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, PFaecalibacterium 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, PFaecalibacterium 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.针对器官移植受者，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，因为患者间及患者自身在药物吸收、代谢与处置过程中存在显著差异。鉴于已有研究报道肠道微生物群（gut microbiota）对药物代谢的影响，本项针对成人肾移植受者的初步研究探讨了肠道微生物群与他克莫司给药需求量之间的关联。 本研究共纳入19名成人肾移植受者，其中5名受者在移植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名受者无需调整剂量（剂量稳定组，n=14）；并在移植后第一个月内连续收集所有受者的粪便标本。通过对聚合酶链式反应（PCR）扩增的16S核糖体RNA（16S rRNA）V4-V5区域进行深度测序，对粪便标本中的细菌群落组成进行表征，并验证“肠道微生物群落组成与他克莫司给药需求量相关”这一假说。 两组初始他克莫司给药剂量无显著差异（剂量递增组：4.2±1.1 mg/天，剂量稳定组：3.8±0.8 mg/天，采用对照设计的组间双向方差分析（two-way between-group ANOVA），P=0.61）；至移植后第一个月末，剂量递增组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）。移植后第一周的普拉梭菌（Faecalibacterium prausnitzii）丰度在剂量递增组为11.8%，剂量稳定组为0.8%（威尔科克森秩和检验（Wilcoxon Rank Sum test），P=0.002）；普拉梭菌丰度与移植后1个月的未来他克莫司给药剂量呈正相关（相关系数R=0.57，P=0.01），经多元线性回归（multivariable linear regression）分析后，其回归系数±标准误为1.0±0.6（P=0.08）。 本研究的创新性发现有助于进一步阐释他克莫司给药剂量的个体差异，以实现目标治疗血药浓度。