{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T10:07:25Z","timestamp":1789034845005,"version":"build-2803163510"},"reference-count":59,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008064","name":"Georgetown University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100008064","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/05vzafd60","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>The gastrointestinal tract is a critical target of acute radiation exposure. Severe radiation exposure can deplete epithelial stem and progenitor cells, compromise barrier integrity, alter host\u2013microbe interactions, and drive fluid loss, inflammation, and systemic decline. Mammalian models remain essential for clinical translation, but their cost and complexity constrain sample sizes, statistical power, large-scale mechanistic discovery, and countermeasure screening. The adult Drosophila melanogaster midgut provides a complementary in vivo platform containing intestinal stem cells, absorptive enterocytes, enteroendocrine cells, epithelial junctions, an associated microbiota, and conserved innate immune and injury-response pathways. Direct irradiation studies have demonstrated DNA damage, altered stem cell proliferation and differentiation, epithelial plasticity, apoptosis, autophagy-associated responses, morphological disruption, barrier failure, microbiome changes, and reduced survival. These phenotypes can be modulated by genotype, sex, diet, microbial status, antioxidant capacity, and regenerative signaling. This review evaluates the biological rationale, direct evidence, experimental assays, and countermeasure applications supporting the fly midgut as a model for studying gastrointestinal radiation injury. Although Drosophila has a long history of use in radiation research, our analysis indicates that the fly midgut is best positioned not as a miniature model of clinical gastrointestinal acute radiation syndrome, but as a genetically precise and scalable system for identifying conserved mechanisms and prioritizing interventions for validation in mammalian models.<\/jats:p>","DOI":"10.3390\/ijms27177949","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T13:53:28Z","timestamp":1788789208000},"page":"7949","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Drosophila melanogaster as a Model for Gastrointestinal Radiation Injury: Conserved Mechanisms, Experimental Approaches, and Countermeasure Discovery"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2784-0168","authenticated-orcid":false,"given":"Robert P.","family":"Volpe","sequence":"first","affiliation":[{"name":"School of Medicine, Georgetown University, Washington, DC 20057, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3482-1849","authenticated-orcid":false,"given":"Tomoko Y.","family":"Steen","sequence":"additional","affiliation":[{"name":"School of Medicine, Georgetown University, Washington, DC 20057, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"D\u00f6rr, H., and Meineke, V. (2011). Acute radiation syndrome caused by accidental radiation exposure: Therapeutic principles. BMC Med., 9.","DOI":"10.1186\/1741-7015-9-126"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1097\/HP.0b013e318266ee13","article-title":"Acute gastrointestinal syndrome in high-dose irradiated mice","volume":"103","author":"Booth","year":"2012","journal-title":"Health Phys."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1126\/science.1060191","article-title":"Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice","volume":"293","author":"Paris","year":"2001","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1080\/09553002.2018.1552377","article-title":"Morphological and functional impairment in the gut in a partial body irradiation minipig model of GI-ARS","volume":"96","author":"Kaur","year":"2020","journal-title":"Int. J. Radiat. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1097\/HP.0b013e31826525f0","article-title":"The acute gastrointestinal subsyndrome of the acute radiation syndrome: A rhesus macaque model","volume":"103","author":"MacVittie","year":"2012","journal-title":"Health Phys."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1097\/HP.0000000000000903","article-title":"The gastrointestinal subsyndrome of the acute radiation syndrome in rhesus macaques: A systematic review of the lethal dose-response relationship with and without medical management","volume":"116","author":"MacVittie","year":"2019","journal-title":"Health Phys."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1667\/RADE-23-00196.1","article-title":"Gastrointestinal acute radiation syndrome: Mechanisms, models, markers, and medical countermeasures","volume":"201","author":"Winters","year":"2024","journal-title":"Radiat. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/s41420-025-02525-6","article-title":"Gastrointestinal acute radiation syndrome: Current knowledge and perspectives","volume":"11","author":"Freeman","year":"2025","journal-title":"Cell Death Discov."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1016\/j.cell.2009.05.014","article-title":"Cytokine\/Jak\/Stat signaling mediates regeneration and homeostasis in the Drosophila midgut","volume":"137","author":"Jiang","year":"2009","journal-title":"Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.ydbio.2012.10.023","article-title":"The Upd3 cytokine couples environmental challenge and intestinal stem cell division through modulation of JAK\/STAT signaling in the stem cell microenvironment","volume":"373","author":"Zhou","year":"2013","journal-title":"Dev. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1084\/jem.20082683","article-title":"STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing","volume":"206","author":"Pickert","year":"2009","journal-title":"J. Exp. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1667\/RR13330.1","article-title":"Oral interleukin 11 as a countermeasure to lethal total-body irradiation in a murine model","volume":"180","author":"Burnett","year":"2013","journal-title":"Radiat. