Gut-brain axis biomarkers link intestinal inflammation to post-traumatic stress disorder vulnerability.

Abstract

BACKGROUND: Patients with ulcerative colitis (UC) exhibit an elevated risk for post-traumatic stress disorder (PTSD) and frequently demonstrate severe symptomatology, suggesting a gut-brain axis connection. UC-associated chronic inflammation and immune dysregulation can influence central nervous system function via neuroimmune signaling, potentially reshaping molecular and transcriptional programs within fear-related neural circuits. However, the molecular mechanisms underlying this clinical association remain poorly characterized. METHODS: We analyzed PTSD and UC microarray data from the Gene Expression Omnibus (GEO) following background correction and normalization. Disease-associated genes were identified through differentially expressed gene (DEG) analysis and weighted gene co-expression network analysis (WGCNA), followed by gene set enrichment analysis (GSEA), Gene Ontology (GO) enrichment, CIBERSORT immune profiling, and protein-protein interaction (PPI) analysis. Key targets were validated in intestinal tissue from a murine model of UC and blood samples from a murine model of PTSD. A combined UC-PTSD mouse model was established for behavioral validation; viral knockdown targeting the prelimbic cortex (PL) was employed to test candidate genes functionally. CONCLUSION: We identified shared molecular pathways and core genes linking UC and PTSD. The comorbid model demonstrated that UC intensifies PTSD-like behaviors. Furthermore, Knockdown of Glrx in the PL alleviated fear retrieval following UC induction, establishing Glrx as a mechanistic node along the gut-brain axis in UC-associated PTSD vulnerability.