Activation of notch signaling pathway is a potential mechanism for mucin2 reduction and intestinal mucosal barrier dysfunction in high-altitude hypoxia

Abstract

Abstract High-altitude hypoxia can cause gastrointestinal issues and damage the intestinal mucosal barrier, which is crucial for digestion and nutrient absorption. The Notch signaling pathway affects this barrier’s integrity. This study explores the Notch pathway’s role in hypoxia-induced intestinal injury. C57BL/6 mice were used to model intestinal mucosal barrier injury through dextran sodium sulfate (DSS) and hypobaric hypoxia (simulating 5000 m altitude for 7 days). Mice were treated with Notch inhibitor Dibenzazepine (DBZ) and Mucin2 (MUC2) activator Prostaglandin E2 (PGE2). We evaluated weight, colon length, histology, Zonula occludens 1 (ZO-1) and Claudin-1 levels, MUC2 and Notch1 staining, serum diamine oxidase (DAO) and D-lactate (D-La), inflammatory markers, and Notch pathway proteins. DSS and hypoxia caused weight loss, colon shortening, ulcers, and inflammation, with fewer goblet cells and lower MUC2 levels. Elevated serum DAO, D-La, and inflammatory markers indicated severe intestinal damage. DBZ treatment post-DSS and hypoxia significantly reduced these symptoms. PGE2 activation of MUC2 also alleviated symptoms and mitigated intestinal damage. Hypoxia worsens DSS-induced mucosal barrier disruption by activating the Notch pathway, shifting stem cell differentiation towards absorptive cells instead of goblet cells, reducing MUC2 secretion, and intensifying damage. Targeting the Notch pathway and enhancing MUC2 expression could effectively treat hypoxia-induced intestinal injury.

Keywords

• High-altitude hypoxia
• Intestinal mucosa barrier
• MUC2
• Notch signaling pathway