Janus kinase (JAK) inhibition is a novel therapeutic approach in the management of Ulcerative Colitis (UC). However, the role of JAK inhibition with respect to cell-specific immunometabolic properties is not known.
The overall aim of this multi-year research proposal is to generate deeper understanding of the interplay of JAK inhibition and immunometabolic properties in the intestinal mucosa at a cellular level and thereby to open up new avenues in biomarker development and novel targeted interventions in UC. This aim is being pursued by (i) identifying immunometabolomic signatures of JAK inhibition in UC patients using multi-omics analysis of longitudinal therapy response cohorts and (ii) modelling the impact of two metabolic principles, namely amino acide (e.g. tryptophan) and short-chain fatty acids (e.g. butyrate), on the efficacy of JAK inhibition in ex vivo organisms.
In order to identify the immunometabolic signatures of therapeutic responses to JAK inhibition in UC patients, advantage will be taken of two longitudinally recruited UC cohorts from Leuven and Kiel in which standardised biosampling has been performed before and after therapy induction, along with detailed clinical characterization of therapeutic outcome. By combining targeted metabolomics, microbial metagenomics and transcriptomics, these cohorts will be exploited as hypothesis generation cohorts to identify (microbial) immunometabolic principles that are dysregulated in UC and restored under JAK inhibition therapy (tofacitinib). This will be done in order to understand the primary cellular target of JAK inhibition in UC and to identify cell type-specific effects of JAK inhibition on the cellular immunometabolism.
While this hypothesis generation approach will generate an understanding of (i) how JAK inhibition affects cell-type specific immunometabolism in UC patients and (ii) whether disease-specific immunometabolism is affected by microbial metabolic signals, in the second part of the funding phase, as mentioned above, the applicants aim to model the impact of immunometabolic principles on the efficacy of JAK inhibition in IBD. To this purpose, the molecular mechanism of key metabolites associated with the efficacy of JAK inhibition in clinical cohorts will be further explored in ex vivo cultures. Patient-derived intestinal organoids and peripheral blood mononuclear cells from healthy controls and UC patients will be used and cultivated in the presence/absence of a target metabolite in order to understand the impact of a microbial/cellular metabolite on Jak/STAT signalling. Ultimately this approach will be pursued to generate a priori knowledge on the efficacy of JAK inhibition in individual patients and to help translate molecular knowledge into precision medicine in IBD.