Irradiation at Ultra-high (FLASH) Dose Rates Reduces Acute Normal Tissue Toxicity in the Mouse Gastrointestinal System

Jia-Ling Ruan; Carl Lee; Shari Wouters; Iain D.C. Tullis; Mieke Verslegers; Mohamed Mysara Ahmed; Chee Kin  Then; Sean C. Smart; Mark A. Hill; Ruth J. Muschel; Amato J. Giaccia; Borivoj Vojnovic; Anne E. Kiltie; Kristoffer Petersson

doi:10.1016/j.ijrobp.2021.08.004

Irradiation at Ultra-high (FLASH) Dose Rates Reduces Acute Normal Tissue Toxicity in the Mouse Gastrointestinal System

Jia-Ling Ruan, Carl Lee, Shari Wouters, Iain D.C. Tullis, Mieke Verslegers, Mohamed Mysara Ahmed, Chee Kin Then, Sean C. Smart, Mark A. Hill, Ruth J. Muschel, Amato J. Giaccia, Borivoj Vojnovic, Anne E. Kiltie, Kristoffer Petersson

Research output › peer-review

Abstract

Purpose: Preclinical studies usingultra-high dose rate (FLASH) irradiationhave demonstratedreducednormal tissue toxicity comparedwith conventional dose rate (CONV) irradiation, although this findingis not universal. We investigatedthe effect of temporal pulse structure andaverage dose rate ofFLASH comparedwith CONV irradiationonacute intestinal toxicity. Materials and Methods: Whole abdomens ofC3Hmice were irradiatedwith a single fractionto various doses,usinga 6MeV electronlinearacceleratorwith single pulse FLASH (dose rate = 2-6 £ 106 Gy/s) orconventional (CONV;0.25Gy/s) irradiation. At 3.75 days postirradiation, fresh feces were collectedfor16S rRNA sequencing to assess changes inthe gut microbiota. A Swiss roll-based crypt assay was used to quantify acute damage to the intestinal crypts to determine how tissue toxicitywas affectedbythe different temporal pulse structures ofFLASH delivery. Results: We foundstatisticallysignificant improvements incrypt survival formice irradiatedwith FLASH at doses between 7.5 and12.5 Gy, with a dose modifyingfactorof 1.1 forFLASH (7.5 Gy, P < .01; 10 Gy, P < .05; 12.5 Gy, P < .01). This sparingeffect was lost whenthe deliverytime was increased, eitherbyincreasingthe numberof irradiationpulses orbyprolongingthe time between2 successive pulses. Sparingwas observedforaverage dose rates of ≥280 Gy/s. Fecal microbiome analysis showedthat FLASH irradiationcausedfewerchanges to the microbiota thanCONV irradiation. Conclusions: This studydemonstrates that FLASH irradiationcanspare mouse small intestinal crypts andreduce changes in gut microbiome composition compared with CONV irradiation. The higher the average dose rate, the larger the FLASH effect,which is also influencedbytemporal pulse structure of the delivery.Ó 2021 ElsevierInc.All rights reserved.

Original language	English
Pages (from-to)	1250-1261
Number of pages	12
Journal	International Journal of Radiation Oncology, Biology, Physics
Volume	111
Issue number	5
DOIs	https://doi.org/10.1016/j.ijrobp.2021.08.004
State	Published - 1 Dec 2021

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Ruan, J.-L., Lee, C., Wouters, S., Tullis, I. D. C., Verslegers, M., Ahmed, M. M., Then, C. K., Smart, S. C., Hill, M. A., Muschel, R. J., Giaccia, A. J., Vojnovic, B., Kiltie, A. E., & Petersson, K. (2021). Irradiation at Ultra-high (FLASH) Dose Rates Reduces Acute Normal Tissue Toxicity in the Mouse Gastrointestinal System. International Journal of Radiation Oncology, Biology, Physics, 111(5), 1250-1261. https://doi.org/10.1016/j.ijrobp.2021.08.004

