Wang Lin, Liu Linsheng, Liu Xiaoxue, Xiang Min, Zhou Ling, Huang Chenrong, Shen Zhenya, Miao Liyan
College of Pharmaceutical Science, Soochow University, Suzhou, China; Suzhou Vocational Health College, Suzhou, China.
Department of Clinical Pharmacology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Pharmacol Res. 2020 Sep;159:104979. doi: 10.1016/j.phrs.2020.104979. Epub 2020 Jun 4.
Numerous algorithms based on patient genetic variants have been established with the aim of reducing the risk of GI bleeding and thromboembolism during warfarin administration. However, approximately 35 % of individual warfarin sensitivity still remains unexplained. Few of warfarin algorithms take into account gut microbiota profiles. The identification of certain microbiome will provide new targets and new strategies for reducing the risk of bleeding and thromboembolism during warfarin administration. In this study, we collected plasma and stool samples from 200 inpatients undergoing heart valve replacement (HVR), which were classified as low responder (LR), high responder (HR) and normal responder (NR). Significant differences were observed in the diversity and relative abundance of the gut microbiota among the three groups. The genus Escherichia-Shigella was enriched significantly in the LRs (P = 3.189e), while the genus Enterococcus was enriched significantly in the HRs (P = 1.249e). The amount of VK2 synthesized by gut microbiota in LR group was much higher than that in HR group (P = 0.005). Whole genome shotgun sequencing indicated that the relative abundance of enzymes and modules associated with VK biosynthesis was significantly higher in LRs than in HRs or NRs. The 12 microbial markers were identified through tenfold cross-validation with a random forest model. The results provided a new microbial diagnostic model that can be used to inform modulation of warfarin dosage on the basis of patient intestinal flora composition.
为降低华法林治疗期间胃肠道出血和血栓栓塞的风险，已经建立了许多基于患者基因变异的算法。然而，约35%的个体对华法林的敏感性仍无法解释。很少有华法林算法考虑肠道微生物群特征。确定某些微生物群将为降低华法林治疗期间出血和血栓栓塞的风险提供新的靶点和新的策略。在本研究中，我们收集了200例接受心脏瓣膜置换术（HVR）的住院患者的血浆和粪便样本，这些患者被分为低反应者（LR）、高反应者（HR）和正常反应者（NR）。三组患者的肠道微生物群在多样性和相对丰度上存在显著差异。大肠埃希菌-志贺菌属在低反应者中显著富集（P = 3.189e），而肠球菌属在高反应者中显著富集（P = 1.249e）。低反应者组中肠道微生物群合成的VK2量远高于高反应者组（P = 0.005）。全基因组鸟枪法测序表明，与VK生物合成相关的酶和模块的相对丰度在低反应者中显著高于高反应者或正常反应者。通过随机森林模型的十折交叉验证确定了12个微生物标志物。结果提供了一种新的微生物诊断模型，可用于根据患者肠道菌群组成调整华法林剂量。
