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.

翻译后摘要：肠道菌群和移植物抗宿主病 造血细胞移植（HCT）可以挽救生命的治疗许多条件，包括 白血病、淋巴瘤、再生障碍性贫血、多发性骨髓瘤、某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，影响高达50%的 异基因移植受者，尽管供体和受者之间的人类白细胞抗原（HLA）匹配 尽管使用了免疫预防。GVHD最常影响肠道、肝脏和皮肤， 腹泻，肝脏炎症和皮疹，不同阶段（程度）的器官参与不同 患者GVHD被认为是由移植物中的免疫细胞（例如T细胞）引起的，所述免疫细胞将宿主组织识别为 并传播炎症反应。目前尚不清楚为什么一些具有等同HLA的HCT受者 匹配发展GVHD，而其他人则幸免，以及为什么一些GVHD患者对免疫应答 糖皮质激素治疗的抑制，而另一些发展为具有高死亡率的类固醇难治性GVHD。 一些小鼠骨髓移植的研究表明，无菌动物可以免受 GVHD和人类研究表明，GVHD患者早期肠道微生物群的多样性较低， 这表明微生物在GVHD中起着重要作用。这项研究将调查哪些肠道 在HCT的纵向研究中，细菌种类或群落与GVHD的风险最相关 接受者每周收集粪便样品，持续100天，然后每月收集，持续9个月，并进行 16 S rRNA基因大范围PCR结合高通量测序用于种级分类鉴定 细菌的。还将测定这些患者的粪便样品中的小分子代谢物， 可能介导GVHD的细菌-宿主相互作用，如短链脂肪酸和胆汁盐。的目标 目的是鉴定GVHD的潜在化学效应物。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， 细菌群落产生与GVHD风险相关的代谢物，并鉴定特定的细菌物种或 菌株与影响GVHD风险的代谢机制。从这项研究中获得的知识可能是 将来用于设计干预措施，以减少基于肠道靶向操作的GVHD风险 微生物群例如，鉴定与防止GVHD相关的特定细菌物种或菌株， 以及介导这种保护的代谢产物的产生，可能导致益生菌的发展， 用于降低GVHD风险或治疗GVHD的工程化细菌群落。或者，增强 通过外源性施用或使用益生元产生有益的代谢物，并阻断 有害代谢物的产生可能成为减轻GVHD的另一种方法，而无需进一步的 免疫抑制在这些非常脆弱的病人。