Oral bacteria accelerate pancreatic cancer development in mice.

Abstract

Epidemiological studies highlight an association between pancreatic ductal adenocarcinoma (PDAC) and oral carriage of the anaerobic bacterium <i>Porphyromonas gingivalis</i>, a species highly linked to periodontal disease. We analysed the potential for <i>P. gingivalis</i> to promote pancreatic cancer development in an animal model and probed underlying mechanisms. We tracked <i>P. gingivalis</i> bacterial translocation from the oral cavity to the pancreas following administration to mice. To dissect the role of <i>P. gingivalis</i> in PDAC development, we administered bacteria to a genetically engineered mouse PDAC model consisting of inducible acinar cell expression of mutant <i>Kras</i> (<i>Kras</i> ⁺/LSL-G12D; Ptf1a-CreER, iKC mice). These mice were used to study the cooperative effects of <i>Kras</i> mutation and <i>P. gingivalis</i> on the progression of pancreatic intraepithelial neoplasia (PanIN) to PDAC. The direct effects of <i>P. gingivalis</i> on acinar cells and PDAC cell lines were studied in vitro. <i>P. gingivalis</i> migrated from the oral cavity to the pancreas in mice and can be detected in human PanIN lesions. Repetitive <i>P. gingivalis</i> administration to wild-type mice induced pancreatic acinar-to-ductal metaplasia (ADM), and altered the composition of the intrapancreatic microbiome. In iKC mice, <i>P. gingivalis</i> accelerated PanIN to PDAC progression. In vitro, <i>P. gingivalis</i> 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. Taken together, our findings demonstrate a causal role for <i>P. gingivalis</i> in pancreatic cancer development in mice.