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Pancreas
Original research
Oral bacteria accelerate pancreatic cancer development in mice
  1. Elias Saba1,
  2. Maria Farhat1,
  3. Alaa Daoud1,
  4. Arin Khashan1,
  5. Esther Forkush2,
  6. Noam Hallel Menahem1,
  7. Hasnaa Makkawi1,
  8. Karthikeyan Pandi1,
  9. Sarah Angabo1,
  10. Hiromichi Kawasaki1,3,
  11. Inbar Plaschkes4,
  12. Oren Parnas5,
  13. Gideon Zamir6,
  14. Karine Atlan7,
  15. Michael Elkin8,
  16. Lior Katz9,
  17. Gabriel Nussbaum1
  1. 1 Institute of Biomedical and Oral Research, Hebrew University-Hadassah, Jerusalem, Israel
  2. 2 Gastroenterology, Hadassah Medical Center, Jerusalem, Israel
  3. 3 Central Research Institute, Wakunaga Pharmaceutical Co Ltd, Koda-cho, Akitakata-shi, Hiroshima, Japan
  4. 4 Info-CORE, Bioinformatics Unit of the I-CORE, Hebrew University of Jerusalem, Jerusalem, Israel
  5. 5 Immunology and Cancer Research, Hebrew University of Jerusalem, Jerusalem, Israel
  6. 6 Experimental Surgery, Hebrew University Hadassah Medical School, Jerusalem, Israel
  7. 7 Hadassah Medical Center, Jerusalem, Israel
  8. 8 Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
  9. 9 Department of Gastroenterology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
  1. Correspondence to Dr Gabriel Nussbaum, Institute of Biomedical and Oral Research, Hebrew University-Hadassah, Jerusalem 91120, Israel; gabrieln{at}ekmd.huji.ac.il

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.

  • PANCREATIC CANCER
  • BACTERIAL INFECTION

Data availability statement

Data are available in a public, open access repository. Next generation sequencing files were deposited in NCBI under BioProject ID PRJNA1005478.

https://doi.org/10.1136/gutjnl-2023-330941

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    Data availability statement

    Data are available in a public, open access repository. Next generation sequencing files were deposited in NCBI under BioProject ID PRJNA1005478.

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    Footnotes

    • ES and MF contributed equally.

    • Contributors GN is responsible for the overall content as the guarantor of the manuscript. ES, MF and GN contributed to conception and design of experiments, data acquisition, analysis and interpretation, and drafted the manuscript. AD, AK, EF, NHM, HM, KP, SA, HK, IP, OP, GZ, KA, ME and LK contributed to data acquisition, analysis and interpretation.

    • Funding These studies were supported by the Israel Science Foundation (grant #2230/20) awarded to GN. Some studies were also supported by grants from the Israel Science Foundation (# 1715/17 and 2292/21) awarded to ME.

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.