Background and Aim: Alterations in the gut microbiota strongly correlate with the onset of pancreatic cancer (PC). However, any causal relationship between gut microbiota alterations and PC risk remains unknown. Methods: We comprehensively investigated PC-related microorganisms in European and East Asian populations through the application of Mendelian randomization (MR). The PC genome-wide association study (GWAS) databases for European and East Asian individuals were acquired from the UK and Japanese Biobanks, respectively. Primary analytical methods, including the inverse variance weighted (IVW) method, weighted median, Maximum likelihood method and MR PRESSO, were employed to estimate the potential causal association between gut microbiota and PC. Additionally, we performed sensitivity analysis and reverse MR analysis. Results: By IVW method, overall 17 bacterial taxa were identified with potential causal correlations to PC. The PC-associated gut microbiota signatures varied across different populations. Among these, 4 specific taxa exhibited potential causality with PC, with statistical significance in all four MR methods. Specifically, the Alcaligenaceae family was identified as protective, while genus Sutterella, order Bacilliales and genus Enterohabdus were associated with increased risk of PC. Among the European population within the UK biobank, the Alcaligenaceae family, genus Sutterella, and order Bacillales were connected to PC, while genus Enterohabdus was linked to PC in the Japanese cohort. Conclusion: Our study implicates certain members of the gut microbiota in PC onset based on genetics. Further investigations of the gut-pancreas axis may lead to the development of novel microbiome targeted prevention strategies for PC.

The authors have declared no competing interest.

This study was supported by funding from National Natural Science Foundation of China (No. 82072749).

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