Fecal Microbiota Transplant National Registry

项目总结 粪便微生物移植(FMT)是治疗难辨梭状芽胞杆菌复发患者的既定治疗方法。 感染(CDI)。虽然大多数CDI患者都可以成功地治疗，但重症危重患者的亚群 暴发性CDI是一个更大的挑战，结肠切除率和死亡率都很高。此外，各种不同的 FMT的安全担忧依然存在。最近有关有害微生物传播的报告强调了有害微生物传播的风险 多重耐药生物的传播和致肠性大肠杆菌(EPEC)。此外，尽管大多数工作都有 专注于细菌，FMT还转移非细菌微生物，这些微生物的临床影响可能是 对充分理解FMT的临床意义很重要。因为肠道微生物区系也在 慢性疾病(如糖尿病、癌症、心脏病)的发病机制，FMT有可能导致 慢性疾病可能需要数年时间才能在临床上表现出来。最后，该领域正在随着发展而迅速演变 使用活微生物配制的商业产品，称为活生物治疗产品(LBPS)。因此， 关于FMT和LBPS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得到回答。 FMT国家登记处是研究这些关键问题的唯一合适的资源。注册表包括32 North 已建立基础设施以收集FMT临床数据的美国站点(以及另外19个待建中心) 捐赠者和接受者，以及一个单独的门户网站，从禁产技术接受者那里收集信息。注册处链接到一个 独立生物库还为研究人类肠道微生物区系的操纵提供了丰富的来源。 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了解 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 慢性医疗条件，与登记参与者中预定义慢性病的发病率进行比较 来自国家数据库的未接受FMT治疗的多次复发CDI患者的对照组；B) 确定FMT和LBPS治疗重症/暴发性住院患者的有效性的真实世界评估 CDI和确定与CURE相关的因素；以及c)扩大登记册，以包括新的LBPS，评估有效性 CDI与FMT在真实人群中的比较，以及检查CDI以外的LBPS的标签外使用情况。 第二个具体目标是表征散弹枪元基因组测序(SMS)和数据的潜在价值 作为一种平台技术的分析技术，用于识别和表征由FMT或LBPS传播的潜在有害微生物 通过首先确定SMS的敏感性和特异性，以使用 新出现的病原体，非典型EPEC(AEPEC)为原型。基因-表型分析将使用 体外生物检测和全基因组测序相结合。短信息系统识别这些疾病的敏感性和特异性 然后将通过粪便添加实验确定菌株及其毒力基因。此外，研究将是 研究FMT/LBP治疗对非细菌微生物耐药性和传播的影响 (病毒组、霉菌组)在严重/暴发性CDI治疗患者中使用SMS。

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.