Fecal Microbiota Transplant National Registry

项目摘要 粪便微生物群移植（FMT）是复发性艰难梭菌患者的既定治疗方法 感染（CDI）。虽然大多数CDI患者可以成功治疗，但严重急性疾病患者的亚组 而暴发性CDI则是一个更大的挑战，结肠切除率和死亡率都很高。此外，各种 FMT的安全问题仍然存在。最近的报告强调了有害微生物传播的风险， 多重耐药微生物和肠致病性E. coli（EPEC）。此外，虽然大多数工作 FMT专注于细菌，也转移非细菌微生物，这些微生物的临床影响可能是 重要的是充分理解FMT的临床意义。因为肠道微生物群也在 慢性医学病症的发病机理（例如，糖尿病，癌症，心脏病），FMT有可能导致 可能需要数年时间才能在临床上表现出来的慢性疾病。最后，该领域正在迅速发展， 用活微生物配制的商业产品，称为活微生物产品（LBP）。因此，在本发明中， 关于裂变材料条约和LBP在现实世界中的安全性和有效性的至关重要的问题仍然没有答案。 裂变材料条约国家登记处是研究这些关键问题的一个独特的适当资源。32北 具有收集FMT临床数据的既定基础设施的美国研究中心（以及19个其他中心待定） 此外，还设立了一个单独的门户网站，从接受资助者那里收集信息。注册表链接到 独立的生物库也为研究人类肠道微生物群的操纵提供了丰富的资源。 我们的第一个具体目标是通过以下方式扩大对FMT长期安全性和有效性的认识：A）继续 系统收集FMT后长达10年的临床元数据，以更好地定义安全性，包括发生 慢性疾病，与登记研究参与者中预定义慢性疾病的发生率进行比较 对照组为来自国家数据库的多次复发CDI患者，未接受FMT治疗; B） 确定FMT和LBP治疗重度/暴发性肺炎住院患者有效性的真实世界估计值 CDI并确定与治愈相关的因素;以及C）扩大登记以包括新的LBP，评估有效性 在现实世界人群中，与FMT相比，CDI，并检查LBP用于CDI以外适应症的标签外使用。 第二个具体目标是表征鸟枪宏基因组测序（SMS）和数据的潜在价值 分析作为一种平台技术，用于识别和表征由FMT或LBP传播的潜在有害微生物 通过首先确定SMS的灵敏度和特异性，以使用 新出现的病原体，非典型EPEC（aEPEC）为原型。将使用 体外生物测定和全基因组测序的组合。SMS识别这些的敏感性和特异性 然后通过粪便加标实验确定菌株及其毒力基因。此外，研究将 用于表征FMT/LBP治疗对非细菌微生物耐药组和传播的影响 （病毒组、真菌生物群）与SMS治疗重度/暴发性CDI患者。

PROJECT SUMMARY Fecal microbiota transplantation (FMT) is an established treatment for patients with recurrent Clostridioides difficile infection (CDI). Although most patients with CDI can be successfully treated, the subset of acutely ill patients with severe and fulminant CDI is a much greater challenge, with high rates of colectomy and mortality. Furthermore, a variety of safety concerns remain for FMT. The risk of transmission of harmful microbes is highlighted by recent reports of transmission of multi-drug resistant organisms and enteropathogenic E. coli (EPEC). In addition, although most work has focused on bacteria, FMT also transfers non-bacterial microorganisms, and the clinical impact of these microbes may be important in fully understanding the clinical implications of FMT. Because the gut microbiota also plays a role in the pathogenesis of chronic medical conditions (e.g., diabetes, cancer, heart disease), FMT has the potential to cause chronic conditions that might take years to manifest clinically. Finally, the field is rapidly evolving with the development of commercial products formulated with live microorganisms, known as live biotherapeutic products (LBPs). Thus, critically important questions regarding the real-world safety and effectiveness of FMT and LBPs remain unanswered. The FMT National Registry is a uniquely suited resource to study these key issues. The Registry includes 32 North American sites (and 19 additional centers pending) with an established infrastructure to collect clinical data on FMT donors and recipients and a separate portal to collect information from FMT recipients. The Registry’s link to an independent biobank also provides a rich source for studying manipulation of the gut microbiota in humans. Our first specific aim is to expand knowledge on the long-term safety and effectiveness of FMT by A) continuing systematic collection of clinical metadata up to 10 years post-FMT to better define safety, including risk of developing chronic medical conditions, with incidence rates for predefined chronic conditions in Registry participants compared with a control group of patients from a national database with multiply recurrent CDI not treated with FMT; B) determining real-world estimates of effectiveness of FMT and LBPs to treat hospitalized patients with severe/fulminant CDI and identify factors associated with cure; and C) expanding the registry to include new LBPs, assessing effectiveness for CDI as compared to FMT in real-world populations and examining off-label use of LBPs for indications beyond CDI. The second specific aim is to characterize the potential value of shotgun metagenomics sequencing (SMS) and data analytics as a platform technology to identify and characterize potentially harmful microbes transmitted by FMT or LBPs by first determining the sensitivity and specificity of SMS to identify and characterize bacterial pathogens using the emerging pathogen, atypical EPEC (aEPEC) as a prototype. Genotype-phenotype analyses will be performed using a combination of in vitro bioassays and whole genome sequencing. The sensitivity and specificity of SMS to identify these strains and their virulence genes will then be determined by fecal spiking experiments. Additionally, studies will be performed to characterize the impact of FMT/LBP therapy on the resistome and transmission of non-bacterial microbes (virome, mycobiome) with SMS in patients treated for severe/fulminant CDI.