Gut microbiota and ulcerative colitis: a transcriptomic and Mendelian randomization study

Ulcerative colitis (UC) is a prevalent chronic inflammatory bowel disease without curative treatments. Although gut microbiota (GM) dysbiosis participates in UC pathogenesis, its genetically supported associations and molecular mechanisms remain unclear. This study aimed to evaluate genetically supported associations between GM taxa and UC and to screen identify UC-associated candidate biomarkers. Based on genome‑wide association study (GWAS) summary data, Mendelian randomization (MR) analysis was used to identify GM taxa showing genetically supported associations with UC. Related metabolites and target genes were predicted, and differentially expressed genes (DEGs) were obtained from UC transcriptomic datasets. Candidate genes were determined by intersecting DEGs, UC‑related genes and metabolite target genes. Metabolite druggability and toxicity were evaluated, and multi‑level regulatory networks were constructed. Machine learning was applied to screen candidate biomarkers, followed by nomogram validation, Gene Set Enrichment Analysis (GSEA), immune infiltration analysis, molecular docking and molecular dynamics simulations. MR identified 11 GM taxa potentially associated with UC, and 44 candidate genes were screened. Several microbial metabolites exhibited favorable druggability. PHLPP2 and SLC10A2 were identified as candidate biomarkers and significantly downregulated in UC. The nomogram showed high discriminatory performance for distinguishing UC from healthy controls. The two candidate biomarkers were closely involved in immune and metabolic pathways and correlated with macrophage polarization and neutrophil infiltration. Molecular docking and simulations provided in silico support for potential interactions between the candidate biomarkers and microbial metabolites. This study provided genetic evidence supporting associations between GM taxa and UC, and nominated PHLPP2 and SLC10A2 as candidate biomarkers, with their roles potentially mediated through immune-metabolic crosstalk. These findings provide insights into UC pathogenesis and a basis for further biomarker validation and mechanistic investigation.