Ghrelin Protects Intestinal Epithelial Cells from Apoptosis in Ulcerative Colitis via the Unfolded Protein Response Pathway

Ulcerative colitis (UC), a form of inflammatory bowel disease (IBD), causes inflammation in the colon and rectum. A key pathological feature in active UC is the excessive apoptosis (programmed cell death) of intestinal epithelial cells (IECs), which compromises the gut lining's integrity. Previous research noted that levels of the gut hormone ghrelin are downregulated during IEC apoptosis induced by tumor necrosis factor-α (TNF-α), a major inflammatory cytokine in UC. This observation suggested a potential protective role for ghrelin. The researchers hypothesized that ghrelin could exert an anti-apoptotic effect during UC progression, potentially offering a new therapeutic avenue for preserving intestinal barrier function.

The study used both in vitro and in vivo models to investigate ghrelin's role. For the in vitro portion, they used the human Caco-2 intestinal cell line, inducing apoptosis with TNF-α. Ghrelin was administered to these cells to assess its protective effects. To confirm the mechanism, they also used [D-lys3]-GHRP-6, a known antagonist of the ghrelin receptor GHS-R1a. The in vivo experiments involved two different mouse models of colitis: one induced by dextran sulfate sodium (DSS) and another by 2,4,6-trinitrobenzenesulfonic acid (TNBS). In these models, mice were treated with ghrelin, and intestinal tissues were analyzed for apoptosis and expression of key regulatory proteins.

Ghrelin demonstrated significant anti-apoptotic effects across all models. In TNF-α-treated Caco-2 cells, ghrelin successfully inhibited apoptosis. This protective action was blocked by the ghrelin receptor antagonist [D-lys3]-GHRP-6, confirming the effect is mediated through the GHS-R1a receptor. Similar results were observed in the animal models. Both DSS- and TNBS-induced colitis in mice showed that ghrelin administration protected intestinal tissues from apoptosis, an effect also dependent on GHS-R1a activation.

The study identified the underlying mechanism, showing that ghrelin modulates the unfolded protein response (UPR) pathway. This regulation led to changes in the expression of key apoptosis-related proteins: ghrelin suppressed the pro-apoptotic factors caspase-3 and BAX while promoting the anti-apoptotic factor Bcl-2.

This cascade of events effectively shifts the balance away from cell death, preserving the integrity of the intestinal epithelium during colitis-induced inflammation.