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：肠道微生物区系与移植物抗宿主病 造血细胞移植(Hct)可以挽救多种疾病的生命，包括 白血病、淋巴瘤、再生障碍性贫血、多发性骨髓瘤、某些免疫缺陷等疾病。 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%的 异基因移植受者，尽管供者和受者的人类白细胞抗原(HLA)相匹配 尽管使用了免疫预防措施。移植物抗宿主病最常影响肠道、肝脏和皮肤，产生 腹泻、肝脏炎症和皮疹，不同阶段(程度)的器官受累不同 病人。GVHD被认为是移植物中识别宿主组织的免疫细胞(例如T细胞)引起的 外来的，并传播炎症反应。目前尚不清楚为什么一些具有相同人类白细胞抗原的红细胞移植受者 为什么一些GVHD患者会对免疫产生反应？ 用糖皮质激素治疗抑制，而其他人发展为激素难治性移植物抗宿主病，死亡率高。 一些小鼠骨髓移植的研究表明，无菌动物可以免受 GHVD和人类研究表明，GVHD患者早期的肠道微生物区系多样性较少 移植后，指出了微生物在移植物抗宿主病中的重要作用。这项研究将调查哪个肠道 在一项关于HCT的纵向研究中，细菌种类或群落与移植物抗宿主病的风险最相关 收件人每周收集粪便样本100天，然后每月收集粪便样本9个月，并接受 广谱16S rRNA基因聚合酶链式反应和高通量测序用于物种水平的分类鉴定 细菌的数量。这些患者的粪便样本也将被检测产生的小分子代谢物 可能介导移植物抗宿主病的细菌-宿主相互作用，如短链脂肪酸和胆盐。的目标是 这一目的是为了确定GVHD的潜在化学效应。将使用粪便DNA的元基因组测序 评估肠道细菌群落的功能和代谢能力，以阐明其特殊性 细菌群落产生与GVHD风险有关的代谢物，并识别特定的细菌物种或 具有影响GVHD风险的代谢机制的菌株。从这项研究中获得的知识可能是 未来用于设计干预措施，以降低GVHD的风险，其基础是对肠道的有针对性的操作 微生物区系。例如，识别与预防GVHD有关的特定细菌物种或菌株， 以及调节这种保护的代谢物的产生，可能导致益生菌或 为降低GVHD风险或治疗GVHD而设计的细菌群落。或者，增强 通过外源给药或使用益生元来产生有益的代谢物，并阻止 有害代谢物的产生可能成为缓解GVHD的另一种方法，而不需要进一步的 免疫抑制在这些严重受损的患者身上。