Investigation of the biomarkers and mechanism based on endoplasmic reticulum stress in irritable bowel syndrome.

Abstract

Background and study aims: Irritable bowel syndrome (IBS) is a common bowel dysfunction disorder. Endoplasmic reticulum (ER) stress plays a key role in the pathogenesis of several gastrointestinal diseases. This study investigated important ER stress-related genes (ERGs) and their mechanisms of action in IBS.

Material and methods: IBS and ERGs data were retrieved from public databases. Differential expression analysis, Venn analysis, and three machine learning algorithms, the most important ERGs in IBS were selected. A nomogram model was then constructed for the clinical predictions based on optimal ERGs. Finally, an LPS-induced Caco-2 cell line was established to simulate intestinal barrier damage and validate the expression of key genes and their underlying mechanisms.

Results: Six key ERGs (EGFR, MET, INSR, RETREG1, MCL1, and BSG) were selected to construct the nomogram model, which showed promising clinical predictive performance. These six genes were significantly correlated with immune response and ER stress-related pathways, such as oxidative phosphorylation. In vitro cell experiments have demonstrated damaged barrier function and ER stress activation in IBS, manifesting as lower transepithelial resistance, higher cell permeability, higher levels of inflammatory cytokines, and higher levels of ER proteins in LPS-induced cells. Furthermore, MET expression was significantly increased in the LPS group, whereas EGFR, INSR, RETREG1, MCL1, and BSG levels were significantly decreased in the LPS group.

Conclusion: Our study demonstrated a six-gene nomogram model for IBS based on ER stress, which showed a strong relationship between ER stress and various diseases.