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 outputpeer-review


    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 languageEnglish
    Pages (from-to)1250-1261
    Number of pages12
    JournalInternational Journal of Radiation Oncology, Biology, Physics
    Issue number5
    StatePublished - 1 Dec 2021

    Cite this