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A metabolic constraint in de novo NAD+ synthesis drives mucosal inflammation in IBD
Lina Wehkamp1,2, Danielle M M Harris1,2, Na-Mi Kim1,2
1Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Kiel, 24105, Germany.
Background:
Inflammatory bowel disease (IBD) is associated with energy deficiency and perturbed metabolism of the essential amino acid tryptophan (Trp).
Objective:
We aimed to determine whether excessive Trp degradation fuels or compensates for inflammation through de novo nicotinamide adenine dinucleotide (NAD+) synthesis.
Design:
A prospective systems medicine approach (metabolomics, transcriptomics) was employed longitudinally in patients with advanced IBD therapy. Findings were validated with targeted Trp metabolomics in experimental colitis and in vitro in fibroblasts, intestinal epithelial cells (IECs), and peripheral blood mononuclear cells (PBMCs).
Results:
Active IBD is marked by enhanced Trp degradation driven by inflammatory cytokines through the JAK/STAT pathway. Trp catabolism results in accumulation of quinolinic acid (QA) and NAD + depletion due to reduced expression of QPRT, the enzyme converting QA to NAD+. QPRT knockdown enhances inflammation, while NAD + precursor supplementation (e.g. nicotinamide riboside [NR]) restores cellular energy and reduces inflammation in vitro and in dextran sodium sulfate (DSS)-induced colitis.
Conclusion:
A metabolic bottleneck at QPRT prevents efficient NAD+ synthesis from Trp in IBD, sustaining inflammation. Restoring NAD + is a promising therapeutic strategy.
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