Intestinal microbiome restoration in allogeneic stem cell transplantation

项目总结 异基因造血细胞移植(allo-hct)通常与已知的临床并发症有关。 移植物抗宿主病(GVHD)是异基因HCT后死亡率的主要驱动因素。当前解决问题的方法 GVHD的预防主要是免疫抑制疗法，它可以抑制预期的 移植免疫细胞对抗肿瘤并导致延迟的免疫重建。胃肠道(GI) 微生物区系是体内最高的微生物定殖率，长期以来一直被认为是导致 移植物抗宿主病的病理生理学。事实上，接受allo-hct的患者会受到戏剧性的免疫学和 微生物区系扰动，在HCT前发展并在移植期间持续；GI微生物组多样性之前 和移植后与临床结果独立相关。当GVHD发生时，胃肠道是 经常受累，患者经常死于移植物抗宿主病。预防GVHD和其他疾病的新方法 移植相关的并发症是迫切需要的。我们假设恢复肠道健康 HCT后早期微生物群落是可行的，并与移植结果和免疫力的改善有关 重建。在两项粪便微生物区系移植(FMT)用于allo-HCT的研究中，我们小组报告了一种FMT 干预是恢复微生物区系多样性的安全方法。然而，FMT具有批次到批次的可变性 对特定的捐赠者有影响，并带有传染生物或抗生素耐药基因传播的风险。 在这里，我们提出了一种全新的方法：一种合理设计的口腔生态胶囊，它提供了一种明确的 纯细菌菌株的组成。一种口服的、明确的菌株混合物提供了可预测和 可重现的药理，并将立即扩展到未来的研究。关于这项多PI提案，我们 将利用正在进行的、由研究人员发起的多中心安慰剂对照1b期试验的样本， 由Pi Doris Ponce领导，这是人类第一次评估克隆衍生的多菌株细菌联合体 胃肠道微生物群的预防和修复(NCT04995653)。我们的团队已经在一个大型的多中心展出 早期肠道微生物群失调在中心间普遍存在并与 移植结果。此外，微生物群失调的创新临床前模型是 翻译研究和拟议的微生物组分析。项目目标：与Pi Marcel van den一起 Brink，评估allo-HCT受者肠道微生物区系恢复的效果。我们将追求2个具体的 旨在评估GI微生物组中微生物组修复的效果，allo-HCT结果，以及 免疫重建。预期结果：结果将为互动提供新的机械性见解 肠道微生物群和宿主免疫之间的关系。影响：研究结果将为未来的研究提供信息，不仅是 减少移植相关并发症，包括移植物抗宿主病，但也适用于胃肠道损伤的其他情况 发生化疗和/或辐射引起的毒性和非恶性炎症性胃肠道疾病。 拟议的项目概述了一种全新的框架，用于靶向HCT中的GI微生物组。

PROJECT SUMMARY Allogeneic hematopoietic cell transplantation (allo-HCT) is often associated with a clinical complication known as graft-versus-host disease (GVHD), a major driver of mortality after allo-HCT. Current approaches to the prophylaxis of GVHD are primarily immunosuppressive therapies that can dampen the intended activity of the transplanted immune cells against the tumor and cause delayed immune reconstitution. Gastrointestinal (GI) microbiota, the highest microbial colonization in the body, has long been understood to contribute to the pathophysiology of GVHD. Indeed, patients undergoing allo-HCT are subject to dramatic immunological and microbiota perturbations, developing pre-HCT and continuing during transplant; GI microbiome diversity before and after transplant are independently associated with clinical outcome. When GVHD occurs, the GI tract is frequently involved, and patients often succumb to GVHD. New approaches to prevent GVHD and other transplant-related complications are urgently needed. We hypothesize that restoring the health of the intestinal microbial community early post-HCT is feasible and associated with improved transplant outcomes and immune reconstitution. In 2 studies of fecal microbiota transplantation (FMT) in allo-HCT, our group reported that an FMT intervention is a safe way to restore microbiota diversity. However, FMT has batch-to-batch variability depending on specific donors and carries the risks of transmission of infectious organisms or antibiotic-resistance genes. Here, we propose an entirely novel approach: a rationally designed oral-ecobiotic capsule that delivers a defined composition of pure bacterial strains. An oral, defined blend of strains offers advantages of predictable and reproducible pharmacology and would be immediately scalable to future studies. On this multi-PI proposal, we will capitalize on samples from an ongoing, investigator-initiated multicenter placebo-controlled phase 1b trial, led by PI Doris Ponce, which is first-in-human evaluating a clonally-derived multi-strain bacterial consortia for the prevention and restoration of the GI microbiome (NCT04995653). Our group has shown in a large multicenter study that early intestinal microbiome dysbiosis occurred universally among centers and had an association with transplant outcomes. In addition, innovative preclinical models of microbiome dysbiosis serve as the basis for the translational study and proposed microbiome analyses. Project objectives: Along with PI Marcel van den Brink, to evaluate the effects of intestinal microbiota restoration in allo-HCT recipients. We will pursue 2 specific aims that will evaluate the effects of microbiome restoration in the GI microbiome, allo-HCT outcomes, and immune reconstitution. Expected outcome: Results will provide new mechanistic insights into interactions between the intestinal microbiome and host immunity. Impact: Findings will inform future research not only for the reduction of transplant-related complications including GVHD, but also for other conditions in which GI injury occurs such as chemotherapy and/or radiation-induced toxicity and non-malignant inflammatory GI conditions. The proposed project outlines an entirely novel framework for targeting the GI microbiome in HCT.