BACKGROUND : The use of nutraceutical-based products has increased in recent years due to their demonstrated efficacy and their good safety profile. Onion is one of the most commonly used plants in the traditional medicine for the management of various conditions including inflammatory and gastrointestinal diseases. However, little is known regarding the molecular mechanism of the anti-inflammatory effects of onion particularly in inflammatory bowel disease (IBD). OBJECTIVE : To test the anti-inflammatory effects of onion bulb extract (OBE) in an IBD mouse model and the molecular mechanisms responsible for these effects such as modulation of the expression and/or the activity profile of various pro-inflammatory molecules. METHODS : Colitis was induced in mice by dextran sulfate sodium (DSS) daily administration for 5 days. Animals were sacrificed, colons were removed and the severity of the inflammation was determined by the gross and histological assessments. The colonic level/activity of various cytokines and chemokines were measured using proteome profiling-based assay, western blotting, and immunofluorescence techniques. RESULTS : DSS-induced colitis was significantly reduced by the daily OBE treatment and 5-aminosalicylic acid (5-ASA, positive control), particularly at 100-200 mg/kg doses, at both the gross and histological levels. OBE was also shown to reduce colonic expression and activity of several pro-inflammatory molecules and signaling pathways, such as mitogen activated protein kinase family, mammalian target of rapamycin, cyclooxygenase-2, and tissue inhibitors of metalloproteinases. In addition, OBE reduced the expression of interferon-γ, various C-C and C-X-C chemokines, and molecules involved in the apoptotic machinery such as cytochrome c, caspase-3 and -8, B-cell lymphoma-extra-large and -2. CONCLUSIONS : OBE showed anti-inflammatory actions in IBD mouse model, which is attributed, in part, to the modulation of the expression and the activity of important pro-inflammatory molecules and signaling pathways involved in the inflammatory response. These data suggest that OBE may be a promising lead in the therapeutic management of IBD.