The Gut Microbiota and Graft versus Host Disease (GVHD)

肠道微生物群和移植物抗宿主病 (GVHD)

• 批准号: 10287495
• 负责人: DAVID Neal FREDRICKS
• 金额: $ 23.18万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-11-09 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10287495
• 关键词: Affect; Allogenic; Animals; Aplastic Anemia; Bacillus; Bacteria; Bacterial Genes; Bacteroidaceae; Bile Acids; Bile Acids and Salts; Bile fluid; Biochemical Pathway; Biological Assay; Biological Markers; Biota; Bone Marrow Transplantation; Butyrates; Cells; Cellular Metabolic Process; Cessation of life; Chemicals; Chromatography; Communities; Complication; Coupled; DNA; Data; Development; Diagnosis; Diarrhea; Diet; Dietary Carbohydrates; Disease; Disease Outcome; Engineering; Engraftment; Environment; Enzymes; Exanthema; Family; Feces; Food; Future; Genes; Germ-Free; Glucocorticoids; Goals; HLA Antigens; High-Throughput Nucleotide Sequencing; Homologous Transplantation; Human; Immune; Immunity; Immunologic Deficiency Syndromes; Immunosuppression; Immunosuppressive Agents; Inflammatory Response; Intestines; Knowledge; Lead; Life; Link; Liver; Longitudinal Studies; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Metabolic; Metabolic Pathway; Metabolism; Metagenomics; Microbe; Mucins; Multiple Myeloma; Mus; Organ; Outcome; Pathology; Patients; Play; Prevention; Prevention approach; Probiotics; Production; Proteobacteria; Quality of life; Recovery; Refractory; Research; Risk; Risk Assessment; Role; Severities; Shotgun Sequencing; Skin; Steroids; Symptoms; T-Lymphocyte; Taxonomy; Tissues; Toxic effect; Transplant Recipients; Transplantation; United States; Volatile Fatty Acids; bacterial community; base; bile salts; chronic graft versus host disease; cohort; disorder control; disorder risk; fecal transplantation; gene network; graft vs host disease; gut bacteria; gut microbes; gut microbiota; hematopoietic cell transplantation; human data; immunoprophylaxis; intestinal epithelium; leukemia/lymphoma; liver inflammation; macromolecule; member; metagenome; metagenomic sequencing; microbial; microbial community; microbiota; mortality; novel strategies; organ injury; prebiotics; prevent; rRNA Genes; restoration; small molecule; stool sample; therapy design; treatment response; wound healing

Abstract: The Gut Microbiota and Graft-versus-Host Disease Hematopoietic cell transplantation (HCT) can be lifesaving for the treatment of numerous conditions, including leukemia, lymphoma, aplastic anemia, multiple myeloma, some immunodeficiencies, and other diseases. Unfortunately, graft-versus-host disease (GVHD) is a common complication of HCT, affecting up to 50% of allogeneic transplant recipients, despite human leukocyte antigen (HLA) matching between donor and recipient and despite use of immunoprophylaxis. GVHD most commonly affects the gut, liver, and skin, producing diarrhea, liver inflammation, and rashes, with varying stages (degrees) of organ involvement in different patients. GVHD is thought to arise from immune cells (e.g. T cells) in the graft that recognize host tissues as foreign and propagate an inflammatory response. It is unclear why some HCT recipients with equivalent HLA matching develop GVHD while others are spared, and why some patients with GVHD respond to immune suppression with glucocorticoid treatment while others develop steroid-refractory GVHD with high mortality. Some murine studies of bone marrow transplantation have shown that germ-free animals are protected from GHVD, and human studies have suggested that patients with GVHD have a less diverse gut microbiota early after transplant, pointing to the important role that microbes play in GVHD. This study will investigate which gut bacterial species or communities are most associated with risk of GVHD in a longitudinal study of HCT recipients where stool samples are collected weekly for 100 days, then monthly for 9 months, and subjected to broad-range 16S rRNA gene PCR with high-throughput sequencing for species-level taxonomic identification of bacteria. Stool samples from these patients will also be assayed for small molecule metabolites produced by the bacteria-host interaction that may mediate GVHD, such as short chain fatty acids and bile salts. The goal of this aim is to identify potential chemical effectors of GVHD. Metagenomic sequencing of stool DNA will be used to assess the functional and metabolic capability of gut bacterial communities to illuminate how particular bacterial communities produce metabolites linked to GVHD risk, and to identify particular bacterial species or strains with the metabolic machinery for impacting GVHD risk. Knowledge gained from this study could be used in the future to design interventions to reduce the risk of GVHD based on targeted manipulation of the gut microbiota. For example, identification of particular bacterial species or strains linked to protection from GVHD, and to the production of metabolites that mediate this protection, could lead to the development of probiotics or engineered bacterial communities for reducing GVHD risk or treating GVHD. Alternatively, enhancing the production of beneficial metabolites through exogenous administration or use of prebiotics, and blocking the production of harmful metabolites could emerge as another approach for mitigating GVHD without further immune suppression in these very compromised patients.

摘要：肠道微生物群和移植物 - 宿主病 造血细胞移植（HCT）可以挽救许多疾病，包括 白血病，淋巴瘤，性贫血，多发性骨髓瘤，一些免疫缺陷和其他疾病。 不幸的是，移植物抗宿主病（GVHD）是HCT的常见并发症，影响多达50％ 尽管人类白细胞抗原（HLA）匹配供体和接受者，但同种异体移植受者 尽管使用了免疫预防。 GVHD最常见地影响肠道，肝脏和皮肤，产生 腹泻，肝炎和皮疹，器官参与不同的阶段（程度） 患者。 GVHD被认为是由移植物中的免疫细胞（例如T细胞）识别为宿主组织为 外国并传播炎症反应。目前尚不清楚某些具有等效HLA的HCT接收者 匹配开发GVHD，而其他人则幸免，以及一些GVHD患者对免疫的反应 糖皮质激素治疗抑制，而其他人则发展具有高死亡率的类固醇难治性GVHD。 一些对骨髓移植的鼠研究表明，无菌动物受到保护 GHVD和人类研究表明，GVHD患者的肠道菌群早期较少 移植后，指出微生物在GVHD中起的重要作用。这项研究将调查哪个肠道 在HCT的纵向研究中，细菌物种或社区与GVHD的风险最重要 每周收集粪便样品100天，然后每月9个月，并受到约束的接收者 宽范围16S rRNA基因PCR具有高通量测序，用于物种级分类学识别 细菌。这些患者的粪便样品也将被分析用于由小分子代谢产生的小分子代谢物 可能介导GVHD的细菌宿主相互作用，例如短链脂肪酸和胆汁盐。目标 该目的是确定GVHD的潜在化学效应因子。将使用粪便DNA的宏基因组测序 评估肠道细菌群落的功能和代谢能力，以阐明 细菌群落产生与GVHD风险相关的代谢产物，并确定特定的细菌物种或 具有影响GVHD风险的代谢机械的菌株。从这项研究中获得的知识可能是 将来用于设计干预措施，以降低基于肠道的针对性操纵的GVHD风险 微生物群。例如，鉴定与GVHD保护有关的特定细菌物种或菌株， 并生产介导这种保护的代谢产物，可能导致益生菌的发展或 设计的细菌群落可降低GVHD风险或治疗GVHD。或者，增强 通过外源给药或使用益生元来生产有益的代谢产物，并阻止 生产有害代谢产物可以作为减轻GVHD的另一种方法而无需进一步的方法 这些非常受损的患者中的免疫抑制。