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title = "Irradiation at Ultra-high (FLASH) Dose Rates Reduces Acute Normal Tissue Toxicity in the Mouse Gastrointestinal System",

abstract = "Purpose: Preclinical studies usingultra-high dose rate (FLASH) irradiationhave demonstratedreducednormal tissue toxicity comparedwith conventional dose rate (CONV) irradiation, although this findingis not universal. We investigatedthe effect of temporal pulse structure andaverage dose rate ofFLASH comparedwith CONV irradiationonacute intestinal toxicity. Materials and Methods: Whole abdomens ofC3Hmice were irradiatedwith a single fractionto various doses,usinga 6MeV electronlinearacceleratorwith single pulse FLASH (dose rate = 2-6 £ 106 Gy/s) orconventional (CONV;0.25Gy/s) irradiation. At 3.75 days postirradiation, fresh feces were collectedfor16S rRNA sequencing to assess changes inthe gut microbiota. A Swiss roll-based crypt assay was used to quantify acute damage to the intestinal crypts to determine how tissue toxicitywas affectedbythe different temporal pulse structures ofFLASH delivery. Results: We foundstatisticallysignificant improvements incrypt survival formice irradiatedwith FLASH at doses between 7.5 and12.5 Gy, with a dose modifyingfactorof 1.1 forFLASH (7.5 Gy, P < .01; 10 Gy, P < .05; 12.5 Gy, P < .01). This sparingeffect was lost whenthe deliverytime was increased, eitherbyincreasingthe numberof irradiationpulses orbyprolongingthe time between2 successive pulses. Sparingwas observedforaverage dose rates of ≥280 Gy/s. Fecal microbiome analysis showedthat FLASH irradiationcausedfewerchanges to the microbiota thanCONV irradiation. Conclusions: This studydemonstrates that FLASH irradiationcanspare mouse small intestinal crypts andreduce changes in gut microbiome composition compared with CONV irradiation. The higher the average dose rate, the larger the FLASH effect,which is also influencedbytemporal pulse structure of the delivery.{\'O} 2021 ElsevierInc.All rights reserved.",

keywords = "FLASH irradiation, Gut microbiome, Intestinal health, Dysbiosis",

author = "Jia-Ling Ruan and Carl Lee and Shari Wouters and Tullis, {Iain D.C.} and Mieke Verslegers and Ahmed, {Mohamed Mysara} and Then, {Chee Kin} and Smart, {Sean C.} and Hill, {Mark A.} and Muschel, {Ruth J.} and Giaccia, {Amato J.} and Borivoj Vojnovic and Kiltie, {Anne E.} and Kristoffer Petersson",

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doi = "10.1016/j.ijrobp.2021.08.004",

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Ruan, J-L, Lee, C, Wouters, S, Tullis, IDC, Verslegers, M, Ahmed, MM, Then, CK, Smart, SC, Hill, MA, Muschel, RJ, Giaccia, AJ, Vojnovic, B, Kiltie, AE & Petersson, K 2021, 'Irradiation at Ultra-high (FLASH) Dose Rates Reduces Acute Normal Tissue Toxicity in the Mouse Gastrointestinal System', International Journal of Radiation Oncology, Biology, Physics, vol. 111, no. 5, pp. 1250-1261. https://doi.org/10.1016/j.ijrobp.2021.08.004

TY - JOUR

T1 - Irradiation at Ultra-high (FLASH) Dose Rates Reduces Acute Normal Tissue Toxicity in the Mouse Gastrointestinal System

AU - Ruan, Jia-Ling

AU - Lee, Carl

AU - Wouters, Shari

AU - Tullis, Iain D.C.

AU - Verslegers, Mieke

AU - Ahmed, Mohamed Mysara

AU - Then, Chee Kin

AU - Smart, Sean C.

AU - Hill, Mark A.

AU - Muschel, Ruth J.

AU - Giaccia, Amato J.

AU - Vojnovic, Borivoj

AU - Kiltie, Anne E.

