OLFM4, LCN2 and FAM3B as Potential Biomarkers for Gut–Brain Axis Dysfunction in IBD-MDD Comorbidity

Background: Inflammatory bowel disease (IBD) and major depressive disorder (MDD) exhibit bidirectional pathogenic interactions through the gut–immune–brain axis, but robust common biomarkers remain elusive. This study aimed to identify the core hub genes and their conserved signaling pathways in IBD-MDD comorbidity. Methods: We analyzed two transcriptome datasets, GSE117993 (pediatric IBD biopsy) and GSE98793 (MDD whole blood), to screen for shared differentially expressed genes (DEGs). Multi-algorithm machine learning, marker pathway correlation analysis, immune infiltration assessment and ROC validation were performed. Results: A total of 25 overlapping DEGs were identified, and three common core genes, OLFM4, LCN2, and FAM3B, were unanimously selected. Marker pathway analysis revealed that these genes were significantly associated with conserved inflammatory cascades in both diseases, including TNF/NF-κB and JAK-STAT signaling pathways, as well as interferon response and metabolic stress pathways. Analysis of immune infiltration indicated an association with neutrophils, M1 macrophages, and other immune subsets. The combined three-gene signature shows preliminary diagnostic performance within these datasets for IBD and MDD. Conclusions: This study identifies OLFM4/LCN2/FAM3B as potential shared biomarkers hinting at molecular links between IBD and MDD, providing new insights into candidate shared inflammatory mechanisms underlying gut–immune–brain axis dysfunction.