The role of intestinal microbiota in graft-versus-host disease

肠道微生物群在移植物抗宿主病中的作用

基本信息

批准号：
9899952
负责人：
Marcel R M van den Brink
金额：
$ 55.02万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9899952
关键词：
Affect Allogenic Anaerobic Bacteria Animal Experiments Animal Model Animals Antibiotic Therapy Antibiotics Antibody Therapy Applications Grants Bacteria Bacteriophages Bone Marrow Transplantation Chemotherapy and/or radiation Clinic Clinical Clinical Trials Collection Colon Communities Complex Development Diet Disease Ecology Enterococcus Enterococcus faecalis Eubacterium Feces Fever Functional disorder Gnotobiotic Goals Health Hematologic Neoplasms Hematopoietic Hematopoietic Neoplasms Homeostasis Human Immune system Immunosuppression Individual Infection Inflammation Injury Intake Intestines Life Maintenance Microbe Morbidity - disease rate Mucolytics Mucous Membrane Mucous body substance Mus Neuraminidase Neutropenia Nutritional Organism Outcome Patients Pre-Clinical Model Precision therapeutics Quality of life RNA, Ribosomal, 16S Radiation therapy Regimen Relapse Role Safety Sampling Sepsis Series Severity of illness Structure Surface Time Tissues Toxic effect Translating Transplant Recipients Transplantation Volatile Fatty Acids Work base cancer recurrence cancer therapy commensal bacteria commensal microbes conditioning dysbiosis experience graft vs host disease gut microbiota hematopoietic cell transplantation human model immune function immunoregulation improved infection risk inhibitor/antagonist intestinal barrier man microbial community microbiota microbiota metabolites microbiota transplantation mortality mouse model next generation sequencing nutrition pathogenic bacteria post-transplant prebiotics precision medicine precision oncology precursor cell preservation prevent recurrent infection therapy development

项目摘要

Allogeneic hematopoietic-cell transplantation (allo-HCT) is an important treatment for hematological malignancies. The intestinal microbiota consists of a community of diverse microbes that reside in the intestine and are critical for host development, homeostasis, and immune regulation. In human analyses and animal experiments, we and others have shown that the intestinal microbiota contribute to the pathophysiology of all three major complications of allo-HCT: infections, GVHD, and relapse. Using 16S ribosomal RNA next-generation sequencing, we examined the intestinal microbiota of allo-HCT patients and found a post- transplant “microbiota injury”. This dysbiosis is likely due to the combined effects of (a) broad- spectrum antibiotics for the treatment of post-transplant febrile neutropenia and (b) the profound nutritional alterations experienced by these patients. We found an inverse relationship between a loss of the genus Blautia after allo-HCT and GVHD mortality. We observed that broad- spectrum antibiotics that target the anaerobic commensal flora are particularly associated with increases in GVHD-related mortality and in fact worsened intestinal GVHD in our animal model. The protective layer of intestinal mucus that normally contributes to barrier function was depleted in animals suffering from GVHD and treated with anaerobe-targeted antibiotics. Finally, we and others have observed an association between Enterococcus and the development of GVHD in mouse and man. Therefore, we hypothesize that the intestinal microbiota can regulate the development of GVHD and can be targeted to prevent or treat GVHD. We propose to study in Aim 1 the mechanisms by which microbiota (in particular Blautia and Enterococcus) and their metabolites modulate GVHD using gnotobiotic mice. In Aim 2 we will study the role of nutrition in the development of GVHD both in humans and mouse models. In allo-HCT patients we will correlate nutritional intake, microbiota composition and GVHD. In mouse models we will study a) the effects of the diet on the mucus layer, b) sialidase inhibitors to prevent mucus layer degradation, c) prebiotics to mitigate damage to the microbiota and mucus layer, and d) effects of short chain fatty acids on GVHD. In addition to elucidating the interactions of the intestinal microbiota and nutrition in the development of GVHD, this work will form the basis of clinical trials to reduce GVHD and transplant-related mortality.

异基因造血细胞移植（allo-HCT）是一种重要的治疗方法血液系统恶性肿瘤。肠道微生物群由多种微生物群组成。存在于肠道中的微生物对于宿主发育、体内平衡和在人体分析和动物实验中，我们和其他人已经证明了这一点。肠道微生物群对所有三种主要并发症的病理生理学都有贡献 allo-HCT：使用下一代 16S 核糖体 RNA 进行感染、GVHD 和复发。测序后，我们检查了异基因 HCT 患者的肠道微生物群，发现了移植“微生物群损伤”可能是由于（a）广泛的综合影响。用于治疗移植后发热性中性粒细胞减少症的谱抗生素和 (b) 我们发现这些患者经历的营养改变之间存在反比关系。 allo-HCT 和 GVHD 死亡率后，Blautia 属丧失。针对厌氧共生菌群的谱抗生素与在我们的动物模型中，GVHD 相关死亡率增加，事实上肠道 GVHD 恶化。通常有助于屏障功能的肠粘液保护层是在患有 GVHD 的动物中耗尽并用针对厌氧菌的抗生素进行治疗。我们和其他人观察到肠球菌与以下疾病的发展之间存在关联小鼠和人的 GVHD 因此，我们认为肠道微生物群可以调节。我们建议研究GVHD的发展并可以有针对性地预防或治疗GVHD。目标 1 微生物群（特别是布劳特氏菌和肠球菌）及其微生物的机制在目标 2 中，我们将研究营养的作用。在人类和小鼠模型中，我们将在异基因 HCT 患者中研究 GVHD 的发展。我们将在小鼠模型中研究营养摄入、微生物群组成和 GVHD 之间的关系。 a) 饮食对粘液层的影响，b) 唾液酸酶抑制剂阻止粘液层降解，c) 益生元减轻对微生物群和粘液层的损害，以及 d) 影响除了阐明肠道的相互作用外，还研究了短链脂肪酸对 GVHD 的影响。 GVHD 发展中的微生物群和营养，这项工作将构成临床基础降低 GVHD 和移植相关死亡率的试验。