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

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. 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. 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. • WGCNA analysis was first applied in UC and PTSD patients to identify and validate key susceptibility genes. • EIF5a2, GlRX, and SAMD9 have been identified as potential biomarkers with significant diagnostic value for both UC and PTSD • A comorbid UC-PTSD animal model was established for the first time, demonstrating that UC increases vulnerability to PTSD-like behaviors.