Intestinal epithelial expression of neutral ceramidase determines severity of chemical colitis in mice

Abstract

Abstract Sphingolipids are important eukaryotic signaling molecules and regulate inflammation and immunity. Elevated levels of sphingolipid metabolites, e.g. S1p, are found in many chronic inflammatory disorders, including inflammatory bowel disease (IBD). Neutral ceramidase (NcDase) is a key regulator of ceramide, the central intermediate in the sphingolipid metabolism. The contribution of intestinal epithelial cells (IEC) NcDase to IBD is not well understood. Here we demonstrate that mice with IEC-specific loss of NcDase (NcDase ΔIEC) developed less severe DSS-induced colitis than control mice. Deletion of IEC NcDase leads to increase of antimicrobial peptides, anti-inflammatory cytokines and regulatory T (Treg) cells; and reduction of dysbiosis and gut inflammation. Mechanistically, IEC NcDase is required for the generation of ganglioside GD3, which controls the enteric immune response by activating Treg cells and preventing activation of T-helper (Th)17 cells. Administration of dietary GD3 reduces mucosal inflammation. Thus, GD3 is a key epithelial-derived glycosphingolipid that regulates distinct subsets of intestinal CD4 +T cells during inflammatory conditions, a finding with potential implications for treatment of chronic inflammatory disorders. Supported by grants from NIH R21AI159194, R01 DK115406, and R01DK131442 (Z.D.).