Orexins (orexin-A and orexin-B) are hypothalamic peptides involved in the sleep/wake control which interact with two GPCR sub-types, OX1R and OX2R. We have demonstrated that OX1R was highly expressed in digestive cancer cell lines derived from colon, pancreas and liver cancers (1). Our immunohistochemistry studies indicate that OX1R was also detected in 100 % of human Inflammatory Bowel Disease (IBD) epithelia including Crohn's disease (21 samples) and Ulcerative Colitis (UC, 20 samples). We have investigated the role of orexin A (OxA) on acute inflammation in two UC mice models including chemically mice treated with Dextran Sulfate Sodium (DSS) and EXCY2 mice genetically invalidated for IL10 and Nox1 genes (IL10-/and Nox1-/-) which develop spontaneous UC-like disease (2). The daily intraperitoneal injection of OxA (0,22 μmol/Kg) in orally DSS-treated mice ameliorates the Disease Activity Index scored by measuring weight, length of colon, diarrhea and blood presence in the stool as compared to untreated mice. Moreover, OxA improves also histologic aspect of colon epithelium. The cytokinic profile analysis revealed that OxA reduces the pro-inflammatory cytokines secretion such as TNFα, IL6, IL8 homolog and IL1B in DSS-induced colitis mice colon extracts. In contrast, OxA has no effect on INFγ, IL10, and IL12 cytokine secretions. The recent development of a new spontaneous UC-like mouse model EXCY2, is ideally suited to study the OxA effect on spontaneous colitis. Indeed, EXCY2 mice develop a spontaneous colitis at 6/7 weeks of age with an upwards gradient from the rectum and reproduce all molecular characteristics seen in UC including, loss of goblet cells, deregulation of endoplasmic reticulum stress, tobacco protective effect ... Intraperitoneal injection (2/week) of OxA (0,22 μmol/Kg) during 21 days alleviated severe colitis in 10 week-old EXCY2 mice, OxA-treated EXCY2 mice exhibited a normal colonic mucosa (general crypts aspect, crypt size, presence of goblet cells, absence of immune cells infiltration) as compared to vehicle treated EXCY2 mice. These data indicate that OxA 1) exerts an original anti-inflammatory properties in DSS-treated mouse model; 2) and strongly protects from spontaneous colitis developed in EXCY2 mice model and trigger mucosal healing certainly by controlling the different pathways involved in the onset of UC. In conclusion, the system orexins/OX1R may represents an innovative and effective target in the treatment of UC. 1Voisin et al., Cancer research 2011, 71:3341-51 2Treton et al., PLOS One 2014, 9:e101669