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 (Δ G = −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 ( Clostridium spp.‐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.