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

) 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.