Bowel inflammation in cancer patients: the microbiome, antibiotics and interleukin-9

Summary

Microbiome composition can impact disease courses and also immunotherapy outcomes in solid tumours. It is still unclear how the microbiome might impact treatments in oncology, but also how modulation via antibiotics might interfere. Elegant work now identified interleukin-9 and dysbiosis as relevant factors, providing some answers for these questions.

Main

The microbiome has attracted increasing scientific attention in the last 5 years.1,2,3,4 In light of the better understanding of the composition of what constitutes the microbiome in the gut and in other organs,5,6 one central question is still out in the open: how much influence the composition of the microbiome exerts on organ function and can we modulate this? There are elegant studies in animal models, indicating, among other things, that there is a direct relationship between the composition of the microbiome in the gut and immunotherapy outcome.3,5,7,8,9

Looking beyond animal models into the clinical situation, the picture becomes much fuzzier. Do we need to treat patients with antibiotics10,11,12 (or other biome-modulating agents) to induce treatment responses in oncology? Do we need to refrain from giving antibiotics to patients for fear of abrogating anti-tumour responses? Published data show poorer treatment responses in patients with antibiotics,13,14,15 but this is not a surprise for an oncologist: patients who need antibiotic treatment are clearly worse in their overall outlook compared with those who do not need antibiotics. And even one step beyond this: “what constitutes a ‘normal’ microbiome”?16 Is there a holy grail of beneficial bugs living in the guts of super-responders? These are questions being investigated currently and we have to wait for more insights before we can move to action in the clinic.

In light of these pressing questions, one aspect now has been addressed in the manuscript from Almeida et al.17 This elegant work now brought up interleukin-9 (IL-9) as an induced parameter by specific microbial communities. IL-9 is a well-known immunologically pleiotropic molecule.18,19 In inflammatory bowel disease, gut-residing T cells produce high amounts of IL-9. In model systems of colitis, IL-9-producing T cells critically interfered with an intact barrier function of the intestinal epithelium by modulating cellular proliferation and tight junction control. Inhibiting IL-9 ameliorated the inflammation and severity of inflammatory bowel disease. As for cancer diseases, this indicates, in light of the new data from Almeida et al.,17 that there could be a link to gut inflammation, which enforces anti-tumoural effects through barrier-breaching and bacterial product presence beyond the gut. It is an interesting hypothesis that comes from this: is there a beneficial inflammatory signature that is mediated by IL-9 and resembles a state of colitis? Almeida et al.17 found that the host microbiota enhances in vivo T-cell-derived secretion of IL-9, thereby limiting cancer outgrowth (see Fig. 1). So maybe we have to rethink the current clinical concepts for gut inflammation and antibiotic use. We need to understand better inflammatory states especially for IL-920 and not rush too easily into combating all forms of inflammation. There is more clinical and biological data from translational studies needed to clarify this situation.

Fig. 1: Differential effects for IL-9 in the mucosa.
figure1

Schematic summary of the differential effects of microbiome composition (i.e. differing microbial composition and dysbiosis shown on the right panel) on the generation of interleukin-9-producing T cells.

References

  1. 1.

    Routy, B., Gopalakrishnan, V., Daillere, R., Zitvogel, L., Wargo, J. A. & Kroemer, G. The gut microbiota influences anticancer immunosurveillance and general health. Nat. Rev. Clin. Oncol. 15, 382–396 (2018).

    CAS  Article  Google Scholar 

  2. 2.

    Gopalakrishnan, V., Spencer, C. N., Nezi, L., Reuben, A., Andrews, M. C., Karpinets, T. V. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 6371, 97–103 (2018).

    Article  Google Scholar 

  3. 3.

    Routy, B., Le Chatelier, E., Derosa, L., Duong, C. P. M., Alou, M. T., Daillere, R. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 6371, 91–97 (2018).

    Article  Google Scholar 

  4. 4.

    Zitvogel, L., Daillere, R., Roberti, M. P., Routy, B. & Kroemer, G. Anticancer effects of the microbiome and its products. Nat. Rev. Microbiol. 15, 465–478 (2017).

    CAS  Article  Google Scholar 

  5. 5.

    Shui, L., Yang, X., Li, J., Yi, C., Sun, Q. & Zhu, H. Gut microbiome as a potential factor for modulating resistance to cancer immunotherapy. Front. Immunol. 10, 2989 (2019).

    CAS  Article  Google Scholar 

  6. 6.

    Mehta, R. S., Nishihara, R., Cao, Y., Song, M., Mima, K., Qian, Z. R. et al. Association of dietary patterns with risk of colorectal cancer subtypes classified by Fusobacterium nucleatum in tumor tissue. JAMA Oncol. 3, 921–927 (2017).

    Article  Google Scholar 

  7. 7.

