Radiation induces proinflammatory dysbiosis: transmission of inflammatory susceptibility by host cytokine induction

Shiran Gerassy-Vainberg, Alexandra Blatt, Yael Danin-Poleg, Katya Gershovich, Edmond Sabo, Alex Nevelsky, Shahar Daniel, Aviva Dahan, Oren Ziv, Rishu Dheer, Maria T Abreu, Omry Koren, Yechezkel Kashi, Yehuda Chowers

Research output: Contribution to journalArticle

39 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)97-107
Number of pages11
JournalGut
Volume67
Issue number1
DOIs
StatePublished - Jan 1 2018

Keywords

  • COLONIC MICROFLORA
  • CYTOKINES
  • INFLAMMATION
  • RADIATION THERAPY

ASJC Scopus subject areas

  • Gastroenterology

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    Gerassy-Vainberg, S., Blatt, A., Danin-Poleg, Y., Gershovich, K., Sabo, E., Nevelsky, A., Daniel, S., Dahan, A., Ziv, O., Dheer, R., Abreu, M. T., Koren, O., Kashi, Y., & Chowers, Y. (2018). Radiation induces proinflammatory dysbiosis: transmission of inflammatory susceptibility by host cytokine induction. Gut, 67(1), 97-107. https://doi.org/10.1136/gutjnl-2017-313789