Veillonella promotes pancreatic cancer progression as revealed by integrated functional, Mendelian randomization, and transcriptomic analyses

Gut microbiota dysbiosis is closely associated with the development and progression of pancreatic cancer; however, the specific bacterial taxa involved and their underlying molecular mechanisms remain largely unknown. Metagenomic sequencing was employed to screen significantly differential bacterial taxa between healthy adults and advanced pancreatic cancer patients. Representative differential taxa were selected for co-culture with pancreatic cancer cell lines PANC-1 and BxPC-3. Cell viability was assessed by CCK-8 assay, proliferation capacity by colony formation assay, migratory ability by wound healing and Transwell assays. Transcriptomic sequencing was performed on co-cultured pancreatic cancer cells and control cells to explore underlying molecular mechanisms. Two-sample MR analysis was conducted using summary data from large-scale genome-wide association studies (GWAS) to explore potential genetic associations. Compared with healthy individuals, the abundance of Veillonella was significantly increased in the intestinal microbiota of advanced pancreatic cancer patients. Bacteria-cell co-culture experiments demonstrated that Veillonella parvula significantly enhanced the proliferation and migration capabilities of pancreatic cancer cells. Transcriptomic analysis revealed significant enrichment of PI3K/AKT pathway-related genes, pointing to a potential regulatory link that warrants functional dissection.Further MR analysis provided genetic evidence supporting a potential association between Veillonella and pancreatic cancer risk (inverse variance weighted [IVW] OR = 1.39, 95% CI: 1.05–1.83, P = 0.02). The enrichment of Veillonella in the gut of advanced pancreatic cancer patients may promote malignant phenotypes of pancreatic cancer cells in vitro, with potential mechanisms involving the PI3K/AKT signaling axis as indicated by transcriptional enrichment. This study provides, for the first time, genetic evidence supporting a potential causal link between the two, while acknowledging that residual pleiotropy and weak instrument bias cannot be fully excluded.