    Fares, C. M., Van Allen, E. M., Drake, C. G., Allison, J. P. & Hu-Lieskovan, S. Mechanisms of resistance to immune checkpoint blockade: why does checkpoint inhibitor immunotherapy not work for all patients? Am. Soc. Clin. Oncol. Educ. Book/ASCO Am. Soc. Clin. Oncol. Meet. 39, 147–164 (2019).

    Article  Google Scholar 

  8. 8.

    Pitt, J. M., Vetizou, M., Waldschmitt, N., Kroemer, G., Chamaillard, M., Boneca, I. G. et al. Fine-tuning cancer immunotherapy: optimizing the gut microbiome. Cancer Res. 76, 4602–4607 (2016).

    CAS  Article  Google Scholar 

  9. 9.

    Sivan, A., Corrales, L., Hubert, N., Williams, J. B., Aquino-Michaels, K., Earley, Z. M. et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350, 1084–1089 (2015).

    CAS  Article  Google Scholar 

  10. 10.

    Cao, Y., Wu, K., Mehta, R., Drew, D. A., Song, M., Lochhead, P. et al. Long-term use of antibiotics and risk of colorectal adenoma. Gut. 67, 672–678 (2018).

    CAS  Article  Google Scholar 

  11. 11.

    Suez, J., Zmora, N., Zilberman-Schapira, G., Mor, U., Dori-Bachash, M., Bashiardes, S. et al. Post-antibiotic gut mucosal microbiome reconstitution is impaired by probiotics and improved by autologous FMT. Cell 174, 1406–23.e16 (2018).

    CAS  Article  Google Scholar 

  12. 12.

    Gury-BenAri, M., Thaiss, C. A., Serafini, N., Winter, D. R., Giladi, A., Lara-Astiaso, D. et al. The spectrum and regulatory landscape of intestinal innate lymphoid cells are shaped by the microbiome. Cell 166, 1231–46.e13 (2016).

    CAS  Article  Google Scholar 

  13. 13.

    Huang, X. Z., Gao, P., Song, Y. X., Xu, Y., Sun, J. X., Chen, X. W. et al. Antibiotic use and the efficacy of immune checkpoint inhibitors in cancer patients: a pooled analysis of 2740 cancer patients. Oncoimmunology 8, e1665973 (2019).

    Article  Google Scholar 

  14. 14.

    Pinato, D. J., Howlett, S., Ottaviani, D., Urus, H., Patel, A., Mineo, T. et al. Association of Prior Antibiotic Treatment With Survival and Response to Immune Checkpoint Inhibitor Therapy in Patients With Cancer. JAMA Oncol. 12, 1774–1778 (2019).

    Article  Google Scholar 

  15. 15.

    Sen, S., Carmagnani Pestana, R., Hess, K., Viola, G. M. & Subbiah, V. Impact of antibiotic use on survival in patients with advanced cancers treated on immune checkpoint inhibitor phase I clinical trials. Ann. Oncol. 29, 2396–2398 (2018).

    CAS  Article  Google Scholar 

  16. 16.

    Elinav, E., Garrett, W. S., Trinchieri, G. & Wargo, J. The cancer microbiome. Nat. Rev. Cancer 19, 371–376 (2019).

    CAS  Article  Google Scholar 

  17. 17.

    Almeida, R. R., Vieira R.d.S., Castoldi, A., Terra, F. F., Melo, A. C. L., Canesso, M. C. C. et al. Host dysbiosis negatively impacts IL-9-producing T-cell differentiation and antitumor immunity. Br. J. Cancer 123, 534–541 (2020).

    CAS  Article  Google Scholar 

  18. 18.

    Gerlach, K. & Weigmann, B. The dichotomous function of interleukin-9 in cancer diseases. J. Mol. Med. 97, 1377–1383 (2019).

    CAS  Article  Google Scholar 

  19. 19.

    Matusiewicz, K., Iwanczak, B. & Matusiewicz, M. Th9 lymphocytes and functions of interleukin 9 with the focus on IBD pathology. Adv. Med. Sci. 63, 278–284 (2018).

    Article  Google Scholar 

  20. 20.

    Purwar, R., Schlapbach, C., Xiao, S., Kang, H. S., Elyaman, W., Jiang, X. et al. Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells. Nat. Med. 18, 1248–1253 (2012).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

None.

Author information

Affiliations

Authors

Contributions

N.H. wrote the manuscript and drafted the figure.

Corresponding author

Correspondence to Niels Halama.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Data availability

Not applicable

Competing interests

N.H. is a Subject Editor for the BJC.

Funding information

No specific funding for this manuscript.

Additional information

Note This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Halama, N. Bowel inflammation in cancer patients: the microbiome, antibiotics and interleukin-9. Br J Cancer (2020). https://doi.org/10.1038/s41416-020-01030-0

Download citation

Search