Gut Microbial Metabolite Crosstalk in Crohn's Disease: Network Pharmacology Unveils Dual-Axis Pathogenesis and Therapeutic Targets.

Crohn's disease (CD), a chronic inflammatory bowel disorder, is driven by dysregulated interactions between gut microbiota and host metabolism. Here, we developed a computational framework integrating multiomics profiling, network pharmacology, and molecular dynamics simulations to systematically map microbiota-metabolite-target-signaling (M-M-T-S) networks and identify therapeutic candidates. By analyzing gut microbial metabolomics and CD-associated targets (via SwissTargetPrediction [STP]/SEA), we constructed a protein-protein interaction (PPI) network enriched for 50 intestinal hub targets (IL6, AKT1, PPARG; degree centrality [CD] > 19.4), which orchestrate inflammatory (TNF/IL-17/TLR, FDR = 3.8 × 10-12) and metabolic (PPAR, FDR = 1.5 × 10-10) pathways. Structure-based screening (AutoDock Vina/AMBER20) revealed 3-indolepropionic acid (IPA) as a high-affinity AKT1 binder (ΔG = -67.4 kJ/mol), while Genipin exhibited robust binding to PTGS2, both validated by 100-ns dynamics simulations (RMSD < 3.8 Å). Mechanistic network analysis uncovered a dual-axis regulatory paradigm: a pro-inflammatory axis (Clostridiumspp.-derived LPS aggravates Th17 polarization via TLR4/IL-17 signaling) and a reparative axis (Faecalibacterium prausnitzii-produced butyrate enhances barrier integrity through PPARγ-mediated NF-κB suppression). Phylogenetic analysis linked microbial functional traits (e.g., LPS/SCFA synthesis) to evolutionary conservation, highlighting clade-specific roles in CD progression. Drug-likeness evaluation (SwissADME/ADMETlab 2.0) prioritized IPA as a lead candidate due to its superior solubility (7.65 mg/mL), nonhepatotoxic profile, and AhR agonism, outperforming Genipin. This study establishes IL6/AKT1/PPARG as central therapeutic hubs and positions IPA for clinical translation. Our framework bridges multiomics integration with precision medicine, offering a scalable strategy to decode microbiome-driven pathologies and accelerate metabolite-based therapeutics.