A central event in inflammatory bowel disease is the disruption of the mucosal homeostasis. Trefoil peptides [(TFF)] are emerging as key mediators in the defense and repair of the gastrointestinal mucosa. Here, we demonstrate induction of TFF by CLA with therapeutic antiinflammatory effects in a mouse model of inflammatory bowel disease. SW480 cells were treated with linoleic acid or CLA (0-2.5 μmol/L) in the absence or presence of the PPARγ inhibitor GW9662. Cells treated with CLA showed an upregulation of the intestinal trefoil factor, which was prevented by pretreatment with GW9662. Dextran sulfate sodium (2%) was used to induce colitis in mice and they were simultaneously fed with a standard or a CLA-supplemented (100 mg · kg(-1) · d(-1)) diet for 7 d. The CLA-enriched diet prevented the colon shortening induced by DSS and markedly reduced the disease activity index and the colonic expression of inducible NO synthase and NF-κB. Immunohistochemistry revealed an increase in PPARγ and TFF3 expression after CLA administration. Altogether, these results indicate that dietary CLA protects against DSS-induced colitis in a process involving induction of PPARγ and TFF3.