BACKGROUND: Irritable Bowel Syndrome (IBS) and Major Depressive Disorder (MDD) exhibit high comorbidity, driven by dysregulation of gut-brain axis interactions. Despite evidence of shared pathophysiology, the core molecular mechanisms and therapeutic targets remain elusive, largely due to clinical heterogeneity and fragmented research approaches.
METHODS: We established an integrated framework combining: (1) Bidirectional epidemiological analysis using the CHARLS cohort; (2) Multi-tissue transcriptomics (intestinal mucosa/prefrontal cortex) from GEO datasets using differential expression analysis, WGCNA, and machine learning (LASSO/RF/SVM-RFE); (3) PPI network reconstruction followed by multi-algorithm topological validation; (4) Functional enrichment and immune deconvolution (CIBERSORTx); (5) Bidirectional pharmacology (CTD-based compounds screening and TCM network pharmacology); (6) Molecular docking and short-term molecular dynamics (MD) simulations for binding stability assessment; (7) ADME/Tox Profiling.
RESULTS: Epidemiological analysis indicated bidirectional IBS-MDD risk (Digestive to Mental: OR=1.82(95%CI:1.65-6.79), Mental to Digestive: OR=3.34(95%CI:1.17-2.82)). Integrated transcriptomics identified MPO, LCN2, and GMPPB as core comorbidity genes, validated across cohorts and linked to neutrophil activation, iron dysregulation, and glycosylation defects. Immune profiling revealed tissue-specific dysregulation, with gut-dominated neutrophil/M2 macrophage infiltration in IBS versus brain-enriched CD8⁺ T/NK cells in MDD. Bidirectional pharmacology prioritized bisphenol A/lipopolysaccharide (pathogenic) and resveratrol/quercetin (therapeutic) as high-affinity binders to core targets (ΔG < -7.0 kcal/mol). Short-term MD simulations provided preliminary support for the binding of key therapeutic compounds to targets GMPPB and MPO, supported by TCM herbs (e.g., Jujubae Fructus).
CONCLUSION: Our study analyzes neuro-immune-endocrine crosstalk underlying IBS-MDD comorbidity, nominating MPO/LCN2/GMPPB as diagnostic biomarkers and therapeutic targets. Environmental toxins and natural compounds offer actionable strategies for gut-brain axis modulation.
