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: 10524114
• 负责人: Marcel R M van den Brink
• 金额: $ 4.13万
• 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/10524114
• 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.

同种异体造血细胞移植（allo-HCT）是一种重要的治疗方法