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 _1-3 R) 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 GAL ₂ R and GAL ₃ R contribute to murine colitis. Immunohistochemical analysis revealed that granulocytes in colon specimens of IBD patients (Crohn's disease and ulcerative colitis) expressed GAL ₂ R and GAL ₃ R but not GAL ₁ R. After colitis induction with 2% dextran sulfate sodium (DSS) for 7 days, mice lacking GAL ₃ R (GAL ₃ R-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 GAL ₃ R 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 GAL ₃ R-KO mice, characterized by elevated numbers of enterobacteria and bifidobacteria. In contrast, GAL ₂ R deletion did not influence the course of colitis. In conclusion, granulocyte GAL ₂ R and GAL ₃ R expression is related to IBD activity in humans, and DSS-induced colitis in mice is strongly affected by GAL ₃ R loss. Consequently, GAL ₃ R poses a novel therapeutic target for IBD.