SCOPE: beta-casofensin, also known as peptide beta-CN(94-123), is a milk bioactive peptide that modulates the intestinal barrier through its action on goblet cells. Here, we evaluated whether oral administration of beta-casofensin can prevent indomethacin-induced injury of the jejunum in rats. METHODS AND RESULTS: Rats received beta-casofensin (0.01-100 muM) or tap water by daily gavage (4 muL/g) for eight days, then two subcutaneous injections of indomethacin (10 mg/kg, days 9 and 10) and were euthanized on day 12. In vitro, we investigated the effects of beta-casofensin on the restitution of a wounded monolayer. Preventive administration of beta-casofensin (100 muM) reduced intestinal macroscopic and microscopic damage induced by indomethacin. beta-casofensin also prevented the depletion of goblet cells and increased myeloperoxidase activity, as well as tumor necrosis factor-a (TNF-a) expression and immunostaining of active caspase-3 in the jejunum of rats treated with indomethacin. In wound healing experiments, beta-casofensin promoted epithelial restitution with no effect on cell proliferation. This effect was inhibited by pre-incubation with an anti-CC chemokine receptor 6 (CCR6) neutralizing antibody. CONCLUSIONS: beta-casofensin exerts protective effects in indomethacin-induced enteritis through preservation of goblet cells and improvement in wound healing. beta-casofensin could therefore become vital in nutritional programs for the prevention of intestinal diseases.