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Study on the molecular mechanisms by which gut microbiota dysbiosis promotes the development of cholangiocarcinoma through immunometabolic reprogramming
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Abstract:
[Abstract] Objective: To comprehensively elucidate the potential mechanisms of gut microbiota in the occurrence and development of cholangiocarcinoma (CCA) and identify related key genes through integrative multi-omics analysis. Methods: Based on 16S rRNA sequencing data from the SRA database, the gut microbiota composition of CCA patients was compared with that of healthy controls. Mendelian randomization (MR) analysis was employed to assess the genetic association between specific microbiota and CCA risk. Relevant metabolites and genes were obtained from the gutMGene and GeneCards databases for metabolic and functional enrichment analyses. GEO single-cell transcriptomic data (GSE213452) was integrated to characterize the cellular composition of the tumor microenvironment, with a particular focus on T cell subsets and their functional states. The expression differences of key candidate genes were validated using the TCGA-CHOL dataset. Results: Compared with the healthy control group, the gut microbiota composition of CCA patients was significantly altered, characterized by an abnormal enrichment of the phylum Proteobacteria (LDA > 4). MR analysis further demonstrated that genetic predispositions to both the order Enterobacterales and the family Enterobacteriaceae were positively associated with the risk of CCA. Metabolic pathway enrichment analysis suggested that microbiota-related metabolites were mainly involved in pathways such as purine metabolism and glycolysis/gluconeogenesis; functional enrichment analysis showed that related genes were significantly enriched in inflammatory-immune pathways including NOD-like receptor, IL-17, Toll-like receptor, and NF-κB signaling pathways. Single-cell transcriptomic analysis revealed a significantly increased proportion of cancer cells (P < 0.05) and an elevated T cell proportion (from 20.7% to 39.2%) in CCA tissues. Pseudotime analysis indicated that MKI67+ T cells were at a late differentiation stage and exhibited high proliferative features. Differential genes of these T cells intersected with microbiota-related genes, among which SERPINA1 and IFNG showed significant changes in expression in the tumor immune microenvironment (P < 0.001) and may play a core regulatory role. Validation using the TCGA-CHOL dataset revealed that SERPINA1 was significantly downregulated in CCA tumor tissues (P < 0.001), whereas IFNG showed no significant difference between tumor and normal tissues (P > 0.05). Conclusion: Gut microbiota dysbiosis, particularly the abnormal proliferation of Enterobacteriaceae, may promote CCA progression via a metabolic-immune regulatory network. Specifically, alterations in T cell function are closely linked to the differentiated expression patterns of the key genes (SERPINA1 and IFNG) within MKI67+ T cells.
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