Crohn′s disease (CD) is a complex inflammatory bowel disorder with multifactorial etiology involving genetic susceptibility, metabolic dysregulation, and intestinal microbiome alterations. Although individual omics studies have provided insights into CD pathogenesis, integrative analyses linking these molecular layers remain limited. Here, we performed a comprehensive multiomics investigation combining genome‐wide association study (GWAS) data, untargeted metabolomics profiling of paired intestinal tissue samples from six CD patients, RNA‐seq–based tissue microbiome analysis from 376 samples, and validation by 16S rRNA gene sequencing in an independent cohort. GWAS meta‐analysis identified 24 susceptibility variants across 13 chromosomal regions, with NOD2 and IL23R showing the strongest associations and adaptive immunity pathways being most prominently represented. Metabolomic profiling revealed significant elevation of lactic acid in CD lesional tissue (1.73‐fold, p = 0.028) with enrichment of glycolysis‐related pathways including the Warburg effect, pyruvate metabolism, and gluconeogenesis. Tissue microbiome analysis demonstrated reduced alpha diversity ( p = 0.02) and dysbiosis characterized by depletion of beneficial commensals and enrichment of opportunistic pathogens including Escherichia coli and Bacillus cereus . Multiomics integration identified 49 significant cross‐omics correlations between genetic variants and microbiome taxa, and machine learning analysis achieved excellent disease classification (AUC = 0.977) with polygenic risk score, Limosilactobacillus reuteri , and propionic acid emerging as top biomarkers. Pathway‐level analysis revealed convergence of multiomics signals on innate immunity, adaptive immunity, and autophagy pathways. Validation by 16S sequencing confirmed key microbial alterations and established a mechanistic link between B. cereus abundance and lactic acid accumulation ( ρ = 0.82, p = 0.019). Our findings demonstrate that integration of genetic, metabolic, and microbial data provides comprehensive insights into CD pathophysiology and identifies potential therapeutic targets at the intersection of host immunity, energy metabolism, and microbiome homeostasis.
Qu et al. (Thu,) studied this question.