Galanin receptor 3 attenuates inflammation and influences the gut microbiota in an experimental murine colitis model

The regulatory (neuro)peptide galanin and its three receptors (GAL_1-3R) are involved in immunity and inflammation. Galanin alleviated inflammatory bowel disease (IBD) in rats. However, studies on the galanin receptors involved are lacking. We aimed to determine galanin receptor expression in IBD patients and to evaluate if GAL₂R and GAL₃R contribute to murine colitis. Immunohistochemical analysis revealed that granulocytes in colon specimens of IBD patients (Crohn's disease and ulcerative colitis) expressed GAL₂R and GAL₃R but not GAL₁R. After colitis induction with 2% dextran sulfate sodium (DSS) for 7 days, mice lacking GAL₃R (GAL₃R-KO) lost more body weight, exhibited more severe colonic inflammation and aggravated histologic damage, with increased infiltration of neutrophils compared to wild-type animals. Loss of GAL₃R resulted in higher local and systemic inflammatory cytokine/chemokine levels. Remarkably, colitis-associated changes to the intestinal microbiota, as assessed by quantitative culture-independent techniques, were most pronounced in GAL₃R-KO mice, characterized by elevated numbers of enterobacteria and bifidobacteria. In contrast, GAL₂R deletion did not influence the course of colitis. In conclusion, granulocyte GAL₂R and GAL₃R expression is related to IBD activity in humans, and DSS-induced colitis in mice is strongly affected by GAL₃R loss. Consequently, GAL₃R poses a novel therapeutic target for IBD.