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

中文翻译：

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一项安慰剂对照临床试验揭示了研究性微生物治疗药物 RBX2660 对肠道微生物组和耐药组的影响。


肠道微生物群的恢复可以通过用健康捐赠者的微生物群补充受试者受干扰的微生物群来实现。复发性艰难梭菌感染（rCDI）是这种治疗的关键应用之一。另一个令人感兴趣的新兴应用是减少抗生素抗性基因（ARG）和生物体（ARO）。在这项研究中，我们研究了基于微生物群的研究药物 RBX2660 的多中心、随机、双盲、安慰剂对照 2b 期研究的粪便标本。通过灌肠向患者施用安慰剂、1 剂 RBX2660 和 1 剂安慰剂，或 2 剂 RBX2660，并纵向跟踪其微生物组和抗生素耐药组的变化。所有患者在治疗后的前 7 天内都表现出肠道微生物组多样性的显着恢复和 ARG 相对丰度的降低。然而，与安慰剂相比，RBX2660 接受者的微生物组和抗性组从未受干扰的个体向平均配置的转变更为显着且持续时间更长。我们使用一种新颖的“移植指数”指标量化了 RBX2660 对微生物组和抗性组的修饰。我们确定了区分非移植患者的基线微生物组和移植过程中特别富集的分类群的分类学和代谢特征。我们阐明了抗性组和分类学移植与患者特异性和 RBX2660 特异性 ARG 的治疗后动态之间的相关性。对 RBX2660 产品和患者样本培养的 ARO 进行全基因组测序表明，通过 RBX2660 给药，患者体内的 ARO 被根除，但在较小程度上也引入了 RBX2660 衍生的 ARO。 通过鸟枪法宏基因组测序，我们阐明了 RBX2660 在微生物组和抗性组中的作用。仅停用抗生素即可导致肠道微生物多样性显着恢复并降低 ARG 相对丰度，但通过将 RBX2660 微生物群移植到受体中，RBX2660 给药可以更快、更彻底地改变患者微生物组、耐药组和 ARO 定植的组成。尽管 ARG 和 ARO 是通过 RBX2660 传播的，但 RBX2660 后的抗药性组更类似于施用产品（供体的代表）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