Gut Microbiota and Tacrolimus Trough Variability in Kidney Transplant Recipients

肾移植受者的肠道微生物群和他克莫司谷变异性

• 批准号: 10575456
• 负责人: Hyunyoung Jeong
• 金额: $ 26.15万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10575456
• 关键词: Acute; Biological Markers; Blood; Clinical; Clinical Research; Collection; Development; End stage renal failure; Immunologics; Immunosuppressive Agents; In Vitro; Individual; Kidney Transplantation; Life; Measurement; Metabolism; Monitor; Oral Administration; Organism; Outcome; Parents; Patients; Pharmaceutical Preparations; Pilot Projects; Population; Predictive Factor; Procedures; Production; Research Design; Risk; Specimen; Study Section; Tacrolimus; Therapeutic; Therapeutic immunosuppression; Transplant Recipients; Transplantation; Work; bacterial metabolism; blood-based biomarker; donor-specific antibody; gut microbes; gut microbiome; gut microbiota; high risk; improved; in vivo; metagenomic sequencing; nephrotoxicity; neurotoxicity; novel strategies; patient variability; personalized approach; predictive marker; prevent; recruit; secondary analysis; Acute; Biological Markers; Blood; Clinical; Clinical Research; Collection; Development; End stage renal failure; Immunologics; Immunosuppressive Agents; In Vitro; Individual; Kidney Transplantation; Life; Measurement; Metabolism; Monitor; Oral Administration; Organism; Outcome; Parents; Patients; Pharmaceutical Preparations; Pilot Projects; Population; Predictive Factor; Procedures; Production; Research Design; Risk; Specimen; Study Section; Tacrolimus; Therapeutic; Therapeutic immunosuppression; Transplant Recipients; Transplantation; Work; bacterial metabolism; blood-based biomarker; donor-specific antibody; gut microbes; gut microbiome; gut microbiota; high risk; improved; in vivo; metagenomic sequencing; nephrotoxicity; neurotoxicity; novel strategies; patient variability; personalized approach; predictive marker; prevent; recruit; secondary analysis

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.

项目摘要 肾脏移植是末期肾脏疾病患者的挽救生命程序。他克莫司被利用 为了防止拒绝肾脏移植，但具有狭窄的治疗窗口，他克莫司 与与肾毒性相关的急性排斥和急性上的水平相关的水平 神经毒性。重要的是，他克莫司槽变异性的肾脏移植受者，即明显的患者 他克莫司谷水平的变化，急性排斥和肾脏移植损失的风险增加。这 然而，预测患者他克莫司槽变异性的因素尚不清楚。我们的初步 研究支持他克莫司的肠道细菌代谢与他克莫司槽变异性之间的关系。 这项研究的总体目的是定义肠道微生物群和他克莫司之间的关系 肾脏移植受体的槽变异性。我们的中心假设是特定的肠道微生物物种 与他克莫司和患者他克莫司槽变异性的代谢有关。该假设是 基于我们的试点研究和启发：（1）粪便菌，蓝菌和其他共生生物 将他克莫司直接代谢成M1，在较小的活性他克莫司代谢物（2）M1产生中存在于 肾移植受体的粪便标本（3）在口服后肾脏移植受体中检测到血液M1 他克莫司的给药（Guo等人，药物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个肾脏移植受者，以串行第一个粪便标本的系列收集 移植后3个月，将使用元基因组测序介绍肠道微生物组。如体内 细菌他克莫司代谢的生物标志物，我们将介绍血液M1（细菌他克莫司代谢产物） 水平和定量的粪便M1产生，以评估其与患者内他克莫司槽的关系 可变性以及急性排斥和从头供体特异性抗体开发针对肾脏 移植。在AIM 1中，我们将确定与他克莫司代谢相关的肠道细菌。在AIM 2中， 我们将确定肠道细菌和血液谱与患者内他克莫司槽变异性相关。 意义。我们的研究将使基于肠道和基于血液的生物标志物能够识别肾脏 克莫司槽变异性高风险的移植受者。我们的研究将为 在肾脏移植受者中提供了改进的免疫抑制疗法的精确递送。