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

31 Citations (Scopus)

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

Fingerprint

Dysbiosis
Microbiota
Radiation
Cytokines
Interleukin-1
Proctitis
Dextran Sulfate
Radiation Injuries
Interleukin-1 Receptors
Coculture Techniques
Tumor Necrosis Factor-alpha
Radiation Effects
Colitis
Interleukin-6
Mucous Membrane
Radiotherapy

Keywords

  • COLONIC MICROFLORA
  • CYTOKINES
  • INFLAMMATION
  • RADIATION THERAPY

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Gerassy-Vainberg, S., Blatt, A., Danin-Poleg, Y., Gershovich, K., Sabo, E., Nevelsky, A., ... 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

Radiation induces proinflammatory dysbiosis : transmission of inflammatory susceptibility by host cytokine induction. / Gerassy-Vainberg, Shiran; Blatt, Alexandra; Danin-Poleg, Yael; Gershovich, Katya; Sabo, Edmond; Nevelsky, Alex; Daniel, Shahar; Dahan, Aviva; Ziv, Oren; Dheer, Rishu; Abreu, Maria T; Koren, Omry; Kashi, Yechezkel; Chowers, Yehuda.

In: Gut, Vol. 67, No. 1, 01.01.2018, p. 97-107.

Research output: Contribution to journalArticle

Gerassy-Vainberg, S, Blatt, A, Danin-Poleg, Y, Gershovich, K, Sabo, E, Nevelsky, A, Daniel, S, Dahan, A, Ziv, O, Dheer, R, Abreu, MT, Koren, O, Kashi, Y & Chowers, Y 2018, 'Radiation induces proinflammatory dysbiosis: transmission of inflammatory susceptibility by host cytokine induction', Gut, vol. 67, no. 1, pp. 97-107. https://doi.org/10.1136/gutjnl-2017-313789
Gerassy-Vainberg S, Blatt A, Danin-Poleg Y, Gershovich K, Sabo E, Nevelsky A et al. Radiation induces proinflammatory dysbiosis: transmission of inflammatory susceptibility by host cytokine induction. Gut. 2018 Jan 1;67(1):97-107. https://doi.org/10.1136/gutjnl-2017-313789
Gerassy-Vainberg, Shiran ; Blatt, Alexandra ; Danin-Poleg, Yael ; Gershovich, Katya ; Sabo, Edmond ; Nevelsky, Alex ; Daniel, Shahar ; Dahan, Aviva ; Ziv, Oren ; Dheer, Rishu ; Abreu, Maria T ; Koren, Omry ; Kashi, Yechezkel ; Chowers, Yehuda. / Radiation induces proinflammatory dysbiosis : transmission of inflammatory susceptibility by host cytokine induction. In: Gut. 2018 ; Vol. 67, No. 1. pp. 97-107.
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T2 - transmission of inflammatory susceptibility by host cytokine induction

AU - Gerassy-Vainberg, Shiran

AU - Blatt, Alexandra

AU - Danin-Poleg, Yael

AU - Gershovich, Katya

AU - Sabo, Edmond

AU - Nevelsky, Alex

AU - Daniel, Shahar

AU - Dahan, Aviva

AU - Ziv, Oren

AU - Dheer, Rishu

AU - Abreu, Maria T

AU - Koren, Omry

AU - Kashi, Yechezkel

AU - Chowers, Yehuda

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N2 - 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.

AB - 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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