The mycobiota, bone marrow transplantation, and clinical outcomes

真菌群、骨髓移植和临床结果

• 批准号: 10415200
• 负责人: TOBIAS M HOHL
• 金额: $ 22.13万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10415200
• 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; Resolution; Ribosomal DNA; 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）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重大障碍。最近的一项工作介绍了 人类肠道细菌微生物群的组成和密度的变化塑造了 allo-HCT 的概念 结果，包括总生存率、非复发死亡率、急性移植物抗宿主病（GvH）和 侵袭性细菌感染。主要的知识差距与非细菌微生物群成分的作用有关 同种异体 HCT 结果。我们建立了高分辨率生物信息学管道来分析肠道的作用 真菌（真菌生物群）在同种异体 HCT 结果中的作用。在初步研究中，我们发现肠道真菌病原体， 特别是念珠菌属，可以主导微生物群并穿过肠粘膜转移到 引起侵袭性真菌血流感染。在小鼠主要抗原错配同种异体 HCT 模型中，我们发现 念珠菌肠道定植会加剧移植结果，而药物诱导的消除 来自肠道的肠道真菌分别改善移植结果。然而，如何组成， 真菌群的多样性和规模与人类同种异体 HCT 结果相关，特别是总体和 非复发生存率、GvH 的发生和移植并发症仍不清楚。基于 根据这些发现，该提案的中心假设是人类同种异体 HCT 诱导肠道变化 真菌群（密度、组成和多样性）并促进预测风险的真菌失调状态 急性 GvH 以及总体死亡率和非复发死亡率。为了检验这个假设，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）将被跟踪 两年。该假设将在以下目标中进行探讨。目标 1 将定义震级、组成、 人类同种异体 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 影响真菌群动态的药物。目标 2 将定义肠道菌群与广泛的菌群之间的关系 allo-HCT 的临床结果范围。拟议的研究将测量肠道的动态 allo-HCT 期间的真菌群，定义与移植相关和支持性护理相关的生态失调状态 实践，并定义分枝菌群变化与移植结果之间的关系。洞察 菌群在同种异体 HCT 结果中的作用将为测试基于菌群或菌群的机会提供机会 扰乱干预措施以获得临床益处。这项探索性研究依赖于独特的患者生物储存库和 菌群分析的创新方法。除了allo-HCT之外，我们的研究结果可能还有 对于了解真菌群在其他器官移植中的影响有潜力提供丰富的信息 免疫受损的患者群体。