The mycobiota, bone marrow transplantation, and clinical outcomes

真菌群、骨髓移植和临床结果

• 批准号: 10303678
• 负责人: TOBIAS M HOHL
• 金额: $ 26.55万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303678
• 关键词: Acute Graft Versus Host Disease; Affect; Allogenic; Anaerobic Bacteria; Anti-Bacterial Agents; Antibiotics; Antifungal Agents; Antigens; Archaea; Bacteria; Bacterial Antibiotic Resistance; Bacterial Infections; Bone Marrow Transplantation; Candida; Clinical; Clinical Trials; Cohort Studies; Communities; Complex; Data; Development; Engraftment; Enterococcus faecium; Fluconazole; Goals; Hematologic Neoplasms; Hematological Disease; Human; Immune; Incidence; Infection; Intervention; Intestinal Mucosa; Intestines; Knowledge; Life; Link; Longterm Follow-up; Malignant - descriptor; Measures; Medical; Medicine; Methodology; Modeling; Morbidity - disease rate; Mucous Membrane; Mus; Mycoses; Nature; Nested Case-Control Study; Non-Malignant; Organ Transplantation; Outcome; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pilot Projects; Pre-Clinical Model; Prophylactic treatment; Publishing; Randomized; Recombinant DNA; Resolution; Risk; Role; Sampling; Sepsis; Severities; Shapes; Structure; Supportive care; Swab; Testing; Transplant Recipients; Transplantation; Vancomycin resistant enterococcus; Virus; antimicrobial; arm; bacterial community; base; bench to bedside; biobank; bioinformatics pipeline; candidemia; chemotherapy; clinically relevant; cohort; conditioning; curative treatments; density; dysbiosis; fungal microbiota; fungus; gastrointestinal; graft vs host disease; gut colonization; gut microbiota; hematopoietic cell transplantation; improved; innovation; insight; microbiota; mortality; mouse model; pathobiont; patient population; prevent; prospective

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.

项目摘要。 尽管同种异体造血细胞移植（Allo-HCT）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。最近的工作介绍了 人类肠道细菌菌群的组成和密度转移的概念会塑造allo-hct 结局，包括总体生存，非释放死亡率，急性移植物抗宿主病（GVH）和 侵入性细菌感染。一个主要的知识差距与非细菌微生物群成分的作用有关 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，以分析肠的作用 真菌，Mycobiota，在Allo-HCT结果中。在试点研究中，我们发现肠道真菌病原体， 特别是念珠菌物种，可以统治微生物群，并在肠粘膜上转运至 引起侵入性真菌血液感染。在我们发现的鼠主要抗原不匹配的Allo-HCT模型中 念珠菌肠道定植加剧了移植结果，而药物引起的消除 来自肠道的肠道真菌分别改善了移植结果。但是，构图如何 Mycobiota的多样性和大小与人类Allo-HCT结果有关，特别是整体和 非释放生存，GVH的发展和移植并发症，仍然未知。基于 这些发现，该提议的中心假设是人类Allo-HCT引起了肠道的变化 Mycobiota（密度，组成和多样性）并促进真菌营养不良状态，以预测风险 急性GVH，总体和非释放死亡率。为了检验这一假设，我们组装了287名患者 Allo-HCT研究队列（在2017年1月1日至2018年12月31日之间移植）将遵循 两年。该假设将在以下目的中进行探讨。 AIM 1将定义大小，组成， 人类Allo-HCT期间肠道菌群的多样性和稳定性，并确定抗真菌的影响 菌根动力学上的药物。 AIM 2将定义肠道菌群与广泛的关系之间的关系 Allo-HCT中的临床结果范围。拟议的研究将测量肠的动力学 在Allo-HCT期间的菌根，定义与移植相关和支持性护理有关的营养不良状态 实践，并定义了amcobiota的转变与移植结果之间的关系。深入了解 Mycobiota在Allo-HCT结果中的作用将为测试基于Mycobiota或Mycobiota- 为临床益处的干预措施。这项探索性研究依赖于独特的患者生物疗法和 Mycobiota分析中的创新方法。除了Allo-HCT之外，我们研究的结果可能具有 有可能了解Mycobiota对其他器官移植的影响的潜力 免疫损害患者人群。