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

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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.