The mycobiota, bone marrow transplantation, and clinical outcomes

项目总结。 尽管异基因造血细胞移植(allo-HCT)取得了进展，但与移植相关的发病率和 死亡率仍然是改善临床结果的重大障碍。最近的一系列工作介绍了 人类肠道细菌微生物区系组成和密度的变化形成allo-hct的概念 结果，包括总存活率、无复发死亡率、急性移植物抗宿主病(GVH)和 侵袭性细菌感染。一个主要的知识差距与非细菌微生物区系成分的作用有关。 在allo-HCT结果中。我们建立了一个高分辨率的生物信息学管道来分析肠道的作用 真菌，真菌生物群，在allo-HCT结果中。在试点研究中，我们发现肠道真菌致病菌， 尤其是假丝酵母菌，可以支配微生物区系，并通过肠道粘膜转移到 导致侵袭性真菌血液感染。在我们发现的小鼠主要抗原不匹配的allo-hct模型中 念珠菌的肠道定植加剧了移植结果，而药物诱导的消除 来自肠道的肠道真菌分别改善了移植结果。但是，构图是怎样的， 真菌区系的多样性和大小与人类异体血细胞移植的结果有关，特别是对于总体和 无复发存活率、GVH的发展和移植并发症仍不清楚。基于 这些发现，这一提议的中心假设是，人类allo-hct诱导肠道移位 真菌区系(在密度、组成和多样性方面)，并促进预测风险的真菌生物失调状态 急性GVH的死亡率和总的无复发死亡率。为了验证这一假设，我们召集了287名患者 Allo-HCT研究队列(在2017年1月1日至2018年12月31日期间移植)，将用于 两年了。这一假说将从以下几个方面进行探讨。目标1将定义规模、组成、 人类allo-HCT期间肠道真菌区系的多样性和稳定性以及抗真菌药物的影响 药物对真菌生物群动态的影响。目标2将定义肠道真菌生物群和广泛的 Allo-HCT的临床结果范围。这项拟议的研究将测量肠道的动力学。 异体HCT期间的真菌生物群，定义与移植相关和支持性护理相关的生物失调状态 实践，并定义了真菌生物群的转变和移植结果之间的关系。洞察 霉菌群在allo-HCT结果中的作用将打开测试基于真菌生物群或霉菌生物群的机会。 扰乱临床利益的干预措施。这项探索性研究依赖于独特的患者生物信息库和 真菌生物区系分析的创新方法。除了allo-HCT，我们的研究结果可能会有 对于理解真菌生物群在其他器官移植和治疗中的影响具有很高的信息量 免疫功能受损的患者群体。

PROJECT SUMMARY. Despite advances in allogeneic hematopoietic cell transplantation (allo-HCT), transplant-related morbidity and mortality remain substantial barriers to improving clinical outcomes. A recent body of work introduced the concept that shifts in the composition and density of the human intestinal bacterial microbiota shapes allo-HCT outcomes, including overall survival, non-relapse mortality, acute graft-versus-host disease (GvH), and invasive bacterial infections. A major knowledge gap relates to the role of non-bacterial microbiota constituents in allo-HCT outcomes. We established a high-resolution bioinformatics pipeline to analyze the role of intestinal fungi, the mycobiota, in allo-HCT outcomes. In pilot studies, we discovered that intestinal fungal pathobionts, specifically Candida species, can dominate the microbiota and translocate across the intestinal mucosa to cause invasive fungal bloodstream infections. In a murine major antigen mismatch allo-HCT model we found that Candida intestinal colonization exacerbates transplant outcomes while drug-induced elimination of intestinal fungi from the gut ameliorates transplant outcomes, respectively. However, how the composition, diversity, and magnitude of the mycobiota relates to human allo-HCT outcomes, specifically for overall and non-relapse survival, the development of GvH, and transplant complications, remains unknown. Based on these findings, the central hypothesis of this proposal is that human allo-HCT induces shifts in the intestinal mycobiota (in density, composition, and diversity) and promotes states of fungal dysbiosis that predict the risk of acute GvH, and overall and non-relapse mortality. To test this hypothesis, we have assembled a 287 patient allo-HCT study cohort (transplanted between January 1, 2017 and December 31, 2018) that will be followed for two years. This hypothesis will be explored in the following aims. Aim 1 will define the magnitude, composition, diversity, and stability of the intestinal mycobiota during human allo-HCT and identify the impact of antifungal drugs on mycobiota dynamics. Aim 2 will define the relationship between the intestinal mycobiota and a broad range of clinical outcomes in allo-HCT. The proposed study will measure the dynamics of the intestinal mycobiota during allo-HCT, define states of dysbiosis linked to transplant-related and supportive care practices, and define the relationship between shifts in the mycobiota and transplant outcomes. Insight into the role of mycobiota in allo-HCT outcomes will open opportunities to test mycobiota-based or mycobiota- perturbing interventions for clinical benefit. This exploratory study relies on a unique patient biorepository and innovative methodologies in mycobiota analyses. Beyond allo-HCT, the results of our study may have the potential to be highly informative for understanding the impact of the mycobiota in other organ transplant and immune compromised patient populations.