Macrophage-derived CD38 mediates colitis through NAD⁺ depletion

Colitis, a chronic inflammatory bowel disease (IBD), is pathologically linked to immune dysregulation; however, the contribution of cellular metabolic alterations to its pathogenesis remains incompletely understood. In this study, untargeted metabolomic analysis revealed marked disruption of NAD⁺ metabolism, accompanied by increased expression of CD38, a major NAD⁺-glycohydrolase, in colitis. Restoring NAD⁺ levels through supplementation with its precursors or pharmacological inhibition of CD38 activity effectively alleviated the pathological symptoms of colitis. Mechanistically, colitis induced a pronounced upregulation of CD38 specifically in macrophages. Myeloid-specific deletion of Cd38 significantly attenuated both metabolic disturbances and inflammatory responses associated with colitis. These findings identify macrophage CD38 as a critical regulator of intestinal inflammation and highlight the CD38/NAD⁺ axis as a potential therapeutic target for IBD. KEY POINTS: Altered NAD⁺ metabolism is closely associated with intestinal inflammation, yet the specific cellular mechanisms contributing to this decline remain to be fully elucidated. By supplementing with nicotinamide mononucleotide or inhibiting the enzyme CD38 that consumes NAD⁺ with drugs, the NAD⁺ level can be effectively restored, which can alleviate the colitis induced by dextran sulphate sodium to a certain extent. During intestinal inflammation, the upregulation of CD38 is predominantly driven by infiltrating macrophages. Myeloid-specific deletion of CD38 preserves NAD⁺ homeostasis and ameliorates colitis, highlighting its essential role in disease progression. Targeting macrophage CD38 establishes a key regulatory link between NAD⁺ metabolism and intestinal inflammation, providing a potential therapeutic strategy for inflammatory bowel diseases.