The mycobiota, bone marrow transplantation, and clinical outcomes

项目摘要。 尽管异基因造血细胞移植（allo-HCT）取得了进展，但移植相关的发病率和 死亡率仍然是改善临床结果的实质性障碍。最近的一系列工作介绍了 人类肠道细菌微生物群的组成和密度变化的概念塑造了allo-HCT 结局，包括总生存期、非复发死亡率、急性移植物抗宿主病（GvH），以及 侵入性细菌感染。一个主要的知识差距涉及非细菌微生物群成分的作用 allo-HCT结果。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。在初步研究中，我们发现肠道真菌致病菌， 特别是念珠菌属，可以支配微生物群并穿过肠粘膜移位， 导致侵袭性真菌血流感染。在小鼠主要抗原错配allo-HCT模型中，我们发现 念珠菌肠道定植会加重移植结果，而药物诱导的 来自肠道的肠道真菌分别改善移植结果。然而，如何组成， 真菌生物群的多样性和数量与人类allo-HCT结果有关，特别是总体和 无复发存活率、GvH的发展和移植并发症仍然未知。基于 根据这些发现，这一提议的中心假设是人allo-HCT诱导肠道内 真菌生物群（密度，组成和多样性），并促进预测风险的真菌生态失调状态 急性GvH，以及总体和非复发死亡率。为了验证这一假设，我们收集了287名患者 allo-HCT研究队列（2017年1月1日至2018年12月31日期间移植），将随访 两年这一假设将在以下目标中进行探讨。目标1将定义规模，组成， 人类allo-HCT期间肠道菌群的多样性和稳定性，并确定抗真菌药物的影响 关于真菌动力学的药物目的2将定义肠道菌群与广泛的 allo-HCT的临床结局范围。这项拟议的研究将测量肠道动力学， allo-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态失调状态 实践，并定义真菌生物群变化与移植结果之间的关系。洞察 真菌生物群在allo-HCT结果中的作用将为测试基于真菌生物群或真菌生物群的结果提供机会。 干扰干预以获得临床益处。这项探索性研究依赖于一个独特的患者生物储存库， 真菌生物群分析的创新方法。除了allo-HCT，我们的研究结果可能具有 对于了解真菌生物群在其他器官移植中的影响具有高度信息性的潜力， 免疫受损的患者群体。

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.