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Original article
Radiation induces proinflammatory dysbiosis: transmission of inflammatory susceptibility by host cytokine induction
  1. Shiran Gerassy-Vainberg1,2,
  2. Alexandra Blatt1,
  3. Yael Danin-Poleg2,
  4. Katya Gershovich1,
  5. Edmond Sabo3,
  6. Alex Nevelsky4,
  7. Shahar Daniel4,
  8. Aviva Dahan1,
  9. Oren Ziv5,
  10. Rishu Dheer6,
  11. Maria T Abreu6,
  12. Omry Koren5,
  13. Yechezkel Kashi2,
  14. Yehuda Chowers1
  1. 1Department of Gastroenterology, Rambam Health Care Campus, Ruth and Bruce Rappaport School of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
  2. 2Faculty of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa, Israel
  3. 3Department of Pathology, Rambam Medical Center, Haifa, Israel
  4. 4Radiation Unit, Department of Oncology, Rambam Medical Center, Haifa, Israel
  5. 5Faculty of Medicine, Bar-Ilan University, Safed, Israel
  6. 6Division of Gastroenterology, University of Miami, Miller School of Medicine, Miami, USA
  1. Correspondence to Dr Yehuda Chowers, Department of Gastroenterology, Rambam Health Care Campus, Haifa 3109601, Israel; ychowers{at}gmail.com

Abstract

Objective Radiation proctitis (RP) is a complication of pelvic radiotherapy which affects both the host and microbiota. Herein we assessed the radiation effect on microbiota and its relationship to tissue damage using a rectal radiation mouse model.

Design We evaluated luminal and mucosa-associated dysbiosis in irradiated and control mice at two postradiation time points and correlated it with clinical and immunological parameters. Epithelial cytokine response was evaluated using bacterial–epithelial co-cultures. Subsequently, germ-free (GF) mice were colonised with postradiation microbiota and controls and exposed to radiation, or dextran sulfate-sodium (DSS). Interleukin (IL)-1β correlated with tissue damage and was induced by dysbiosis. Therefore, we tested its direct role in radiation-induced damage by IL-1 receptor antagonist administration to irradiated mice.

Results A postradiation shift in microbiota was observed. A unique microbial signature correlated with histopathology. Increased colonic tumor necrosis factor (TNF)α, IL-1β and IL-6 expression was observed at two different time points. Adherent microbiota from RP differed from those in uninvolved segments and was associated with tissue damage. Using bacterial–epithelial co-cultures, postradiation microbiota enhanced IL-1β and TNFα expression compared with naïve microbiota. GF mice colonisation by irradiated microbiota versus controls predisposed mice to both radiation injury and DSS-induced colitis. IL-1 receptor antagonist administration ameliorated intestinal radiation injury.

Conclusions The results demonstrate that rectal radiation induces dysbiosis, which transmits radiation and inflammatory susceptibility and provide evidence that microbial-induced radiation tissue damage is at least in part mediated by IL-1β. Environmental factors may affect the host via modifications of the microbiome and potentially allow for novel interventional approaches via its manipulation.

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Footnotes

  • Contributors YC, YK and SG-V: study concept and design; SG-V, AB, KG, AD, RD and OZ: acquisition of data; YC, YK, SG-V, AB, YD-P and RD: analysis/interpretation of data; ES: histological analysis; AN and SD: irradiation procedures; YC, YK, MTA, OK and OZ: critical revision of the manuscript for important intellectual content; YC, YK and SG-V: drafting of the manuscript; YC and YK: study supervision.

  • Funding This work was supported by grants from the Israel Cancer Association (grant 2017562) and BSF USA—Israel Binational Science Foundation (grant 2009076).

  • Competing interests None declared.

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

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