Multi-dimensional resolution of tryptophan-driven immune-metabolism as a novel pathophysiologicalprinciple in inflammatory bowel disease

In the past years multi-omics analysis of inflammatory bowel disease (IBD)has painted a multifaceted picture of this complex immune-mediateddisorder. A thorough understanding of the molecular causations that lead tomanifestation 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 theimpact of tryptophan-driven immune-metabolic crosstalk on thepathogenesis of IBD and to identify novel interaction points within thetryptophan metabolism as therapeutic or diagnostic features. To thatpurpose we will use existing multi-omics data sets of IBD samples andperform an additional 13C-tryptophan molecular tracing study in human IBDpatients to identify potential diagnostic and therapeutic entry points withinthe tryptophan metabolism. We will further refine our understanding oftryptophan metabolism by the assessment of directionality of its multi-branched metabolism (e.g. kynurenine, serotonin, indole) within variousbody compartments (microbiota, mucosa, blood) using combinedmetabolome, transcriptome and metabolic flux analysis. In-vitro gut modelsand mouse models of inflammation will be used to test potential therapeuticcandidates of targeted tryptophan metabolism restoration in IBD andimplement magnetic resonance imaging (MRI) of tryptophan metabolismusing hyperpolarized tryptophan-tracers in-vivo. Hence, potentialexploitation results will include a new diagnostic test for complex disease,the use of tryptophan derivatives as magnetic resonance (MR) contrastagents and eventually a refinement and individualization of therapeutictargeting of the tryptophan pathway.