FOR 5042:  The microbiome as a therapeutic target in inflammatory bowel diseases

• Subject Area: Medicine
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 426660215

Inflammatory bowel diseases (IBD) are chronic diseases of the gastro-intestinal tract, with complex pathophysiology involving genetic, environmental, microbiome, immunological and potentially other factors. Past 16S and metagenomic-based investigations systematically revealed differences in microbiome compositions of IBD patients compared to healthy controls. However, substantial heterogeneity in the identity of microbial signatures was observed between patients, and across cohorts. Thus, the disease-relevant gut microbes and associated features (e.g., metabolites) remain unknown. Our Research Unit (RU) miTarget brings together an interdisciplinary group of experts in a coordinated program to study a single economically important and prototypically group of complex diseases. In funding phase I, we focused on identifying consistent and early changes in the microbiome of IBD patients and their first-degree relatives that are at high-risk for IBD, functionally understanding these changes and their impact on pathogenic immune reactions, defining new target species in the IBD gut microbiome, and developing innovative tools for microbiome research. In phase II of our RU, we want to build on previous findings by focusing on the experimental validations of identified targets and implementing intervention studies for paving the way into clinical translation. For example, in the first funding phase we identified intestinal yeasts as drivers of pathogenic CD4+ T cell reactions in patients with CD, as well as alterations of yeast-responsive T cells already occurring in first-degree relatives of IBD patients. In the next funding phase, we aim to provide proof-of-concept data on the effect of a short-term yeast-reduction diet on the pathogenic T cell reaction, and on its potential clinical efficacy in CD patients. In another project, which integrates newly recruited principal investigators, we aim to extend our anaerobic culturomics expertise by establishing a continuous flow bioreactor system to enable unique intervention-oriented studies on the microbiome. Such an in vitro system is capable of stably maintaining cultures of complex microbial communities in anaerobic conditions for long periods of time, offering the possibility of investigating various modulation mechanisms of the microbiome. For instance, we aim to design and assemble various microbial synthetic communities and to investigate their potential to restore healthy microbial features in perturbed microbiomes from ulcerative colitis patients. This bioreactor system will also be incorporated into several established projects to validate computational predictions, study various microbial functions, and investigate microbiome evolution. Besides the outlined scientific agenda, miTarget creates the added value of a local network of specialized and interdisciplinary researchers working on the same disease, excellent measures to support young scientists, and a state-of-the-art infrastructure.

• DFG Programme: Research Units

Projects

• Bacterial evolution during chronic inflammation and its potential for ancestral state restorative therapy (Applicants Baines, John F. ;  Hövener, Jan-Bernd ;  Unterweger, Daniel )
• Coordination Funds (Applicant Franke, Andre )
• Cultivation and characterization of IBD-relevant microbes (Applicants Rupp, Jan ;  Tholey, Andreas )
• INF: Data management, bioinformatics and statistics for metagenome analyses (Applicants Dempfle, Astrid ;  Ellinghaus, Ph.D., David )
• P2: Ecology and function of synthetic bacterial communities to understand and modulate IBD-associated microbiomes (Applicants Groussin, Mathieu ;  Poyet, Mathilde )
• Pregnancy as a perturbation principle of the intestinal microbiota: impact on intestinal inflammation and inflammation-associated cancer (Applicant Rosenstiel, Ph.D., Philip Caspar )
• Restoration of microbial tryptophan metabolism via inhibition of amino acid decarboxylase as novel therapeutic principle in IBD (Applicant Aden, Konrad )
• Targeting intestinal yeasts and pathogenic yeast-responsive CD4+ T cells in Crohn’s disease (Applicants Bacher, Petra ;  Franke, Andre )
• The role of tobacco smoke-induced changes of the microbiome in shaping risk for inflammatory bowel diseases (Applicants Häsler, Robert ;  Krauss-Etschmann, Susanne )
• Therapeutic targeting of hexokinase in intestinal inflammation (Applicant Sommer, Ph.D., Felix )
• Z: Metabolomics, microbial community modelling and data integration (Applicants Heinzmann, Silke ;  Kaleta, Christoph )

• Spokesperson: Professor Dr. Andre Franke