Polyethylene terephthalate microplastics exposure enhances the risk of ulcerative colitis: insights from multiomics integration, machine learning, and molecular docking reveal intestinal toxicity mechanisms

BACKGROUND: In recent decades, the widespread use of polyethylene terephthalate (PET) has led to the proliferation of PET microplastics (PET-MPs) in the environment, posing potential threats to human health, including ulcerative colitis (UC). However, the underlying molecular mechanisms remain unclear. METHODS: Data sourced from public databases were harnessed to predict the targets of PET-MPs and identify UC-related differentially expressed genes. Functional enrichment analyses were conducted to uncover relevant biological pathways. Three machine learning (ML) algorithms were utilized to screen for hub genes associated with PET-MPs-induced UC, followed by the evaluation of these hub genes using eight ML algorithms via SHapley Additive exPlanations (SHAP) analysis. Subsequently, a nomogram was constructed and validated based on a risk prediction model, and single-cell sequencing analysis and molecular docking were performed. An animal model was established via coadministration of 3% dextran sulfate sodium (DSS) and PET-MPs. Western blot analysis was employed to verify the protein expression levels in intestinal tissues. RESULTS: Eleven potential targets related to PET-MPs-induced UC toxicity were identified. Four hub genes (CTSK, NAAA, PDE4B, and PFKFB3) were successfully screened out, exhibiting significant expression disparities in UC samples. The constructed risk prediction model demonstrated high prediction accuracy. Single-cell analysis revealed distinct expression patterns of the hub genes across different cell types, and molecular docking confirmed strong binding affinities between PET-MPs and these genes. Animal experiments revealed that the expression levels of CTSK, PDE4B, and PFKFB3 in the DSS + PET-MPs group were significantly upregulated, while the expression level of NAAA was significantly downregulated, compared with the DSS group. CONCLUSION: This study offers valuable insights into the molecular mechanisms by which PET-MPs may induce UC, providing a theoretical foundation for understanding the potential health risks associated with PET-MPs exposure.