Ghrelin Protects Gut Cells from Apoptosis in Ulcerative Colitis by Activating UPR

Ulcerative Colitis (UC) is a chronic inflammatory bowel disease characterized by significant intestinal epithelial cell (IEC) apoptosis, leading to impaired gut barrier function and disease progression. While Ghrelin, a hormone primarily known for regulating appetite, has demonstrated anti-inflammatory properties, its specific role and underlying mechanisms in mitigating IEC apoptosis in UC have remained unclear.

They found that Ghrelin treatment significantly reduced the disease activity index (DAI), colon shortening, and histological damage score in UC mice compared to control groups. Furthermore, Ghrelin effectively inhibited the apoptosis of intestinal epithelial cells (IECs) in both UC mice and TNF-α-treated NCM460 cells, as evidenced by decreased TUNEL staining and caspase-3 activity. The most critical finding was that Ghrelin activated the Unfolded Protein Response (UPR) pathway, evidenced by increased expression of GRP78, p-PERK, p-eIF2α, and ATF4. This activation was crucial, as pharmacological inhibition of the UPR pathway by 4-PBA completely abolished Ghrelin's anti-apoptotic effects, confirming the pathway's involvement. Ghrelin also reduced pro-apoptotic proteins like CHOP and caspase-12 while increasing anti-apoptotic Bcl-2 expression.