Restoration of Microbial Tryptophan Metabolism via Inhibition of Amino Acid Decarboxylase as a Novel Therapeutic Principle in Inflammatory Bowel Disease (IBD)

Introduction

Inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, arise from a disrupted interplay between microbial metabolic processes and the host immune system. A critical pathological factor is the tryptophan metabolism, which is dysregulated in both the gut microbiota and the host. This dysregulation leads to increased tryptophan degradation and the accumulation of metabolites that promote inflammatory pathways. The enzyme L-tryptophan decarboxylase (L-TrpD) and its product, tryptamine, play a pivotal role in these processes.

Aims

• Investigate the impact of L-TrpD activity on tryptophan metabolism in IBD patients.

• Analyze the mechanisms by which L-TrpD metabolites influence mucosal immunity.

• Develop a non-invasive biomarker based on microbial tryptophan degradation to predict therapeutic response in IBD.
  

Methods:
The project is structured into four work packages (WP):

1. Characterizing microbial tryptophan degradation (WP1): Study L-TrpD activity and its metabolic effects through metagenomic and metabolomic analyses of stool and serum samples.
2. Analyzing immune modulation by L-TrpD metabolites (WP2): Conduct in vitro studies with intestinal organoids and immune cells to assess the impact of tryptamine on barrier integrity and immune responses.
3. In vivo investigations (WP3): Use mouse models (IL-10 KO mice) to validate the role of L-TrpD in IBD pathogenesis and the efficacy of specific enzyme inhibitors.
4. Biomarker development (WP4): Design a functional metabolomics-based biomarker to predict therapy response in UC patients.

Expected Outcomes:

• Demonstration of L-TrpD activity significantly influencing microbial and host tryptophan metabolism.
• Identification of L-TrpD metabolites as drivers of inflammatory processes.
• Development of an innovative biomarker to improve therapeutic decision-making in IBD.

Outlook

This project promises to identify hexokinase and glycolysis regulation by the microbiota as key determinant in the control of inflammation or carcinogenesis. Further studies targeting specific functions of the microbiota through dietary, probiotic or pharmacological approaches may unravel new therapeutic options for intestinal chronic inflammation and cancer.