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

项目摘要/摘要--项目1 胃肠道(GI)微生物群与维持健康和疾病结局有关， 包括移植物抗宿主病(GVHD)，这是异基因造血最重要的并发症 细胞移植(allo-HCT)。微生物群在移植物抗宿主病中的作用及其影响的研究现状 仅限于相关性。移植物抗宿主病的生物学是复杂的，并且大多被理解和治疗。 靶向，从供体和宿主来源的免疫细胞的角度。细胞的内在作用 GVHD的上皮靶点，如宿主肠道上皮细胞(IECS)还不是很清楚。一个 生物学中新出现的概念是，细胞新陈代谢的重新连接对它们应对压力的弹性至关重要。 在GVHD过程中，宿主IECs处于供者T细胞的持续应激状态和炎症状态。但 IECS的代谢反应是否发生改变，并对GVHD的严重程度起关键作用，从来没有过 探索过了。微生物群通过产生代谢物在滋养IECS方面起着关键作用， 包括短链脂肪酸，丁酸，作为宿主饮食的功能。它们在新陈代谢中的作用 异基因红细胞移植后的IECS，以及它是否调节GVHD的严重程度尚不清楚。这项提案旨在填补 上述知识差距和检验的中心前提是丁酸盐和 宿主IECS的线粒体纠正其细胞代谢缺陷，减轻移植物抗宿主病。这项提议将 建立在令人兴奋和开创性的初步数据基础上，这些数据表明，在allo-HCT之后，东道主IECS 表现出以线粒体复合体II缺乏为特征的严重代谢缺陷，以及 丁酸盐减轻了缺陷，减弱了移植物抗宿主病。因此，我们将探索迄今未被探索的联系 微生物组代谢产物与宿主代谢途径在GVHD调控中的作用。如果 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 在不引起全球免疫抑制的情况下缓解GVHD。

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.