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1016\/j.stem.2008.07.024","article-title":"JNK activity in somatic stem cells causes loss of tissue homeostasis in the aging Drosophila gut","volume":"3","author":"Biteau","year":"2008","journal-title":"Cell Stem Cell"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Chakrabarti, S., Poidevin, M., and Lemaitre, B. (2014). The Drosophila MAPK p38c regulates oxidative stress and lipid homeostasis in the intestine. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004659"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1177\/1947601913485414","article-title":"Mitogen-activated protein kinases and their role in radiation response","volume":"4","author":"Munshi","year":"2013","journal-title":"Genes Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1242\/dev.056671","article-title":"EGF signaling regulates the proliferation of intestinal stem cells in Drosophila","volume":"138","author":"Biteau","year":"2011","journal-title":"Development"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.stem.2010.11.026","article-title":"EGFR\/Ras\/MAPK signaling mediates adult midgut epithelial homeostasis and regeneration in Drosophila","volume":"8","author":"Jiang","year":"2011","journal-title":"Cell Stem Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9119","DOI":"10.1038\/s41598-018-27353-w","article-title":"Pharmacological activation of epidermal growth factor receptor signaling inhibits colitis-associated cancer in mice","volume":"8","author":"Liu","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e135923","DOI":"10.1172\/jci.insight.135923","article-title":"Elevating EGFR-MAPK program by a nonconventional Cdc42 enhances intestinal epithelial survival and regeneration","volume":"5","author":"Zhang","year":"2020","journal-title":"JCI Insight"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1038\/nature07329","article-title":"Paracrine Wingless signalling controls self-renewal of Drosophila intestinal stem cells","volume":"455","author":"Lin","year":"2008","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3901","DOI":"10.1038\/emboj.2012.248","article-title":"Inducible progenitor-derived Wingless regulates adult midgut regeneration in Drosophila","volume":"31","author":"Cordero","year":"2012","journal-title":"EMBO J."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Tian, A., Benchabane, H., Wang, Z., and Ahmed, Y. (2016). Regulation of stem cell proliferation and cell fate specification by Wingless\/Wnt signaling gradients enriched at adult intestinal compartment boundaries. PLoS Genet., 12.","DOI":"10.1371\/journal.pgen.1005822"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1038\/nature06196","article-title":"Identification of stem cells in small intestine and colon by marker gene Lgr5","volume":"449","author":"Barker","year":"2007","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.stem.2013.11.008","article-title":"Lgr5-positive stem cells are indispensable for radiation-induced intestinal regeneration","volume":"14","author":"Metcalfe","year":"2014","journal-title":"Cell Stem Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1126\/science.1136606","article-title":"Multipotent Drosophila intestinal stem cells specify daughter cell fates by differential Notch signaling","volume":"315","author":"Ohlstein","year":"2007","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"aab0988","DOI":"10.1126\/science.aab0988","article-title":"Bidirectional Notch signaling regulates Drosophila intestinal stem cell multipotency","volume":"350","author":"Guo","year":"2015","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1038\/nature03659","article-title":"Notch\/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells","volume":"435","author":"Riccio","year":"2005","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1242\/dev.070763","article-title":"Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells","volume":"139","author":"VanDussen","year":"2012","journal-title":"Development"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1002\/cbin.11591","article-title":"Valproic acid protects intestinal organoids against radiation via NOTCH signaling","volume":"45","author":"Park","year":"2021","journal-title":"Cell Biol. Int."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4135","DOI":"10.1242\/dev.060483","article-title":"The Hippo tumor suppressor pathway regulates intestinal stem cell regeneration","volume":"137","author":"Karpowicz","year":"2010","journal-title":"Development"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4147","DOI":"10.1242\/dev.052506","article-title":"The Hippo pathway regulates intestinal stem cell proliferation during Drosophila adult midgut regeneration","volume":"137","author":"Shaw","year":"2010","journal-title":"Development"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1016\/j.cub.2010.07.041","article-title":"Warts and Yorkie mediate intestinal regeneration by influencing stem cell proliferation","volume":"20","author":"Staley","year":"2010","journal-title":"Curr. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1038\/nature15382","article-title":"Yap-dependent reprogramming of Lgr5-positive stem cells drives intestinal regeneration and cancer","volume":"526","author":"Gregorieff","year":"2015","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.stem.2017.11.001","article-title":"YAP\/TAZ-dependent reprogramming of colonic epithelium links ECM remodeling to tissue regeneration","volume":"22","author":"Yui","year":"2018","journal-title":"Cell Stem Cell"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Lee, H.J., Lee, S.H., Lee, J.H., Kim, Y., Seong, K.M., Jin, Y.W., and Min, K.J. (2021). Role of commensal microbes in the \u03b3-ray irradiation-induced physiological changes in Drosophila melanogaster. Microorganisms, 9.","DOI":"10.3390\/microorganisms9010031"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e00155-18","DOI":"10.1128\/mBio.00155-18","article-title":"The Drosophila melanogaster gut microbiota provisions thiamine to its host","volume":"9","author":"Sannino","year":"2018","journal-title":"mBio"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Volpe, R.P., Sen, A., Sharma, A., Kathiresan, V., Hoffman, B.M., and