The study shows that the hormone ghrelin can protect gut lining cells from dying in ulcerative colitis, but this protective effect is blocked when the ghrelin receptor antagonist [D-lys3]-GHRP-6 is used. In both cell cultures and mouse models, ghrelin’s anti‑death action involves the unfolded protein response pathway.

Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) that occurs in the lining of the rectum and colon. Apoptosis of the intestinal epithelial cells (IECs) is common in active UC patients. Ghrelin is reported to be downregulated in apoptosis of IECs induced by tumor necrosis factor-&#x3b1; (TNF-&#x3b1;). Therefore, we hypothesized that ghrelin might play an antiapoptotic role in UC progression, which was investigated using <i>in vitro</i> and <i>in vivo</i> studies. The TNF-&#x3b1;-treated Caco-2 cell model and mouse colitis model induced by dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzenesulfonic acid (TNBS) were established and employed. We found that ghrelin could inhibit the apoptosis of Caco-2 cells induced by TNF-&#x3b1;, which could be disturbed by [D-lys3]-GHRP-6, the antagonist of ghrelin receptor GHS-R1a. Similarly, in the DSS- and TNBS-induced mouse colitis models, ghrelin could also protect intestinal tissues from apoptosis in DSS- and TNBS-induced colitis depending on GHS-R1a. Furthermore, ghrelin modulated the unfolded protein response (UPR) pathway and regulated the expressions of caspase-3, BAX, and Bcl-2, which contributed to the inhibition of cell apoptosis. In conclusion, ghrelin protects IECs from apoptosis during the pathogenesis of colitis by regulating the UPR pathway.