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

GVHD 中宿主 (IEC) 线粒体和微生物代谢之间的串扰

• 批准号: 10650317
• 负责人: PAVAN REDDY
• 金额: $ 32.73万
• 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/10650317
• 关键词: 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 Cells; Epithelium; Exposure to; Generations; Glycolysis; Hematological Disease; Hypoxia; Immune; Immune System Diseases; Immunosuppression; Inflammation; Knowledge; Maintenance; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Oxygen; Play; Regulation; Research Personnel; Role; Secondary to; Seminal; Severities; Severity of illness; Stress; Stress and Coping; 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）微生物组在维持热量和疾病结局中隐含 包括移植物与宿主疾病（GVHD），这是同种异体造血的最显着并发症 细胞移植（Allo-HCT）。当前对微生物组作用及其对GVHD的影响的理解 仅限于相关性。 GVHD的生物学很复杂，并且主要理解和治疗 从捐赠者和宿主衍生的免疫细胞的角度进行针对性。细胞的固有作用 GVHD的上皮靶标，例如宿主肠上皮细胞（IEC）。一个 生物学中的新兴概念是，将细胞代谢的重新布线对于它们对压力的韧性至关重要。 宿主IEC处于供体T细胞的恒定压力状态和GVHD期间的炎症。但 IEC的代谢反应是否发生了变化，对于GVHD严重程度至关重要 探索。微生物组在通过产生代谢物的产生IEC中起着至关重要的作用， 包括短链脂肪酸，丁酸作为宿主饮食的函数。它们在代谢中的作用 同种异体HCT之后的IEC以及是否调节GVHD严重性尚不清楚。该建议旨在填补 上述知识差距并测试丁酸酯与 宿主IEC的线粒体纠正其细胞代谢缺陷并减轻GVHD。提案将 建立在令人兴奋的第二个初步数据的基础上，该数据表明，在Allo-HCT之后，主机IECS 表现为以线粒体复合物II的不足和 丁酸酯会减轻缺陷并减轻GVHD。因此，我们将探测迄今为止意外的Nexus 在微生物组衍生的代谢产物和GVHD调节中的宿主代谢途径之间。如果 成功，它可能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而不会引起全球免疫支持。