GPA peptide enhances Nur77 expression in intestinal epithelial cells to exert a protective effect against DSS‐induced colitis

Ulcerative colitis (UC) is a widespread inflammatory bowel disease that causes long‐lasting inflammation and ulcers in the colon and rectum. In the inflamed tissue of patients with UC, the tight junctions are disrupted and large amounts of pro‐inflammatory cytokines are produced, resulting in immune dysregulation. The expression of Nur77 is significantly reduced in the colon of inflammatory bowel disease, while Nur77 deficiency increases the susceptibility to DSS‐induced colitis. Here, we report that Gly‐Pro‐Ala (GPA) peptide isolated from fish skin gelatin hydrolysate can significantly alleviate intestinal inflammation and damage caused by DSS‐induced mice colitis. Besides maintaining the intestinal epithelial barrier, GPA alleviates intestinal inflammation and oxidative stress by inhibiting NF‐κB activation. Interestingly, GPA binds to the ligand‐binding domain of Nur77 and stimulates its autotranscriptional activity to enhance its expression in intestinal epithelial cells. Furthermore, GPA activates the promoter of IκBα to increase its expression, resulting in the abolishment of the NF‐κB pathway. In contrast, the inhibitory effects of GPA on colitis are abolished in Nur77‐/‐ mice. Our results suggest that as a Nur77 modulator, GPA may be applied to the prevention of intestinal inflammation.