Multi-Compartment Metabolic Remodeling in DRA-Deficient Mice Overlaps with Ulcerative Colitis Metabolic Signatures

Background/Objectives: Down-regulated in adenoma (DRA/SLC26A3), an IBD (Inflammatory Bowel Diseases) susceptibility gene and major colonic Cl^-/HCO₃^- exchanger, is reduced in ulcerative colitis (UC). Whether reduced DRA is linked to broader metabolic remodeling during intestinal inflammation remains unclear. We therefore examined DRA-associated metabolic pathways in human UC datasets and metabolic changes across mucosal, luminal, and systemic compartments in DRA-deficient mice. Methods: Six publicly available human colonic transcriptomic cohorts were analyzed to infer KEGG metabolic pathway activity, compare UC with healthy mucosa, and assess associations with DRA expression using random-effects meta-analysis. DRA knockout mice were evaluated by colonic mucosal RNA sequencing, untargeted LC-MS metabolomics of colonic mucosa, feces, and serum, targeted bile acid profiling, MetOrigin analysis, and fecal 16S rRNA sequencing. Results: In the human cohorts, DRA expression was consistently lower in UC. Of the 75 KEGG metabolic pathways evaluated, 48 were altered in UC relative to healthy mucosa, and 45 of these were also associated with DRA expression levels among UC samples. In DRA knockout mice, colonic RNA sequencing identified broad metabolic transcriptional remodeling across 39 KEGG pathways, with metabolic themes that overlapped with the human UC findings. Multi-compartment metabolomics further revealed alterations involving amino acid, nitrogen, redox/cofactor, polyamine, and bile acid metabolism, together with inferred host-microbiota co-metabolic signatures. Conclusions: DRA deficiency was accompanied by broad metabolic remodeling across mucosal, luminal, and systemic compartments. These changes overlapped with DRA-associated signatures in human UC, supporting a role for DRA in epithelial-luminal metabolic homeostasis beyond ion transport.