Date Published:

Abstract:

OBJECTIVE: Epidemiological studies highlight an association between pancreatic ductal adenocarcinoma (PDAC) and oral carriage of the anaerobic bacterium , a species highly linked to periodontal disease. We analysed the potential for to promote pancreatic cancer development in an animal model and probed underlying mechanisms.

DESIGN: We tracked bacterial translocation from the oral cavity to the pancreas following administration to mice. To dissect the role of in PDAC development, we administered bacteria to a genetically engineered mouse PDAC model consisting of inducible acinar cell expression of mutant ( /LSL-G12D; Ptf1a-CreER, iKC mice). These mice were used to study the cooperative effects of mutation and on the progression of pancreatic intraepithelial neoplasia (PanIN) to PDAC. The direct effects of on acinar cells and PDAC cell lines were studied in vitro.

RESULTS: migrated from the oral cavity to the pancreas in mice and can be detected in human PanIN lesions. Repetitive administration to wild-type mice induced pancreatic acinar-to-ductal metaplasia (ADM), and altered the composition of the intrapancreatic microbiome. In iKC mice, accelerated PanIN to PDAC progression. In vitro, 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 in pancreatic cancer development in mice.