Project Details
Projekt
Restoration of microbial tryptophan metabolism via inhibition of amino acid decarboxylase as novel therapeutic principle in IBD
Applicant
Professor Dr. Konrad Aden
Subject Area
Gastroenterology
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 426660215
IBD results from a misled interplay of microbial metabolism and host immune system. A growing body of evidence suggest that independent risk factors of IBD such as individual lifestyle (e.g. smoking, nutrition) and the exposome (e.g. air pollution, climate conditions) may exert their impact on the level of the intestinal microbiome resulting in dysbiosis (e.g. the expansion of pathobionts) and disruption of microbial metabolic pathways. Although the causal impact of the intestinal microbiome is more and more reflected in therapeutic approaches aiming to modulate the microbiome (e.g. fecal microbiome transfer, dietary intervention), the mainstay of IBD therapy still lays in targeted interception of immune pathways (e.g. TNFa, IL-23, JAK-STAT, IL-6) involved in the perpetuation of the mucosal immune response. Within the previous funding phase, we focused on identifying host microbial metabolic hubs, that are dysregulated in IBD and that might serve as putative microbiome-based treatment targets in IBD. We specifically focused on the role of the metabolism of the essential amino acid tryptophan on the host and microbial side as key metabolic principle that is dysregulated in IBD. We were able to establish a LC-MS/MS based method for targeted quantification of tryptophan metabolites in human biosamples. Doing so we could show that IBD is characterized by a profound consumption of tryptophan even in the absence of overt systemic inflammation. On the microbial site we identified that microbial auxotrophy levels in human microbiome is most pronounced for tryptophan, associates with the levels of host tryptophan metabolites and is dysregulated in patients with IBD. As these data point to a critical role of the microbial tryptophan metabolism in the pathogenesis of IBD, we elucidated the microbial metabolism of tryptophan in longitudinal cohorts of IBD patients. Within metagenome analysis of two independent longitudinal IBD therapy intervention cohorts we could identify L-tryptophan decarboxylase to be uniquely overabundant in UC patients with refractory disease course to biologic therapy. Within the proposed funding phase, we now aim to embark on this finding and study the functional metabolic outcome of L-tryptophan decarboxylase activity on the intestinal microbiome. We will combine targeted and untargeted metabolomics with in-vitro culturomics to trace the fate of microbial tryptophan degradation. We will further elucidate the impact of microbial tryptophan degradation on mucosal immunity aim to dissect mechanism on how the microbial metabolism instructs host tryptophan metabolism and subsequent mucosal immunity. Lastly, we anticipate designing a functional assay to dynamically quantify microbial tryptophan degradation along the L-tryptophan decarboxylase route. Within the miTarget network we anticipate implementing this assay as a novel non-invasive biomarker of precision medicine into longitudinal treatment cohort of IBD patients.
DFG Programme
Research Units
