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

• 批准号: 10374029
• 负责人: Marcel R M van den Brink
• 金额: $ 53.92万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 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/10374029
• 关键词: Affect; Allogenic; Anaerobic Bacteria; Animal Experiments; Animal Model; Animals; Antibiotic Therapy; Antibiotics; Antibody Therapy; Applications Grants; Bacteremia; Bacteria; Bacteriophages; Bone Marrow Transplantation; Chemotherapy and/or radiation; Clinic; Clinical; Clinical Trials; Collection; Colonic Diseases; 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; 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; 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

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）是治疗造血干细胞缺乏的重要方法。 血液恶性肿瘤肠道微生物群由多种多样的 肠道内的微生物，对宿主发育、体内平衡和 免疫调节在人体分析和动物实验中，我们和其他人已经表明， 肠道微生物群有助于所有三种主要并发症的病理生理学， allo-HCT：感染、GVHD和复发。使用16 S核糖体RNA下一代 测序，我们检查了allo-HCT患者的肠道微生物群，发现了一个后 移植“微生物群损伤”。这种生态失调可能是由于以下因素的综合影响：（a）广泛的- 用于治疗移植后发热性中性粒细胞减少症的广谱抗生素，和（B） 这些患者所经历的营养变化。我们发现， 在allo-HCT和GVHD死亡后布劳特氏菌属的损失。我们观察到，广泛的- 靶向厌氧藻类植物群的广谱抗生素特别与 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被破坏。 在患有GVHD的动物中耗尽并用厌氧菌靶向抗生素治疗。最后， 我们和其他人已经观察到肠球菌与 因此，我们假设肠道微生物群可以调节小鼠和人的GVHD。 GVHD的发展，并可以有针对性地预防或治疗GVHD。我们建议研究 在目的1中，微生物群（特别是布劳特氏菌属和肠球菌属）及其 代谢物调节GVHD。在目标2中，我们将研究营养的作用 在人类和小鼠模型中GVHD的发展中。在allo-HCT患者中， 将营养摄入、微生物群组成和GVHD相关联。在小鼠模型中， a）饮食对粘液层的影响，B）唾液酸酶抑制剂，以防止粘液层 降解，c）益生元，以减轻对微生物群和粘液层的损害，以及d）影响 对移植物抗宿主病的影响除了阐明肠道的相互作用， 微生物群和营养在GVHD的发展，这项工作将形成临床的基础 减少GVHD和移植相关死亡率的试验。