Orientin is a C-glycosyl flavonoid found abundantly in some fruits and herbs. The present study demonstrated that orientin (50 and 100 mg/kg/d) alleviated the severity of dextran sulphate sodium (DSS)-induced colitis in mice by decreasing the activity of myeloperoxidase (MPO) and the production of cytokines. Concomitant up-regulation of toll-like receptor (TLR)-4 after DSS exposure was associated with an increase in the activation of myeloid differentiation factor 88 (MyD88), IL-1 receptor-associated kinase (IRAK)-1, nuclear factor kappa B (NF-kappa B) p65, as well as the mitogen-activated protein kinase (MAPK) molecules (ERK1/2, JNK and p38), and this upregulation was reversed by orientin administration. Moreover, orientin inhibited the nuclear translocation of NF-kappa B p65, the activity of NF-kappa B-luciferase, and the expression of NF-kappa B target genes. These findings suggest that orientin attenuates experimental inflammatory bowel disease (IBD) via suppression of TLR4 and inactivation Of NF-kappa B and MAPK pathways. (C) 2015 Elsevier Ltd. All rights reserved.