Brain-Gut Axis Mechanism of Psychological Stress-Exacerbated Acid Reflux Esophageal Injury: A Multi-Omics Study Based on the PPAR Signaling Pathway and Lipid Metabolism

Background Psychological stress significantly contributes to refractory gastroesophageal reflux disease, yet the underlying molecular mechanisms remain poorly understood. This study sought to explore the brain-gut axis mechanism through which psychological stress aggravates esophageal injury in a rat model of acid reflux, employing an integrated multi-omics analysis. Methods To achieve this, an acid reflux model was established in rats via hemi-pylorus ligation combined with cardia myotomy. A composite model simulating psychological stress was then created by superimposing chronic unpredictable mild stress. Comprehensive assessments included behavioral evaluations, esophageal pathological examinations, and transcriptomic and metabolomic analyses of the esophagus, hypothalamus, and serum. Statistical comparisons between groups were conducted using t-tests and analysis of variance, with integrated multi-omics analysis subsequently identifying key pathways and targets. Results The findings revealed that psychological stress increased esophageal mucosal epithelial permeability but concurrently reduced gastric acid and bile secretion. This outcome suggests that stress does not exacerbate injury by augmenting the aggressiveness of the refluxate itself. Integrated analysis revealed a specific regulatory axis: psychological stress leading to lipid metabolism disorder, which in turn inhibits the esophageal peroxisome proliferator-activated receptor signaling pathway, ultimately resulting in esophageal barrier injury. Hypothalamic metabolomics primarily highlighted disorders in glycerophospholipid metabolism. Nuclear receptor coactivator 3 (NCOA3) and nuclear receptor subfamily 1, group D, member 2 (NR1D2) were identified as crucial targets bridging central stress signals to peripheral esophageal injury. Furthermore, arachidonic acid metabolism, acting as an upstream regulator of the PPAR pathway, was also implicated in this process. Conclusions Psychological stress does not exacerbate GERD by increasing gastric acid or bile secretion. Instead, it disrupts hypothalamic glycerophospholipid and arachidonic acid metabolism through the identified targets, thereby inhibiting esophageal barrier-protective signaling and compromising mucosal barrier function. This study unveils a novel brain-gut axis mechanism for stress-exacerbated reflux disease, offering a theoretical foundation for reorienting treatment strategies for refractory patients with concomitant psychological stress. Such strategies could shift from traditional acid suppression towards promoting barrier protection and central lipid regulation.