Oral bacteria accelerate pancreatic cancer development in mice

Elias Saba, Maria Farhat, Alaa Daoud, Arin Khashan, Esther Forkush, Noam Hallel Menahem, Hasnaa Makkawi, Karthikeyan Pandi, Sarah Angabo, Hiromichi Kawasaki, Inbar Plaschkes, Oren Parnas, Gideon Zamir, Karine Atlan, Michael Elkin, Lior Katz, Gabriel Nussbaum*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageAmerican English
Article numbergutjnl-2023-330941
JournalGut
Early online date22 Jan 2024
DOIs
StateE-pub ahead of print - 22 Jan 2024

Bibliographical note

Publisher Copyright:
© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.

Keywords

  • BACTERIAL INFECTION
  • PANCREATIC CANCER

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