Submitted Abstract
In the past years multi-omics analysis of inflammatory bowel disease (IBD) has painted a multifaceted picture of this complex immune-mediated disorder. A thorough understanding of the molecular causations that lead to manifestation and result in pathological cytokine signalling is still lacking. We now suggest to integrate a focused metabolic understanding into multi-omics models to elucidate pathophysiological key features of immune-metabolic crosstalk in IBD. The goal of “Try-IBD” is thereby to define the impact of tryptophan-driven immune-metabolic crosstalk on the pathogenesis of IBD and to identify novel interaction points within the tryptophan metabolism as therapeutic or diagnostic features. To that purpose we will use existing multi-omics data sets of IBD samples and perform an additional 13C-tryptophan molecular tracing study in human IBD patients to identify potential diagnostic and therapeutic entry points within the tryptophan metabolism. We will further refine our understanding of tryptophan metabolism by the assessment of directionality of its multi-branched metabolism (e.g. kynurenine, serotonin, indole) within various body compartments (microbiota, mucosa, blood) using combined metabolome, transcriptome and metabolic flux analysis. In-vitro gut models and mouse models of inflammation will be used to test potential therapeutic candidates of targeted tryptophan metabolism restoration in IBD and implement magnetic resonance imaging (MRI) of tryptophan metabolism using hyperpolarized tryptophan-tracers in-vivo. Hence, potential exploitation results will include a new diagnostic test for complex disease, the use of tryptophan derivatives as magnetic resonance (MR) contrast agents and eventually a refinement and individualization of therapeutic targeting of the tryptophan pathway.