Abstract Background Altered tryptophan (Trp) metabolism and disrupted nicotinamide adenine dinucleotide (NAD⁺) synthesis are hallmarks of IBD, yet how intestinal microbiota contribute to these metabolic shifts during intestinal inflammation remains poorly understood. Methods We used targeted metabolomics to systematically profile Trp- and NAD⁺-related metabolites across multiple biological compartments – including tissues, luminal contents, stool, and serum – in mice treated with dextran sulfate sodium (DSS) alone or in combination with a broad-spectrum antibiotic (ABX) cocktail. Results Microbial depletion significantly attenuated colitis and increased host Trp bioavailability, implicating the gut microbiota as a competitive Trp consumer. In DSS colitis, Trp degradation along the kynurenine pathway (KP) was exaggerated but blocked at the key KP enzyme quinolinate phosphoribosyltransferase (QPRT), resulting in mucosal NAD(H) depletion. ABX co-treatment normalized metabolite conversion along the KP and restored mucosal NAD(H) levels, revealing a dual role of the gut microbiota during colitis: while they compete with the host for Trp utilization, they simultaneously shape host KP regulation and NAD⁺de novo synthesis, supporting host energy homeostasis. Conclusion Our findings demonstrate that mucosal NAD⁺de novo synthesis is a microbially regulated metabolic process that alleviates intestinal inflammation and may represent a novel therapeutic target in IBD through modulation of the gut microbiota or their metabolites. Conflict of interest: Dr. Welz, Lina: Received support from Celltrion for independent scientific conference coverage. Alsaadi, Abrar: No conflict of interest Harris, Danielle: No conflict of interest Yu, Meiping: No conflict of interest Mekdoud, Taous: No conflict of interest Bornhäuser, Johanna: No conflict of interest Springer, Eva: No conflict of interest Gilloteau, Clara: No conflict of interest Pothakamury, Anant: No conflict of interest Smith, Jaclyn: No conflict of interest Jenkins, Brenita: No conflict of interest Sommer, Felix: none Waschina, Silvio: No conflict of interest Rosenstiel, Philip: stock ownership Gerion Schreiber, Stefan Wolfgang: Personal Fees: Abbvie, Amgen, Arena, Biogen, Bristol Meyers Squibb, Celgene, Celltrion, Falk, Ferring, Fresenius Kabi, Galapagos, Gilead, IMAB, Janssen, Lilly, MSD, Mylan, Novartis, Pfizer, Protagonist, Provention Bio, Roche, Sandoz/Hexal, Shire, Takeda, Theravance McReynolds, Melanie: No conflict of interest Aden, Konrad: Personal Fees: Lecture fee: Takeda, Janssen, Lilly, Abbvie Consulting fee: Takeda, Jannsen, Lilly, Guidepoint
Welz et al. (Thu,) studied this question.