SP 3 - Try-IBD

Quantitative flux analysis of tryptophan metabolism as a model predictor for metabolic crosstalk in the intestinal mucosa

During the last two decades, the importance of cell metabolism in the context of immunology has been increasingly appreciated. Similar to cancer cells, metabolic rewiring in activated immune cells is essential to meet the increasing biomass and energy demand (e.g. proliferation and tissue invasion). In this logic, targeting metabolic rewiring holds promise for precision medicine. Drugs directly targeting metabolism, are widely used in the clinic and demonstrate that therapeutic windows exist to target the cell’s proliferative capacities at the metabolic level. However, the severe side effects of these established drugs complicate therapy. The identification of more specific metabolic bottlenecks in a given cell type could aid the design of more effective treatments with fewer side effects. Indeed, different metabolic enzymes and transporters are currently undergoing clinical trials.
Evidenced by decreased tryptophan plasma concentrations in IBD and given by the fact that tryptophan is an essential amino acid (thus cannot be synthesised by humans), it is hypothesized that the rate of tryptophan metabolism increases during inflammation and that IDO1, a key enzyme of the kynurenine pathway, is associated with increased tryptophan turnover. However, a direct biochemical proof of these correlations and an understanding of the tissues and cell types involved is lacking until now.
Therefore, the aim of this sub-project is (i) to decipher at the cellular level, how tryptophan is metabolised (kynurenine, indole, serotonin pathway) and which intermediates confer important functions during immune response; (ii) to elucidate at a systemic level which cell types are predominantly involved in tryptophan depletion under IBD conditions.
During the last decades, 13C-assisted metabolic flux analysis emerged as a powerful tool to study the rate and fate of a given metabolite in complex biological systems. Hence, we will employ this tool to study tryptophan metabolism in the context of IBD using both in vitro systems and respective mouse in vivo models.