SP 1 - Try-IBD
Translational models for hypothesis generation of targeted tryptophan intervention in IBD
IBD results from a misled host-microbial crosstalk established within the interplay of genetic susceptibility, environmental factors and individual lifestyle, e.g., adaptation of a westernized high-fat diet. The tryptophan immune-metabolism has been recently identified to be crucially disturbed in IBD and other chronic inflammatory disease as e.g., obesity and diabetes.
However, although tryptophan metabolism centrally orchestrates immunemetabolic crosstalk of the intestinal immunity, the underlying mechanism of action and causality on how disturbed tryptophan metabolism transforms into intestinal inflammation remains to be unravelled. On the clinical levels it is not understood whether (i) decreased serum tryptophan in IBD results from a hypermetabolic tryptophan turnover or from impaired tryptophan bioavailability within the intestinal tract (e.g., nutrition, intestinal resorption, host microbial out competition). The central aim of this subproject is to generate a detailed understanding of compartmentalized (microbiome, mucosa, blood) tryptophan metabolism in the context of IBD using translational approaches, including existing clinical samples, organoid/PBMC biobank, murine models of intestinal inflammation and a clinical 13C-tryptophan exposure experiment.
To this purpose we will
- Exploit clinical multi-omics datasets of IBD patients and reconstruct putative compartmentalized tryptophan immune-metabolic crosstalk in multi-omics data from IBD patients (in collaboration with SP2).
- Perform a clinical exploratory phase in which a small set of IBD patients exposed to 13C-labelled tryptophan/tryptophan derivates. We will thereby test the potential of tracing tryptophan metabolism as a novel diagnostic tool.
- Deconvolution of compartmentalized tryptophan metabolism using gut in-vitro and in-vivo models. We will use intestinal organoid/immune cell co-culturing and in-vivo mouse models of intestinal inflammation to identify compartment-specific tryptophan metabolism and its impact on gut immunity (in collaboration with SP3/4)