Tracing NAD⁺ metabolism uncovers adaptive coordination between host and microbiome during colitis

Host-microbiota metabolic interactions critically regulate nicotinamide adenine dinucleotide (NAD⁺) homeostasis, and their disruption is increasingly linked to chronic diseases, including inflammatory bowel disease (IBD). However, it remains unclear whether NAD⁺ dysregulation in IBD arises from impaired production, enhanced consumption, or both. Using multi-omics approaches and stable isotope-labeled NAD⁺ precursors administered via intravenous infusion in a murine model of dextran sulfate sodium (DSS)-induced colitis, we mapped tissue- and lumen-specific NAD⁺ metabolism under inflammatory stress. Our results reveal tissue-specific rewiring of NAD⁺ metabolism, with increased flux through the salvage pathway compensating for reduced de novo NAD⁺ synthesis from tryptophan. In parallel, microbial de novo NAD⁺ production was elevated, highlighting a cooperative host-microbiota response to inflammatory stress. These findings demonstrate differential regulation of NAD⁺ biosynthesis during acute colitis and underscore the dynamic interplay between host and microbial metabolism in maintaining NAD⁺ homeostasis under inflammatory conditions.