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.