A metabolic constraint in de novo NAD+ synthesis drives mucosal inflammation in IBD.
Обработка статьи · этапы, ошибки и управление
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Wehkamp Lina, Harris Danielle M M, Kim Na-Mi, Alsaadi Abrar I, Wu Qicong, Oumari Mhmd, Taubenheim Jan, Volk Valery, Credidio Graziella, Koncina Eric, Mukherjee Pranab K, Tran Florian, Mekdoud Taous, Yu Meiping, Sievers Laura K, Pavlidis Polychronis, Powell Nick, Wang Shihan, Fung Ivan, Waetzig Georg H, Rousseaux Christel, Desreumaux Pierre, Rieder Florian, Letellier Elisabeth, Waschina Silvio, Meyer Thomas F, Adolph Timon, D'Haens Geert, Kaleta Christoph, Feuerhake Friedrich, Verstockt Bram, McReynolds Melanie R, Rosenstiel Philip, Schreiber Stefan, Aden Konrad
Аннотация
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.