Ghrelin Inhibits Intestinal Epithelial Cell Apoptosis Through the Unfolded Protein Response Pathway in Ulcerative Colitis

Abstract

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-α (TNF-α). Therefore, we hypothesized that ghrelin might play an antiapoptotic role in UC progression, which was investigated using in vitro and in vivo studies. The TNF-α-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-α, 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.

Protective and Healing Effects of Ghrelin and Risk of Cancer in the Digestive System

“…In addition, Cheng et al [ 145 ] reported that ghrelin prevented the breakdown of intestinal barrier function in DSS-induced colitis by inhibiting the activation of nuclear factor kappa B (NFκB). This observation is supported by the findings of Zhang et al [ 139 ], which show that the beneficial effect of ghrelin in DSS-induce colitis involves the inhibition of intestinal cell apoptosis.…”

“…These findings suggest that endogenous ghrelin may protect and accelerate the healing of inflamed colonic mucosa, and that ghrelin could be useful in the treatment of ulcerative colitis [137]. The therapeutic effect of ghrelin in TNBS-induced colitis was also shown by Zhang et al [139].…”

“…The beneficial effect of ghrelin administration was also shown in dextran sodium sulfate (DSS)-induced colitis in rats [ 144 ] and mice [ 139 , 145 ]. In addition, Cheng et al [ 145 ] reported that ghrelin prevented the breakdown of intestinal barrier function in DSS-induced colitis by inhibiting the activation of nuclear factor kappa B (NFκB).…”

Novel Role of Ghrelin Receptor in Gut Dysbiosis and Experimental Colitis in Aging

“…IBD patients, especially UC patients, have high circulating ghrelin [24], and exogenous ghrelin administration has been shown to aggravate experimental colitis [25]. At the same time, other studies showed that ghrelin protects against tissue damage in ulcerative colitis by inhibiting apoptosis of intestinal epithelial cells [26,27].…”

Artemisinin analog SM934 alleviates epithelial barrier dysfunction via inhibiting apoptosis and caspase-1-mediated pyroptosis in experimental colitis

“…Furthermore, apoptosis regulates the replacement rate of the epithelial cells, and an increase in epithelial cell apoptosis in colitis disrupts the mucosal epithelial barrier ( Cai et al, 2018 ; Xiong et al, 2019 ). However, an aberrantly high rate of IEC apoptosis in IBD leads to a positive feedback cycle of epithelial barrier disruption but does not cause an inflammation response ( Bayrer et al, 2018 ; Zhang L. et al, 2021 ).…”