Crosstalk between host (IEC) mitochondria and microbial metabolism in GVHD

GVHD 中宿主 (IEC) 线粒体与微生物代谢之间的串扰

• 批准号: 10441579
• 负责人: PAVAN REDDY
• 金额: $ 33.5万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10441579
• 关键词: Address; Affect; Allogeneic Bone Marrow Transplantation; Allogenic; Apoptosis; Attenuated; Bacteria; Biological; Biology; Butyrates; Cells; Cellular Metabolic Process; Complex; Complication; Data; Defect; Diet; Disease Outcome; Electron Transport; Environment; Epithelial; Epithelial Cells; Exposure to; Generations; Glycolysis; Hematological Disease; Hypoxia; Immune; Immune System Diseases; Immunosuppression; Inflammation; Knowledge; Lead; Maintenance; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Oxygen; Play; Regulation; Research Personnel; Role; Secondary to; Seminal; Severities; Severity of illness; Stress; Succinate Dehydrogenase; T-Lymphocyte; Testing; Tissues; Volatile Fatty Acids; assault; gastrointestinal; graft vs host disease; gut microbiome; hematopoietic cell transplantation; host microbiome; insight; intestinal epithelium; microbial; microbiome; mitochondrial metabolism; novel; resilience; response; side effect; stress state; therapeutic target

PROJECT SUMMARY/ABSTRACT – PROJECT 1 Gastrointestinal (GI) microbiome is implicated in maintenance of heath, and in disease outcomes, including graft versus host disease (GVHD), the most significant complication of allogeneic hematopoietic cell transplantation (allo-HCT). Current understanding of the role of microbiome and its effects on GVHD is limited to correlations. The biology of GVHD is complex, and mostly understood and therapeutically targeted, from the perspective of the donor and host derived immune cells. The cell intrinsic role of the epithelial targets of GVHD, such as the host intestinal epithelial cells (IECs) is not well understood. An emerging concept in biology is that rewiring of cellular metabolism is crucial for their resilience to stress. The host IECs are in a constant state of stress from donor T cells and inflammation during GVHD. But whether the metabolic responses of IECs are altered and are critical for GVHD severity has never been explored. The microbiome plays a critical role in nourishing the IECs through generation of metabolites, including the short chain fatty acids, butyrate, as a function of host diet. Their role in the metabolism of IECs after allogeneic HCT, and whether it regulates GVHD severity is unclear. This proposal aims to fill the above knowledge gaps and test the central premise that the cross-talk between butyrate and the mitochondria of host IECs corrects its cellular metabolic defect and mitigates GVHD. The proposal will build on the exciting and seminal preliminary data, which show that following allo-HCT the host IECs demonstrate profound metabolic defect characterized by deficiency of mitochondrial complex II, and butyrate mitigates the defect and attenuates GVHD. We will thus probe the heretofore unexplored nexus between microbiome derived metabolites and the host metabolic pathways in regulation of GVHD. If successful, it could lead to strategies to rationally modify microbiome to target non-immune host cells and mitigate GVHD without causing global immuno-suppression.

项目摘要/摘要 – 项目 1 胃肠道 (GI) 微生物组与健康的维持和疾病结果有关， 包括移植物抗宿主病（GVHD），这是同种异体造血最重要的并发症 细胞移植（allo-HCT）。目前对微生物组的作用及其对 GVHD 的影响的了解 仅限于相关性。 GVHD 的生物学原理很复杂，并且大多数都被理解和治疗 从供体和宿主衍生的免疫细胞的角度来看，有针对性。细胞的内在作用 GVHD 的上皮靶点，例如宿主肠上皮细胞 (IEC) 尚不清楚。一个 生物学中的一个新兴概念是，细胞代谢的重新布线对于细胞的压力恢复能力至关重要。 在 GVHD 期间，宿主 IEC 始终处于来自供体 T 细胞和炎症的压力状态。但 IEC 的代谢反应是否发生改变以及是否对 GVHD 严重程度至关重要尚未得到证实 探索过。微生物组通过产生代谢物在滋养 IEC 方面发挥着关键作用， 包括短链脂肪酸、丁酸盐，作为宿主饮食的功能。它们在新陈代谢中的作用 同种异体 HCT 后的 IEC，以及它是否调节 GVHD 的严重程度尚不清楚。该提案旨在填补 上述知识差距并测试了丁酸盐和丁酸盐之间的串扰的中心前提 宿主 IEC 的线粒体可以纠正其细胞代谢缺陷并减轻 GVHD。该提案将 建立在令人兴奋和开创性的初步数据的基础上，这些数据表明，在异体 HCT 后，宿主 IEC 表现出以线粒体复合物 II 缺乏为特征的严重代谢缺陷，并且 丁酸盐可减轻缺陷并减弱 GVHD。因此，我们将探讨迄今为止尚未探索的联系 微生物组衍生的代谢物与宿主代谢途径在 GVHD 调节中的关系。如果 如果成功，它可能会导致合理修改微生物组以靶向非免疫宿主细胞的策略 并减轻 GVHD，而不引起全身免疫抑制。