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Influence of gemcitabine chemotherapy on the microbiota of pancreatic cancer xenografted mice

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Abstract

Background and aims

Pancreatic ductal adenocarcinoma (PDAC) represents the fourth cause of cancer-related death. We aimed to evaluate whether gemcitabine treatment shapes the gut microbiota in a model of PDAC xenografted mice.

Materials and methods

Pancreatic cancer xenograft mice were subjected to gemcitabine injection once per week for 3 weeks to assess the tumor volume as compared to control mice injected with normal saline solution. The composition of fecal microbiota, the activation of NF-kB pathway in cancer tissues and the serum metabolomics were further analyzed.

Results

Gemcitabine considerably decreases the proportion of Gram- positive Firmicutes (from about 39 to 17%) and the Gram- negative Bacteroidetes (from 38 to 17%) which are the two dominant phyla in the gut of tumor-bearing control mice. This downshift was replaced by an increase of Proteobacteria (Escherichia coli and Aeromonas hydrophila) from 15 up to 32% and Verrucomicrobia (Akkermansia muciniphila) from 5 to 33% in the gut of drug-receiving mice. An overall increase in inflammation-associated bacteria was observed upon gemcitabine. Consistently, activation of the NF-kB canonical pathway was found in cancer tissues from gemcitabine-treated mice. Serum metabolomics revealed a significant decrease of the purine compounds inosine and xanthine, and a decreasing trend for their metabolically-related molecule hypoxanthine.

Discussion

Understanding chemotherapy side effects may explain the lack of activity or the chemoresistant processes and it may help to set up strategies to improve the effectiveness of therapy.

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Acknowledgements

We thank Morten Danielsen and the MS-Omics for the excellent technical help. No competing interest is declared.

Funding

This research was supported by the ‘‘Ricerca Corrente RC1703GA31’’ funding granted by the Italian Ministry of Health and by the “5 × 1000” voluntary contributions to our Hospital and also by European Regional Development Fund to Competence Center of Food and Fermentation Technologies (EU48667) and Institutional Research Funding to Tallinn University of Technology (IUT 19-27) of the Estonian Ministry of Education and Research.

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Author notes

  1. Concetta Panebianco and Kaarel Adamberg contributed equally.

Authors and Affiliations

  1. Gastroenterology Unit, I.R.C.C.S. “Casa Sollievo della Sofferenza” Hospital, viale dei Cappuccini n.1, 71013, San Giovanni Rotondo, FG, Italy

    Concetta Panebianco, Angelo Andriulli & Valerio Pazienza

  2. Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia

    Kaarel Adamberg, Madis Jaagura, Signe Adamberg, Kaia Kolk & Raivo Vilu

  3. Center of Food and Fermentation Technologies, University of Tallinn, Tallinn, Estonia

    Kaarel Adamberg, Madis Jaagura & Raivo Vilu

  4. Biostatistics Unit, I.R.C.C.S. “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, FG, Italy

    Massimiliano Copetti & Andrea Fontana

Authors
  1. Concetta Panebianco
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  2. Kaarel Adamberg
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  3. Madis Jaagura
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  4. Massimiliano Copetti
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  5. Andrea Fontana
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  6. Signe Adamberg
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  7. Kaia Kolk
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  8. Raivo Vilu
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  9. Angelo Andriulli
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  10. Valerio Pazienza
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Contributions

Conceived the study: VP. Designed the experiments: CP, KA, RV and VP. Performed the experiments: CP, MJ, SA and KK. Biostatistics Analysis: MC and AF. Analyzed the data: CP, KA and VP. Contributed reagents/materials/analysis tools: KA, RV and VP. Wrote the paper: CP, KA, AA and VP.

Corresponding author

Correspondence to Valerio Pazienza.

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Conflict of interest

All authors declare that they have no conflicts of interest.

Ethical approval

The animal study was performed in an AAALAC (Association for Assessment and Accreditation of Laboratory Animal Care International) accredited experimental facility. Principles of laboratory animal care were followed for the welfare of animals in experimental neoplasia and protocols were approved by the Institutional Animal Care and Use Committee, with the approval number ANM14-002.

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Panebianco, C., Adamberg, K., Jaagura, M. et al. Influence of gemcitabine chemotherapy on the microbiota of pancreatic cancer xenografted mice. Cancer Chemother Pharmacol 81, 773–782 (2018). https://doi.org/10.1007/s00280-018-3549-0

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