Cox, R.T. (2025). Prophylactically feeding manganese to Drosophila confers sex-specific protection from acute ionizing radiation independent of MnSOD2 levels. Antioxidants, 14.","DOI":"10.3390\/antiox14020134"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1038\/s41598-025-31545-6","article-title":"Feeding Drosophila highly radioresistant fungi improves survival and gut morphology following acute gamma radiation exposure","volume":"16","author":"Volpe","year":"2026","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1126\/science.66.1699.84","article-title":"Artificial transmutation of the gene","volume":"66","author":"Muller","year":"1927","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1073\/pnas.14.9.714","article-title":"The production of mutations by X-rays","volume":"14","author":"Muller","year":"1928","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","first-page":"430","article-title":"High Altitude Research with V-2 Rockets","volume":"91","author":"Krause","year":"1947","journal-title":"Proc. Am. Philos. Soc."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1242\/dmm.019786","article-title":"A Drosophila model to investigate the neurotoxic side effects of radiation exposure","volume":"8","author":"Sudmeier","year":"2015","journal-title":"Dis. Model Mech."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1016\/j.celrep.2013.04.001","article-title":"Morphological and molecular characterization of adult midgut compartmentalization in Drosophila","volume":"3","author":"Buchon","year":"2013","journal-title":"Cell Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e00886","DOI":"10.7554\/eLife.00886","article-title":"Physiological and stem cell compartmentalization within the Drosophila midgut","volume":"2","author":"Marianes","year":"2013","journal-title":"eLife"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"19080","DOI":"10.1038\/s41598-020-75867-z","article-title":"Musashi expression in intestinal stem cells attenuates radiation-induced decline in intestinal permeability and survival in Drosophila","volume":"10","author":"Sharma","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1667\/RR13545.1","article-title":"Functional modification of Drosophila intestinal stem cells by ionizing radiation","volume":"181","author":"Pyo","year":"2014","journal-title":"Radiat. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"7058","DOI":"10.1038\/ncomms8058","article-title":"Tie-mediated signal from apoptotic cells protects stem cells in Drosophila melanogaster","volume":"6","author":"Xing","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"dev205225","DOI":"10.1242\/dev.205225","article-title":"Xrp1 drives damage-induced cellular plasticity of enteroendocrine cells in the adult Drosophila midgut","volume":"153","author":"Qian","year":"2026","journal-title":"Development"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"167","DOI":"10.33696\/Neurol.5.099","article-title":"Irradiation of Drosophila melanogaster leads to increased autophagy in multiple adult tissues","volume":"5","author":"Trinca","year":"2024","journal-title":"J. Exp. Neurol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1016\/j.stemcr.2020.03.021","article-title":"The Snakeskin-Mesh complex of smooth septate junction restricts Yorkie to regulate intestinal homeostasis in Drosophila","volume":"14","author":"Chen","year":"2020","journal-title":"Stem Cell Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e2722","DOI":"10.21769\/BioProtoc.2722","article-title":"How to catch a Smurf? Ageing and beyond: In vivo assessment of intestinal permeability in multiple model organisms","volume":"8","author":"Martins","year":"2018","journal-title":"Bio Protoc."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"307","DOI":"10.18632\/aging.100743","article-title":"Requirement of ATR for maintenance of intestinal stem cells in aging Drosophila","volume":"7","author":"Park","year":"2015","journal-title":"Aging"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"322","DOI":"10.18632\/aging.101390","article-title":"Deficiency in DNA damage response of enterocytes accelerates intestinal stem cell aging in Drosophila","volume":"10","author":"Park","year":"2018","journal-title":"Aging"},{"key":"ref_54","first-page":"757","article-title":"Inhibition of the metalloprotease ADAM19 as a novel senomorphic strategy to ameliorate gut permeability and senescence markers by modulating senescence-associated secretory phenotype (SASP)","volume":"17","author":"Bar","year":"2025","journal-title":"Aging"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3522","DOI":"10.1039\/D3FO05422E","article-title":"Lactobacillus reuteri\u2019s multifaceted role in mitigating ionizing radiation-induced injury in Drosophila melanogaster","volume":"15","author":"Zhang","year":"2024","journal-title":"Food Funct."},{"key":"ref_56","first-page":"55024","article-title":"The CApillary FEeder assay measures food intake in Drosophila melanogaster","volume":"121","author":"Diegelmann","year":"2017","journal-title":"J. Vis. Exp."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1017\/S0953756200002756","article-title":"Fungi from Chernobyl: Mycobiota of the inner regions of the containment structures of the damaged nuclear reactor","volume":"104","author":"Zhdanova","year":"2000","journal-title":"Mycol. Res."},{"key":"ref_58","unstructured":"Russell, W.M.S., and Burch, R.L. (1959). The Principles of Humane Experimental Technique, Methuen."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1093\/jrr\/rraf060","article-title":"Drosophila melanogaster: An old and future ally to radiobiology","volume":"66","author":"Trinca","year":"2025","journal-title":"J. Radiat. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7949\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T09:14:02Z","timestamp":1789031642000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7949"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,7]]},"references-count":59,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ijms27177949"],"URL":"https:\/\/doi.org\/10.3390\/ijms27177949","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,7]]}}}