Investigation of microbiome-host interactions in intestinal graft-versus-host disease as a clinical relevant condition of microbially triggered immune system modulation.

异基因造血干细胞移植(Allo HSCT)是治疗危及生命的血液病和包括自身免疫性疾病在内的多种疾病的一种重要的免疫介导性疗法。它的主要限制之一是肠道移植物抗宿主病(GVHD)的威胁生命的并发症，GVHD是供者淋巴细胞对受体的免疫反应，导致严重的炎症过程。肠道微生物区系是胃肠道动态平衡和健康的主要调节器。现在，越来越多的证据表明，肠道微生物区系失调在GVHD的病理生理学中起着重要作用。在临床上最相关的是，在独立的临床队列中证明，微生物多样性的丧失和肠道微生物组组成的变化可以预测异基因造血干细胞移植患者的移植相关死亡率。然而，微生物区系和移植物抗宿主病之间联系的潜在机制仅被微不足道地理解。为此，提出了一项研究议程，以研究免疫系统、肠道和微生物区系与肠道之间相互作用的基本原理。具体地说，它计划既追求基础科学，又追求转化的临床方法。首先，它的目的是从机制上研究肠道微生物区系的变化如何决定移植患者移植物抗宿主病的发生，重点是细菌遗传学(16S RNA扩增和元基因组测序)、微生物代谢产物的图谱和宿主免疫参数的分析。在进一步的实验方法中，我们计划研究从GHVD患者到无菌小鼠的微生物群转移的影响，以探讨其在肠道炎症过程中的详细作用。在第二个目标是开发治疗GVHD微生物区系损伤的策略，我们将在小鼠模型中研究特定细菌重新引入对肠道菌群的影响以及特定微生物代谢物(如短链脂肪酸)在GVHD中的作用。在第三个目标中，计划在动物模型中表征具有不同抗菌谱的抗生素对预防肠道微生物失调和减少GVHD样过程的影响。这一研究项目不仅将有助于揭示GVHD的重要病理生理方面，从而将促进新的治疗策略的发展。值得注意的是，它涉及微生物群-宿主相互作用的基本问题，特别是免疫系统调节，因此可能揭示炎症性疾病的病理生理学的一般原理。

Allogeneic hematopoietic stem-cell transplantation (allo HSCT) is an important immune-mediated therapy to cure people of life threatening hematological cancers and a variety of other diseases including autoimmune diseases. One of its major limitations is the life threatening complication of intestinal graft-versus-host disease (GVHD), an immunological reaction by the donor lymphocytes against the recipient causing severe inflammatory processes. The intestinal microbiota is a major modulator of gastrointestinal homeostasis and health. Now, there is increasing evidence that dysbiosis of the gut microbiota play a major role in the pathophysiology of GVHD. Clinically most relevant, it was demonstrated in independent clinical cohorts that a loss of microbial diversity and a shift in the composition of the intestinal microbiome predicts transplant-related mortality in allo HSCT patients. However, the mechanisms underlying the link between microbiota and GVHD are only marginally understood. For this reason, a research agenda is proposed to study basic principles of the interactions between the immune system, the intestines and the microbiota with the intestines. In detail, it is planned to pursue both a basic science and a translational, clinical approach. First, it is aimed to investigate mechanistically how changes in the gut microflora determine the occurrence of GVHD in transplanted patients focusing on bacterial genetics (16S RNA amplicon and metagenome sequencing), profiling of microbial metabolites and analyses of host immune parameters. In a further experimental approach, we plan to study the effects of microflora transfer from GHVD patients to germ-free mice in order to investigate its detailed contribution in inflammatory processes in the intestines. In a second aim targeted at the development of strategies to treat microbiota injury in GVHD, we will examine the effects of specific bacterial re-introduction on the intestinal flora and the action of specific microbial metabolites like short-chain fatty acids on GVHD in mouse models. In a third aim, it is planned to characterize the effects of antibiotics with different antimicrobial spectra to prevent intestinal dysbiosis and reduce GVHD-like processes in animal models. This research project will not only help to uncover important pathophysiological aspects of GVHD and thereby will promote the development of novel treatment strategies. Of note, it deals with fundamental questions of microbiome-host interaction and, especially, immune system regulation, and may therefore reveal general principles in the pathophysiology of inflammatory diseases.