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; 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.

同种异体造血细胞移植（Allo-HCT）是对 血液学恶性肿瘤。肠道菌群由潜水员组成 居住在肠道中的微生物，对于宿主发育，体内稳态和 免疫调节。在人类的分析和动物实验中，我们和其他人表明 肠道菌群有助于所有三个主要并发症的病理生理 Allo-HCT：感染，GVHD和浮雕。使用16S核糖体RNA下一代 测序，我们检查了Allo-HCT患者的肠菌群 移植“微生物损伤”。这种营养不良可能是由于（a）广泛的综合作用 用于治疗移植后热中性减少症和（b）的谱抗生素 这些患者经历的营养改变。我们发现 Allo-HCT和GVHD死亡率后，Blautia属的丧失。我们观察到了广泛的 靶向厌氧共生菌群的光谱抗生素特别与 在我们的动物模型中，与GVHD相关的死亡率增加，实际上使肠道GVHD恶化。 通常有助于屏障功能的肠粘膜保护层是 在患有GVHD的动物中耗尽，并用诱因的抗生素治疗。最后， 我们和其他人观察到肠球菌与发展 鼠标和人的GVHD。因此，我们假设肠菌可以调节 GVHD的发展，可以针对预防或治疗GVHD。我们建议学习 在AIM 1中 代谢物使用Gnotobiotic小鼠调节GVHD。在AIM 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，我们将 相关的营养摄入量，微生物群和GVHD。在鼠标模型中，我们将研究 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）益生元来减轻对菌群和粘液层的损害，d）效果 GVHD上的短链脂肪酸。除了阐明肠的相互作用 在GVHD开发中，微生物群和营养，这项工作将构成临床的基础 降低GVHD和移植相关死亡率的试验。