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Investigation of the gut microbiome, bile acid composition and host immunoinflammatory response in a model of azoxymethane-induced colon cancer at discrete timepoints

British Journal of Cancer volume 128, pages 528–536 (2023)Cite this article

Subjects

Abstract

Background

Distinct sets of microbes contribute to colorectal cancer (CRC) initiation and progression. Some occur due to the evolving intestinal environment but may not contribute to disease. In contrast, others may play an important role at particular times during the tumorigenic process. Here, we describe changes in the microbiota and host over the course of azoxymethane (AOM)-induced tumorigenesis.

Methods

Mice were administered AOM or PBS and were euthanised 8, 12, 24 and 48 weeks later. Samples were analysed using 16S rRNA gene sequencing, UPLC-MS and qRT-PCR.

Results

The microbiota and bile acid profile showed distinct changes at each timepoint. The inflammatory response became apparent at weeks 12 and 24. Moreover, significant correlations between individual taxa, cytokines and bile acids were detected. One co-abundance group (CAG) differed significantly between PBS- and AOM-treated mice at week 24. Correlation analysis also revealed significant associations between CAGs, bile acids and the bile acid transporter, ASBT. Aberrant crypt foci and adenomas were first detectable at weeks 24 and 48, respectively.

Conclusion

The observed changes precede host hyperplastic transformation and may represent early therapeutic targets for the prevention or management of CRC at specific timepoints in the tumorigenic process.

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Fig. 1: Alpha (α) and beta (β) diversity are altered across time in mice treated with either PBS or AOM.
Fig. 2: Histograms of the community composition of gut microbiota at the phylum level and co-abundance groups (CAGs).
Fig. 3: Taxa which differed significantly in their abundance between groups.
Fig. 4: Alterations in faecal bile acid profiles and transporter gene expression between AOM and PBS-treated mice.
Fig. 5: Alterations in immunoregulatory gene expression between AOM and PBS-treated mice.

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Data availability

The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We acknowledge Pat Casey for his assistance with the animal studies. Graphical abstract was created with BioRender.com.

Funding

This work was supported by the APC Innovation Platform. APC Microbiome Ireland is a research institute funded by Science Foundation Ireland (SFI) through the Irish Governments National Development Plan (Grant SFI/12/RC/2273).

Author information

Author notes

  1. These authors contributed equally: S. A. Joyce, C. G. M. Gahan, A. Houston, N. P. Hyland.

Authors and Affiliations

  1. APC Microbiome Ireland, University College Cork, Cork, Ireland

    J. M. Keane, C. J. Walsh, P. Cronin, S. Melgar, P. D. Cotter, S. A. Joyce, C. G. M. Gahan, A. Houston & N. P. Hyland

  2. School of Microbiology, University College Cork, Cork, Ireland

    J. M. Keane & C. G. M. Gahan

  3. Department of Medicine, University College Cork, Cork, Ireland

    J. M. Keane, K. Baker & A. Houston

  4. School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland

    J. M. Keane, P. Cronin & S. A. Joyce

  5. Department of Physiology, University College Cork, Cork, Ireland

    J. M. Keane & N. P. Hyland

  6. Teagasc Food Research Centre, Moorepark, Fermoy, Cork, Ireland

    C. J. Walsh & P. D. Cotter

  7. Department of Pathology, University College Cork, Cork, Ireland

    K. Baker

  8. School of Pharmacy, University College Cork, Cork, Ireland

    C. G. M. Gahan

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Contributions

JMK acquired data and played an important role in interpreting the results and drafted the manuscript. CJW, PC and KB acquired data. SM helped to design the work that led to the submission. PDC helped draft the manuscript, acquired data, and/or played an important role in interpreting the results. SAJ, CGMG, AH and NPH conceived and designed the work that led to the submission, played an important role in interpreting the results and drafted the manuscript. All authors approved the final version and agreed to be accountable for all aspects of the work.

Corresponding author

Correspondence to A. Houston.

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The authors are not aware of any competing interests that might be perceived as affecting the findings of this study.

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Animal experiments were conducted in accordance with the regulations and guidelines of the Irish Department of Health following approval by the University College Cork Animal Experimentation Ethics Committee (2011/023).

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Keane, J.M., Walsh, C.J., Cronin, P. et al. Investigation of the gut microbiome, bile acid composition and host immunoinflammatory response in a model of azoxymethane-induced colon cancer at discrete timepoints. Br J Cancer 128, 528–536 (2023). https://doi.org/10.1038/s41416-022-02062-4

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