，将使用元基因组测序来描述肠道微生物组。就像在体内一样 细菌他克莫司代谢的生物标志物，我们将分析血液M1(细菌他克莫司代谢物) 水平和粪便M1的定量产生以评估它们与患者体内他克莫司低谷的关系 肾脏的变异性、急性排斥反应和新的供体特异性抗体的产生 移植。在目标1中，我们将鉴定与他克莫司代谢相关的肠道细菌种类。在目标2中， 我们将确定与患者体内他克莫司谷变异性相关的肠道细菌和血液图谱。 意义重大。我们的研究将使基于肠道和血液的生物标志物的开发成为可能，以识别肾脏 移植受者他克莫司波谷变异性的高风险。我们的研究将为 为肾移植受者提供更精确的免疫抑制治疗。

PROJECT SUMMARY Kidney transplantation is a life-saving procedure for patients with end-stage renal disease. Tacrolimus is utilized to prevent rejection of the kidney transplant but has a narrow therapeutic window with subtherapeutic tacrolimus levels associated with acute rejection and supratherapeutic levels associated with nephrotoxicity and neurotoxicity. Importantly, kidney transplant recipients with tacrolimus trough variability, i.e. marked intra-patient variation in tacrolimus trough levels, are at increased risk for acute rejection and kidney transplant loss. The factors predicting intra-patient tacrolimus trough variability, however, are not well understood. Our preliminary studies support a relationship between gut bacterial metabolism of tacrolimus and tacrolimus trough variability. The overall objective of this study is to define the relationship between the gut microbiota and tacrolimus trough variability in kidney transplant recipients. Our central hypothesis is that specific gut microbial species are associated with metabolism of tacrolimus and intra-patient tacrolimus trough variability. The hypothesis is based upon and inspired by our pilot studies: (1) Faecalibacterium, Blautia, and other commensal organisms directly metabolize tacrolimus into M1, a lesser active tacrolimus metabolite (2) M1 production is present in the fecal specimens of kidney transplant recipients (3) blood M1 is detected in kidney transplant recipients after oral administration of tacrolimus (Guo et al., Drug Metabo Dispos 47(3):194-202, 2019; Guo et al., Transplant Direct 6(10):e601, 2020). In this study, we will recruit 80 kidney transplant recipients for serial collection of fecal specimens during the first 3 months following transplantation and will profile the gut microbiome using metagenomic sequencing. As in vivo biomarkers of bacterial tacrolimus metabolism, we will profile blood M1 (the bacterial tacrolimus metabolite) levels and quantitative fecal M1 production to assess their relationships with intra-patient tacrolimus trough variability as well as acute rejection and de novo donor specific antibody development against the kidney transplant. In Aim 1, we will identify the gut bacterial species associated with tacrolimus metabolism. In Aim 2, we will determine the gut bacterial and blood profiles associated with intra-patient tacrolimus trough variability. Significance. Our study will enable development of gut-based and blood-based biomarkers to identify kidney transplant recipients at high risk for tacrolimus trough variability. Our study will provide the framework for providing improved precision delivery of immunosuppressive therapies in kidney transplant recipients.