Dysregulated glucocorticoid-responsive immune genes in peripheral blood mononuclear cells as a shared molecular signature of autism spectrum disorder and irritable bowel syndrome.

BACKGROUND: Autism spectrum disorder (ASD) is frequently accompanied by gastrointestinal (GI) disturbances resembling irritable bowel syndrome (IBS). While dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and impaired glucocorticoid-responsive immune (GRI) signaling are proposed links between these disorders, the precise molecular mechanisms remain poorly understood. METHODS: We performed an integrative transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) from ASD and IBS cohorts. Our approach combined single-sample Gene Set Enrichment Analysis (ssGSEA), differential expression profiling, weighted gene co-expression network analysis (WGCNA), and machine-learning-based feature selection. We utilized single-cell RNA sequencing to resolve cellular sources, while transcription factor, miRNA, and Connectivity Map (CMap) analyses identified regulatory mechanisms and potential drug candidates for reversing GRI-associated signatures. RESULTS: GRI-associated transcriptional activity was markedly elevated in the ASD group and moderately upregulated in the IBS group. Network and enrichment analyses revealed a convergence of immune recognition and cytokine signaling pathways. We identified four core genes-LRFN1, NUAK2, TMEM154, and GAPT-that consistently discriminated disease status. These genes were primarily expressed in monocytes, natural killer (NK) cells, and B cells. Regulatory analysis implicated stress-responsive transcriptional control and extensive miRNA modulation in these processes. CMap analysis identified RN-486, saracatinib, and batimastat as compounds predicted to restore GRI homeostasis. CONCLUSIONS: These findings define a shared GRI-associated molecular signature linking systemic stress adaptation to immune dysregulation along the brain-gut axis. This study provides novel mechanistic insights and identifies potential transcriptomic biomarkers and therapeutic targets addressing the shared molecular architecture between ASD and IBS.