ISRIB Inhibits Endoplasmic Reticulum Stress to Ameliorate Chronic Restraint Stress–Induced Intestinal Inflammation

Prolonged psychological stress can cause intestinal barrier dysfunction, increasing its permeability and allowing harmful substances present in the gut, such as bacteria and toxins, to readily traverse the intestinal barrier and enter the bloodstream, ultimately precipitating systemic inflammation. This study used the chronic restraint stress (CRS) model to stimulate intestinal inflammation induced by prolonged psychological stress in humans. Endoplasmic reticulum (ER) stress is closely linked to intestinal diseases. Unresolved and persistent ER stress can damage the intestinal barrier, activating inflammation through the unfolded protein response, leading to intestinal diseases, such as inflammatory bowel disease and irritable bowel syndrome. By examining proteins associated with the PERK pathway, upregulated levels of PERK, P-eIF2α, and C/EBP homologous proteins were observed in the jejunum and colon during CRS-induced intestinal inflammation. Integrated stress response inhibitor (ISRIB), a potent inhibitor of the PERK pathway, plays a crucial role in suppressing integrated stress responses. Herein, ISRIB ameliorated CRS-induced jejunal and colonic mucosal injury and barrier dysfunction by inhibiting ER stress. Prolonged ER stress exposure can lead to the onset of cellular apoptosis. ISRIB effectively prevented the upregulation of CRS-induced apoptosis markers (Caspase-3, Bax/Bcl-2) in the jejunum and colon. Furthermore, ISRIB intervention reversed the CRS-induced elevation of NLRP3 inflammasome and pyroptosis marker GSDMD in the jejunum and colon. Therefore, ISRIB has emerged as a promising therapeutic candidate for treating intestinal inflammation related to prolonged psychological stress.