Targeting the MPO/LCN2/GMPPB axis in IBS-depression comorbidity: Integrated multi-omics and bidirectional network pharmacology for precision diagnostics and therapeutics.

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. 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. 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). 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.