The Gut Microbiota and Graft versus Host Disease (GVHD)

肠道微生物群和移植物抗宿主病 (GVHD)

基本信息

批准号：
10593458
负责人：
DAVID Neal FREDRICKS
金额：
$ 55.98万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-11-09 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10593458
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

项目摘要

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抗宿主病造血细胞移植（HCT）可以挽救生命，治疗多种疾病，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% 的患者同种异体移植受者，尽管供者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措施。 GVHD 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，这些免疫细胞将宿主组织识别为异物并传播炎症反应。目前还不清楚为什么一些 HCT 接受者具有相同的 HLA 匹配导致 GVHD，而其他人则幸免，以及为什么一些 GVHD 患者对免疫有反应糖皮质激素治疗可抑制 GVHD，而其他人则发展为类固醇难治性 GVHD，且死亡率很高。一些骨髓移植的小鼠研究表明，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群多样性较低移植后，指出微生物在 GVHD 中发挥的重要作用。这项研究将调查哪种肠道在 HCT 的纵向研究中，细菌种类或群落与 GVHD 风险最相关接受者每周收集一次粪便样本，持续 100 天，然后每月收集一次，持续 9 个月，并接受广泛的 16S rRNA 基因 PCR 和高通量测序，用于物种水平的分类鉴定的细菌。这些患者的粪便样本也将进行小分子代谢物的检测可能介导 GVHD 的细菌-宿主相互作用，例如短链脂肪酸和胆汁盐。目标是目的是确定 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，以阐明肠道细菌群落的特殊性细菌群落产生与 GVHD 风险相关的代谢物，并识别特定的细菌种类或具有影响 GVHD 风险的代谢机制的菌株。从这项研究中获得的知识可以未来用于设计干预措施，以基于肠道的靶向操作来降低 GVHD 的风险微生物群。例如，鉴定与 GVHD 保护相关的特定细菌种类或菌株，以及介导这种保护的代谢物的产生，可能导致益生菌或用于降低 GVHD 风险或治疗 GVHD 的工程细菌群落。或者，增强通过外源性给药或使用益生元产生有益代谢物，并阻断有害代谢物的产生可能会成为减轻 GVHD 的另一种方法，而无需进一步这些非常受损的患者的免疫抑制。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Graft-Derived Reconstitution of Mucosal-Associated Invariant T Cells after Allogeneic Hematopoietic Cell Transplantation.

同种异体造血细胞移植后粘膜相关不变 T 细胞的移植衍生重建。

DOI：
发表时间：
2018-02
期刊：
影响因子：
0
作者：
Bhattacharyya, Abir;Hanafi, Laïla;Sheih, Alyssa;Golob, Jonathan L;Srinivasan, Sujatha;Boeckh, Michael J;Pergam, Steven A;Mahmood, Sajid;Baker, Kelsey K;Gooley, Ted A;Milano, Filippo;Fredricks, David N;Riddell, Stanley R;Turtle, Cameron
通讯作者：
Turtle, Cameron

Analysis of Antibiotic Exposure and Development of Acute Graft-vs-Host Disease Following Allogeneic Hematopoietic Cell Transplantation.

同种异体造血细胞移植后抗生素暴露和急性移植物抗宿主病发生的分析。

DOI：
发表时间：
2023-06-01
期刊：
影响因子：
13.8
作者：
Rashidi, Armin;Gao, Fei;Fredricks, David N;Pergam, Steven A;Mielcarek, Marco;Milano, Filippo;Sandmaier, Brenda M;Lee, Stephanie J
通讯作者：
Lee, Stephanie J

In silico benchmarking of metagenomic tools for coding sequence detection reveals the limits of sensitivity and precision.

用于编码序列检测的宏基因组工具的计算机基准测试揭示了灵敏度和精度的局限性。

DOI：
发表时间：
2020-10-15
期刊：
影响因子：
3
作者：
Golob, Jonathan Louis;Minot, Samuel Schwartz
通讯作者：
Minot, Samuel Schwartz

The gut microbiota and graft-versus-host disease.

肠道微生物群和移植物抗宿主病。

DOI：
10.1172/jci125797
发表时间：
2019-05-01
期刊：
The Journal of clinical investigation
影响因子：
0
作者：
D. Fredricks
通讯作者：
D. Fredricks

Stool Microbiota at Neutrophil Recovery Is Predictive for Severe Acute Graft vs Host Disease After Hematopoietic Cell Transplantation.

中性粒细胞恢复时的粪便微生物群可预测造血细胞移植后严重的急性移植物抗宿主病。

DOI：
发表时间：
2017-11-29
期刊：
影响因子：
0
作者：
Golob, Jonathan L;Pergam, Steven A;Srinivasan, Sujatha;Fiedler, Tina L;Liu, Congzhou;Garcia, Kristina;Mielcarek, Marco;Ko, Daisy;Aker, Sarah;Marquis, Sara;Loeffelholz, Tillie;Plantinga, Anna;Wu, Michael C;Celustka, Kevin;Morrison, Ale;Wood
通讯作者：
Wood