Research of the past decade identified a fundamental role of the intestinal microbiome in the regulation of human health. Shifts in the composition and activity of this microbial ecosystem (hereafter referred to as microbiome signatures) have been associated with a wide range of human diseases. Nevertheless, and beyond recent enthusiasm, the mechanistic implementation of microbe-host interactions into the pathogenesis of these adverse conditions is still in its infancy, and the search for disease-specific microbiome signatures with prognostic and therapeutic value using 16S rRNA gene-targeted and shotgun metagenomic sequencing is incomplete.
In this Collaborative Research Centre (CRC), we focus on the digestive tract and propose an interdisciplinary approach to characterizing the functional relevance of microbiome signatures in the context of inflammation and cancer.
The digestive tract is an organ with crucial immune and metabolic activities orchestrated in close proximity to a tremendous number and variety of microbes. We chose clinical endpoints that are associated with well-documented changes in the gut microbiome, including infections, graft-versus-host disease (GvHD), inflammatory bowel diseases (IBD) and colorectal cancer, and unravel key mechanisms linked to aberrant immune processing (inflammation) and tissue adaptation (cancer). In clinical and basic science projects, we evaluate the therapeutic relevance of fecal microbiota transplantation (FMT), bacteriophage application and nutritional intervention (e.g. exclusive enteral nutrition), addressing the fundamental question of how relevant and specific these changes really are for the respective disease etiology. To reduce complexity of the microbial and nutritional milieu in the gut and to understand the cellular and molecular mechanisms of signal integration, a hallmark of this research program is the implementation of defined bacterial consortia in both germ-free (mouse) and disease models (mouse and pig). Stable isotope labelling combined with metagenomic and metabolomic analyses will help to further identify metabolites with functional relevance for microbe-nutrition-host interactions in the digestive tract. The long-term perspective of this CRC is to overcome the correlation era in microbiome research and to translate progress into mechanistic understanding of microbiome-host interactions for the purpose of clinical strategies based on targeted nutritional and microbial interventions in patients.
CRC 1371 applies three comprehensive strategies to characterize the functional and clinical relevance of the intestinal microbiome in disease models and patient cohorts:
Strategy 1 - Characterization and functional evaluation of microbiome signatures in inflammation and cancer by applying genetically engineered and gnotobiotic animal models.
Strategy 2 - Identification and functional characterization of bioactive metabolites from the intestinal milieu using a comprehensive repertoire of analytical and computational methodologies.
Strategy 3 - Development and evaluation of microbiome-related therapeutic applications using fecal microbiota transplantation, bacteriophages and dietary interventions.