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: 10241905
• 负责人: PAVAN REDDY
• 金额: $ 34.31万
• 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/10241905
• 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; Gap Junctions; 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.

项目总结/摘要-项目1 胃肠道（GI）微生物组与健康的维持和疾病结局有关， 包括移植物抗宿主病（GVHD），这是同种异体造血干细胞移植的最重要并发症， 细胞移植（allo-HCT）。目前对微生物组的作用及其对GVHD的影响的理解 仅限于相关性。移植物抗宿主病的生物学是复杂的，大多数是理解和治疗 从供体和宿主来源的免疫细胞的角度来看，靶向。细胞的内在作用， GVHD的上皮靶点，如宿主肠上皮细胞（IEC）还不清楚。一个 生物学中的一个新概念是，细胞新陈代谢的重新布线对于它们对压力的恢复至关重要。 宿主IEC在GVHD期间处于来自供体T细胞和炎症的恒定应激状态。但 IEC的代谢反应是否改变以及对GVHD的严重程度是否至关重要， 探讨了微生物组通过产生代谢物在滋养IEC中起着关键作用， 包括短链脂肪酸、丁酸盐，作为宿主饮食的函数。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 上述知识空白和测试的中心前提是，丁酸和 宿主IEC的线粒体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，这些数据表明，在allo-HCT之后，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，和 丁酸盐减轻缺陷并减弱GVHD。我们将探索迄今为止未被探索的 微生物组衍生的代谢物和宿主代谢途径之间的GVHD调节。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 并且减轻GVHD而不引起整体免疫抑制。