Objective Epidemiological studies highlight an association between pancreatic ductal adenocarcinoma (PDAC) and oral carriage of the anaerobic bacterium Porphyromonas gingivalis , a species highly linked to periodontal disease. We analysed the potential for P. gingivalis to promote pancreatic cancer development in an animal model and probed underlying mechanisms. Design We tracked P. gingivalis bacterial translocation from the oral cavity to the pancreas following administration to mice. To dissect the role of P. gingivalis in PDAC development, we administered bacteria to a genetically engineered mouse PDAC model consisting of inducible acinar cell expression of mutant Kras ( Kras +/LSL-G12D; Ptf1a-CreER, iKC mice). These mice were used to study the cooperative effects of Kras mutation and P. gingivalis on the progression of pancreatic intraepithelial neoplasia (PanIN) to PDAC. The direct effects of P. gingivalis on acinar cells and PDAC cell lines were studied in vitro. Results P. gingivalis migrated from the oral cavity to the pancreas in mice and can be detected in human PanIN lesions. Repetitive P. gingivalis administration to wild-type mice induced pancreatic acinar-to-ductal metaplasia (ADM), and altered the composition of the intrapancreatic microbiome. In iKC mice, P. gingivalis accelerated PanIN to PDAC progression. In vitro, P. gingivalis infection induced acinar cell ADM markers SOX9 and CK19, and intracellular bacteria protected PDAC cells from reactive oxygen species-mediated cell death resulting from nutrient stress. Conclusion Taken together, our findings demonstrate a causal role for P. gingivalis in pancreatic cancer development in mice. Data are available in a public, open access repository. Next generation sequencing files were deposited in NCBI under BioProject ID PRJNA1005478.

中文翻译：

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口腔细菌加速小鼠胰腺癌的发展

目的 流行病学研究强调胰腺导管腺癌 (PDAC) 与口腔携带厌氧菌牙龈卟啉单胞菌之间的关联，牙龈卟啉单胞菌是一种与牙周病高度相关的物种。我们分析了牙龈卟啉单胞菌在动物模型中促进胰腺癌发展的潜力，并探讨了潜在的机制。设计 我们追踪了给小鼠施用后牙龈卟啉单胞菌细菌从口腔到胰腺的易位。为了剖析牙龈卟啉单胞菌在 PDAC 发育中的作用，我们将细菌注入基因工程小鼠 PDAC 模型中，该模型由突变型 Kras 的诱导性腺泡细胞表达（Kras +/LSL-G12D；Ptf1a-CreER，iKC 小鼠）组成。这些小鼠用于研究 Kras 突变和牙龈卟啉单胞菌对胰腺上皮内瘤变 (PanIN) 进展为 PDAC 的协同作用。体外研究了牙龈卟啉单胞菌对腺泡细胞和 PDAC 细胞系的直接影响。结果 小鼠牙龈卟啉单胞菌从口腔迁移至胰腺，并可在人类 PanIN 病变中检测到。对野生型小鼠重复施用牙龈卟啉单胞菌可诱导胰腺腺泡导管化生 (ADM)，并改变胰腺内微生物组的组成。在 iKC 小鼠中，牙龈卟啉单胞菌加速了 PanIN 向 PDAC 的进展。在体外，牙龈卟啉单胞菌感染诱导腺泡细胞 ADM 标记物 SOX9 和 CK19，细胞内细菌保护 PDAC 细胞免受营养应激导致的活性氧介导的细胞死亡。结论 综上所述，我们的研究结果证明了牙龈卟啉单胞菌在小鼠胰腺癌发展中的因果作用。数据可在公共、开放访问存储库中获取。下一代测序文件以 BioProject ID PRJNA1005478 保存在 NCBI 中。