Systematic screening of tryptophan metabolism identifies site- and microbial-specific signatures of tryptophan utilization in experimental colitis.
| Title: | Systematic screening of tryptophan metabolism identifies site- and microbial-specific signatures of tryptophan utilization in experimental colitis. |
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| Authors: | Welz L; Alsaadi AI; Harris DM; Yu M; Mekdoud T; Bornhäuser J; Springer E; Gilloteau C; Pothakamury AA; Smith JD; Jenkins BC; Sommer F; Waschina S; Rosenstiel P; Schreiber S; McReynolds MR; Aden K |
| Source: | BioRxiv : the preprint server for biology [bioRxiv] 2025 Dec 18. Date of Electronic Publication: 2025 Dec 18. |
| Publication Type: | Journal Article; Preprint |
| Language: | English |
| Journal Info: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet ISSN: 2692-8205 (Electronic) Linking ISSN: 26928205 NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| 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. |
| Entry Date(s): | Date Created: 20251225 Date Completed: 20251225 Latest Revision: 20251225 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC12724437 |
| DOI: | 10.64898/2025.12.16.693850 |
| PMID: | 41446107 |
| Database: | MEDLINE |
Journal Article; Preprint