AU - Petersson, Kristoffer

N1 - Score=10

PY - 2021/12/1

Y1 - 2021/12/1

N2 - Purpose: Preclinical studies usingultra-high dose rate (FLASH) irradiationhave demonstratedreducednormal tissue toxicity comparedwith conventional dose rate (CONV) irradiation, although this findingis not universal. We investigatedthe effect of temporal pulse structure andaverage dose rate ofFLASH comparedwith CONV irradiationonacute intestinal toxicity. Materials and Methods: Whole abdomens ofC3Hmice were irradiatedwith a single fractionto various doses,usinga 6MeV electronlinearacceleratorwith single pulse FLASH (dose rate = 2-6 £ 106 Gy/s) orconventional (CONV;0.25Gy/s) irradiation. At 3.75 days postirradiation, fresh feces were collectedfor16S rRNA sequencing to assess changes inthe gut microbiota. A Swiss roll-based crypt assay was used to quantify acute damage to the intestinal crypts to determine how tissue toxicitywas affectedbythe different temporal pulse structures ofFLASH delivery. Results: We foundstatisticallysignificant improvements incrypt survival formice irradiatedwith FLASH at doses between 7.5 and12.5 Gy, with a dose modifyingfactorof 1.1 forFLASH (7.5 Gy, P < .01; 10 Gy, P < .05; 12.5 Gy, P < .01). This sparingeffect was lost whenthe deliverytime was increased, eitherbyincreasingthe numberof irradiationpulses orbyprolongingthe time between2 successive pulses. Sparingwas observedforaverage dose rates of ≥280 Gy/s. Fecal microbiome analysis showedthat FLASH irradiationcausedfewerchanges to the microbiota thanCONV irradiation. Conclusions: This studydemonstrates that FLASH irradiationcanspare mouse small intestinal crypts andreduce changes in gut microbiome composition compared with CONV irradiation. The higher the average dose rate, the larger the FLASH effect,which is also influencedbytemporal pulse structure of the delivery.Ó 2021 ElsevierInc.All rights reserved.

AB - Purpose: Preclinical studies usingultra-high dose rate (FLASH) irradiationhave demonstratedreducednormal tissue toxicity comparedwith conventional dose rate (CONV) irradiation, although this findingis not universal. We investigatedthe effect of temporal pulse structure andaverage dose rate ofFLASH comparedwith CONV irradiationonacute intestinal toxicity. Materials and Methods: Whole abdomens ofC3Hmice were irradiatedwith a single fractionto various doses,usinga 6MeV electronlinearacceleratorwith single pulse FLASH (dose rate = 2-6 £ 106 Gy/s) orconventional (CONV;0.25Gy/s) irradiation. At 3.75 days postirradiation, fresh feces were collectedfor16S rRNA sequencing to assess changes inthe gut microbiota. A Swiss roll-based crypt assay was used to quantify acute damage to the intestinal crypts to determine how tissue toxicitywas affectedbythe different temporal pulse structures ofFLASH delivery. Results: We foundstatisticallysignificant improvements incrypt survival formice irradiatedwith FLASH at doses between 7.5 and12.5 Gy, with a dose modifyingfactorof 1.1 forFLASH (7.5 Gy, P < .01; 10 Gy, P < .05; 12.5 Gy, P < .01). This sparingeffect was lost whenthe deliverytime was increased, eitherbyincreasingthe numberof irradiationpulses orbyprolongingthe time between2 successive pulses. Sparingwas observedforaverage dose rates of ≥280 Gy/s. Fecal microbiome analysis showedthat FLASH irradiationcausedfewerchanges to the microbiota thanCONV irradiation. Conclusions: This studydemonstrates that FLASH irradiationcanspare mouse small intestinal crypts andreduce changes in gut microbiome composition compared with CONV irradiation. The higher the average dose rate, the larger the FLASH effect,which is also influencedbytemporal pulse structure of the delivery.Ó 2021 ElsevierInc.All rights reserved.

KW - FLASH irradiation

KW - Gut microbiome

KW - Intestinal health

KW - Dysbiosis

UR - https://ecm.sckcen.be/OTCS/llisapi.dll/open/45837003

U2 - 10.1016/j.ijrobp.2021.08.004

DO - 10.1016/j.ijrobp.2021.08.004

M3 - Article

SN - 0360-3016

VL - 111

SP - 1250

EP - 1261

JO - International Journal of Radiation Oncology, Biology, Physics

JF - International Journal of Radiation Oncology, Biology, Physics

IS - 5

ER -