The Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine in St. Louis, St. Louis, MO, 63110, USA.
Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, 63110, USA.
Microbiome. 2020 Aug 31;8(1):125. doi: 10.1186/s40168-020-00907-9.
Intestinal microbiota restoration can be achieved by complementing a subject's perturbed microbiota with that of a healthy donor. Recurrent Clostridioides difficile infection (rCDI) is one key application of such treatment. Another emerging application of interest is reducing antibiotic-resistant genes (ARGs) and organisms (AROs). In this study, we investigated fecal specimens from a multicenter, randomized, double-blind, placebo-controlled phase 2b study of microbiota-based investigational drug RBX2660. Patients were administered either placebo, 1 dose of RBX2660 and 1 placebo, or 2 doses of RBX2660 via enema and longitudinally tracked for changes in their microbiome and antibiotic resistome.
All patients exhibited significant recovery of gut microbiome diversity and a decrease of ARG relative abundance during the first 7 days post-treatment. However, the microbiome and resistome shifts toward average configurations from unperturbed individuals were more significant and longer-lasting in RBX2660 recipients compared to placebo. We quantified microbiome and resistome modification by RBX2660 using a novel "transplantation index" metric. We identified taxonomic and metabolic features distinguishing the baseline microbiome of non-transplanted patients and taxa specifically enriched during the process of transplantation. We elucidated the correlation between resistome and taxonomic transplantations and post-treatment dynamics of patient-specific and RBX2660-specific ARGs. Whole genome sequencing of AROs cultured from RBX2660 product and patient samples indicate ARO eradication in patients via RBX2660 administration, but also, to a lesser extent, introduction of RBX2660-derived AROs.
Through shotgun metagenomic sequencing, we elucidated the effects of RBX2660 in the microbiome and resistome. Antibiotic discontinuation alone resulted in significant recovery of gut microbial diversity and reduced ARG relative abundance, but RBX2660 administration more rapidly and completely changed the composition of patients' microbiome, resistome, and ARO colonization by transplanting RBX2660 microbiota into the recipients. Although ARGs and AROs were transmitted through RBX2660, the resistome post-RBX2660 more closely resembled that of the administered product-a proxy for the donor-than an antibiotic perturbed state.
ClinicalTrials.gov, NCT02299570 . Registered 19 November 2014 Video Abstract.
通过用健康供体的微生物群来补充受扰主体的微生物群，可以实现肠道微生物群的恢复。复发性艰难梭菌感染（rCDI）是这种治疗的一个关键应用。另一个新兴的应用是减少抗生素耐药基因（ARGs）和生物体（AROs）。在这项研究中，我们调查了来自多中心、随机、双盲、安慰剂对照的 2b 期基于微生物组的研究药物 RBX2660 的粪便标本。患者接受安慰剂、RBX2660 单次剂量和安慰剂、RBX2660 两次灌肠，纵向跟踪他们的微生物组和抗生素抗性组的变化。
所有患者在治疗后 7 天内表现出肠道微生物组多样性显著恢复，ARG 相对丰度下降。然而，与安慰剂相比，RBX2660 受体的微生物组和抗性组向未受干扰个体的平均结构的转变更为显著且持续时间更长。我们使用一种新的“移植指数”度量标准来量化 RBX2660 对微生物组和抗性组的修饰。我们确定了区分未移植患者基线微生物组的分类和代谢特征，以及在移植过程中特异性富集的分类群。我们阐明了抗性组和分类群移植之间的相关性以及患者特异性和 RBX2660 特异性 ARGs 的治疗后动态。从 RBX2660 产品和患者样本中培养的 ARO 的全基因组测序表明，通过 RBX2660 给药可以在患者中消除 ARO，但也在较小程度上引入了 RBX2660 衍生的 ARO。
通过 shotgun 宏基因组测序，我们阐明了 RBX2660 在微生物组和抗性组中的作用。抗生素停药本身导致肠道微生物多样性显著恢复，ARG 相对丰度降低，但 RBX2660 给药更迅速、更完全地改变了患者微生物组、抗性组和 ARO 定植的组成，将 RBX2660 微生物群移植到受体中。尽管 ARGs 和 AROs 通过 RBX2660 传播，但 RBX2660 后的抗性组更类似于给药产品的抗性组，而不是抗生素扰动状态。
ClinicalTrials.gov，NCT02299570。2014 年 11 月 19 日注册 视频摘要。
