Department of Pharmacy Practice, Long Island University, New York, New York, United States of America.
Department of Pharmacy, NewYork-Presbyterian Hospital Columbia University Medical Center, New York, New York, United States of America.
PLoS One. 2020 May 29;15(5):e0233646. doi: 10.1371/journal.pone.0233646. eCollection 2020.
Effective tacrolimus (TAC) dosing is hampered by complex pharmacokinetics and significant patient variability. The gut microbiome, a key mediator of endotoxemia, inflammation and oxidative stress in advanced heart failure (HF) patients, is a possible contributor to interindividual variations in drug efficacy. The effect of alterations in the gut microbiome on TAC dosing requirements after heart transplant (HT) has not been explored.
We enrolled 24 patients (mean age = 55.8 ±2.3 years) within 3 months post-HT. Biomarkers of endotoxemia ((lipopolysaccharide (LPS)), inflammation (tumor necrosis factor-α (TNF-α)) and oxidative stress (8,12-iso-Isoprostane F-2alpha-VI) were measured in 16 blood samples. 22 stool samples were analyzed using 16S rRNA sequencing. TAC dose and serum trough level were measured at the time of stool and blood collection. TAC doses were reported in mg/kg/day and as level-to-dose (L/D) ratio, and categorized as ≤ vs. > median.
The median TAC dose was 0.1 mg/kg/day and L/D ratio was 100.01. Above the median daily weight-based TAC dose was associated with higher gut microbial alpha diversity (p = 0.03); similarly, TNF-α and 8,12-iso-Isoprostane F-2alpha-VI levels were lower and LPS levels were higher in the above median TAC group, although these findings were only marginally statistically significant and dependent on BMI adjustment. We observed n = 37 taxa to be significantly enriched among patients with > median TAC dose (all FDR<0.05), several of which are potential short-chain fatty acid producers with anti-inflammatory properties, including taxa from the family Subdoligranulum.
Our pilot study observed gut microbial alpha diversity to be increased while inflammation and oxidative stress were reduced among patients requiring higher TAC doses early after HT.
有效的他克莫司（TAC）剂量受到复杂的药代动力学和显著的个体差异的影响。肠道微生物组是晚期心力衰竭（HF）患者内毒素血症、炎症和氧化应激的主要调节因子，可能是药物疗效个体差异的一个贡献因素。肠道微生物组的改变对心脏移植（HT）后 TAC 剂量需求的影响尚未得到探索。
我们在 HT 后 3 个月内招募了 24 名患者（平均年龄=55.8±2.3 岁）。在 16 个血液样本中测量了内毒素血症的生物标志物（脂多糖（LPS））、炎症（肿瘤坏死因子-α（TNF-α））和氧化应激（8,12-异前列腺素 F-2alpha-VI）。使用 16S rRNA 测序分析了 22 个粪便样本。在采集粪便和血液时测量了 TAC 剂量和血清谷浓度。TAC 剂量以 mg/kg/天和水平剂量比（L/D）表示，并分为≤中位数和>中位数。
中位 TAC 剂量为 0.1mg/kg/天，L/D 比为 100.01。高于中位数的每日体重基础 TAC 剂量与更高的肠道微生物多样性相关（p=0.03）；同样，TNF-α和 8,12-异前列腺素 F-2alpha-VI 水平较低，LPS 水平较高，高于中位数的 TAC 组，但这些发现仅具有统计学意义边缘，且依赖于 BMI 调整。我们观察到 n=37 种细菌在 TAC 剂量高于中位数的患者中明显富集（所有 FDR<0.05），其中一些是具有抗炎特性的潜在短链脂肪酸产生菌，包括来自 Subdoligranulum 家族的细菌。
我们的初步研究观察到，在 HT 后早期需要更高 TAC 剂量的患者中，肠道微生物多样性增加，而炎症和氧化应激减少。
