Gut Microbiota and Tacrolimus Dosing in Kidney Transplantation

Tacrolimus dosing to establish therapeutic levels in recipients of organ transplants is a challenging task because of much interpatient and intrapatient variability in drug absorption, metabolism, and disposition. In view of the reported impact of gut microbial species on drug metabolism, we investigated the relationship between the gut microbiota and tacrolimus dosing requirements in this pilot study of adult kidney transplant recipients. Serial fecal specimens were collected during the first month of transplantation from 19 kidney transplant recipients who either required a 50% increase from initial tacrolimus dosing during the first month of transplantation (Dose Escalation Group, n=5) or did not require such an increase (Dose Stable Group, n=14). We characterized bacterial composition in the fecal specimens by deep sequencing of the PCR amplified 16S rRNA V4-V5 region and we investigated the hypothesis that gut microbial composition is associated with tacrolimus dosing requirements. Initial tacrolimus dosing was similar in the Dose Escalation Group and in the Stable Group (4.2±1.1 mg/day vs. 3.8±0.8 mg/day, respectively, P=0.61, two-way between-group ANOVA using contrasts) but became higher in the Dose Escalation Group than in the Dose Stable Group by the end of the first transplantation month (9.6±2.4 mg/day vs. 3.3±1.5 mg/day, respectively, P<0.001). Our systematic characterization of the gut microbial composition identified that fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was 11.8% in the Dose Escalation Group and 0.8% in the Dose Stable Group (P=0.002, Wilcoxon Rank Sum test, P<0.05 after Benjamini-Hochberg correction for multiple hypotheses). Fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was positively correlated with future tacrolimus dosing at 1 month (R=0.57, P=0.01) and had a coefficient±standard error of 1.0±0.6 (P=0.08) after multivariable linear regression. Our novel observations may help further explain inter-individual differences in tacrolimus dosing to achieve therapeutic levels.

在器官移植受体中，建立他克莫司（Tacrolimus）治疗血药浓度的给药方案是一项极具挑战性的工作，这是因为患者间与患者内在药物吸收、代谢及处置过程中存在显著异质性。鉴于已有研究报道肠道微生物菌种对药物代谢的影响，本项针对成人肾移植受者的预实验探讨了肠道菌群与他克莫司给药需求量之间的关联。
本研究于肾移植术后第一个月内，收集了19例肾移植受者的系列粪便标本；其中5例受者在术后第一个月内需将初始他克莫司给药剂量提升50%（剂量递增组，n=5），其余14例无需进行此类剂量调整（剂量稳定组，n=14）。研究人员通过对PCR扩增的16S rRNA V4-V5区进行深度测序，对粪便标本中的细菌组成进行了表征，并验证了“肠道菌群组成与他克莫司给药需求量相关”这一研究假说。
剂量递增组与剂量稳定组的初始他克莫司给药剂量相近（分别为4.2±1.1 mg/天与3.8±0.8 mg/天，采用对比法的组间双向方差分析P=0.61）；但至移植术后第一个月末，剂量递增组的给药剂量显著高于剂量稳定组（9.6±2.4 mg/天 vs 3.3±1.5 mg/天，P<0.001）。
本研究对肠道菌群组成的系统性表征分析显示，移植术后第一周的粪便普拉梭菌（Faecalibacterium prausnitzii）丰度，在剂量递增组为11.8%，在剂量稳定组为0.8%（P=0.002，威尔科克森秩和检验；经多重假设检验的本杰米尼-霍赫贝格（Benjamini-Hochberg）校正后P<0.05）。移植术后第一周的粪便普拉梭菌丰度与术后1个月时的后续他克莫司给药剂量呈正相关（R=0.57，P=0.01）；经多变量线性回归分析后，其回归系数±标准误为1.0±0.6（P=0.08）。
本研究的创新性观察结果，或有助于进一步阐明他克莫司给药的个体间差异，从而实现目标治疗血药浓度的精准给药。