Radiation injury and gut microbiota-based treatment

Abstract

The exposure to either medical sources or accidental radiation can cause varying degrees of radiation injury (RI). RI is a common disease involving multiple human body parts and organs, yet effective treatments are currently limited. Accumulating evidence suggests gut microbiota are closely associated with the development and prevention of various RI. This article summarizes 10 common types of RI and their possible mechanisms. It also highlights the changes and potential microbiota-based treatments for RI, including probiotics, metabolites, and microbiota transplantation. Additionally, a 5P-Framework is proposed to provide a comprehensive strategy for managing RI.

Key words： microbiome; ionizing radiation; radiation-induced injury; short-chain fatty acids; fecal microbiota transplant; washed microbiota transplantation; war; nuclear; microbiota medicine

References

1 Abdelazeem KNM, Kalo MZ, Beer-Hammer S et al. The gut microbiota metabolite urolithin A inhibits NF-κB activation in LPS stimulated BMDMs. Sci Rep 2021;11:7117.

2 Al-Qadami G, Van Sebille Y, Le H et al. Gut microbiota: implications for radiotherapy response and radiotherapy-induced mucositis. Expert Rev Gastroenterol Hepatol 2019;13:485–96.

3 Al-Qadami G, Verma G, Van Sebille Y et al. Antibiotic-induced gut microbiota depletion accelerates the recovery of radiation-induced oral mucositis in rats. Int J Radiat Oncol Biol Phys 2022;113:845–58.

4 An L, Wuri J, Zheng Z et al. Microbiota modulate Doxorubicin induced cardiotoxicity. Eur J Pharm Sci 2021;166:105977.

5 Aragón IM, Herrera-Imbroda B, Queipo-Ortuño MI et al. The urinary tract microbiome in health and disease. Eur Urol Focus 2018;4:128–38.

6 Ashack KA, Kuritza V, Visconti MJ et al. Dermatologic sequelae associated with radiation therapy. Am J Clin Dermatol 2020;21:541–55.

7 Bartolomaeus H, Balogh A, Yakoub M et al. Short-chain fatty acid propionate protects from hypertensive cardiovascular damage. Circulation 2019;139:1407–21.

8 Baruch EN, Youngster I, Ben-Betzalel G et al. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science 2021;371:602–9.

9 Bell BI, Vercellino J, Brodin NP et al. Orthovoltage X-rays exhibit increased efficacy compared with gamma-rays in preclinical irradiation. Cancer Res 2022;82:2678–91.

10 Berwick DM, Shine K. Enhancing private sector health system preparedness for 21st-century health threats: foundational principles from a national academies initiative. JAMA 2020;323:1133–4.

11 Chen Z, Wang B, Dong J et al. Gut microbiota-derived l-histidine/ imidazole propionate axis fights against the radiation-induced cardiopulmonary injury. Int J Mol Sci 2021a;22:11436.

12 Chen ZY, Xiao HW, Dong JL et al. Gut microbiota-derived PGF2α fights against radiation-induced lung toxicity through the MAPK/NF-κB pathway. Antioxidants (Basel) 2021b;11:65.

13 Chitapanarux I, Chitapanarux T, Traisathit P et al. Randomized controlled trial of live lactobacillus acidophilus plus Bifidobacterium bifidum in prophylaxis of diarrhea during radiotherapy in cervical cancer patients. Radiat Oncol 2010;5:31.

14 Cohen SH, Louie TJ, Sims M et al. Extended follow-up of microbiome therapeutic SER-109 through 24 weeks for recurrent clostridioides difficile infection in a randomized clinical trial. JAMA 2022;328:2062–64.

15 Cui M, Xiao H, Li Y et al. Faecal microbiota transplantation protects against radiation-induced toxicity. EMBO Mol Med 2017;9:448–61.

16 Darby SC, Ewertz M, McGale P et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med 2013;368:987–98.

17 Davar D, Dzutsev AK, McCulloch JA et al. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science 2021;371:595–602.

18 David RV, Kahokehr AA, Lee J et al. Incidence of genitourinary complications following radiation therapy for localised prostate cancer. World J Urol 2022;40:2411–22.

19 Delia P, Sansotta G, Donato V et al. Use of probiotics for prevention of radiation-induced diarrhea. World J Gastroenterol 2007;13:912–5.

20 Deng F, Zhao BC, Yang X et al. The gut microbiota metabolite capsiate promotes Gpx4 expression by activating TRPV1 to inhibit intestinal ischemia reperfusion-induced ferroptosis. Gut Microbes 2021;13:1–21.

21 Ding X, Li Q, Li P et al. Fecal microbiota transplantation: a promising treatment for radiation enteritis? Radiother Oncol 2020;143:12–8.

22 Dingemanse C, Belzer C, van Hijum SA et al. Akkermansia muciniphila and Helicobacter typhlonius modulate intestinal tumor development in mice. Carcinogenesis 2015;36:1388–96.

23 Dong J, Li Y, Xiao H et al. Oral microbiota affects the efficacy and prognosis of radiotherapy for colorectal cancer in mouse models. Cell Rep 2021;37:109886.

24 Elting LS, Cooksley CD, Chambers MS et al. Risk, outcomes, and costs of radiation-induced oral mucositis among patients with head-and-neck malignancies. Int J Radiat Oncol Biol Phys 2007;68:1110–20.

25 Espinal A, Epperly MW, Mukherjee A et al. Intestinal radiation protection and mitigation by second-generation probiotic Lactobacillus reuteri engineered to deliver inter-leukin-22. Int J Mol Sci 2022;23:5616.

26 Feuerstadt P, Louie TJ, Lashner B et al. SER-109, an oral microbiome therapy for recurrent clostridioides difficile infection. N Engl J Med 2022;386:220–9.

27 Gale RP. Medical and policy considerations for nuclear and radiation accidents, incidents and terrorism. Curr Opin Hematol 2017;24:496–501.

28 Gerassy-Vainberg S, Blatt A, Danin-Poleg Y et al. Radiation induces proinflammatory dysbiosis: transmission of inflammatory susceptibility by host cytokine induction. Gut 2018;67:97–107.

29 Grant EJ, Brenner A, Sugiyama H et al. Solid cancer incidence among the life span study of atomic bomb survivors: 1958–2009. Radiat Res 2017;187:513–537.

30 Green DE, Rubin CT. Consequences of irradiation on bone and marrow phenotypes, and its relation to disruption of hematopoietic precursors. Bone 2014;63:87–94.

31 Guo H, Chou WC, Lai Y et al. Multi-omics analyses of radiation survivors identify radioprotective microbes and metabolites. Science 2020;370:eaay9097.

32 Hall WA, Paulson E, Li XA et al. Magnetic resonance linear accelerator technology and adaptive radiation therapy: an overview for clinicians. CA Cancer J Clin 2022;72:34–56.

33 Hamade DF, Espinal A, Yu J et al. Lactobacillus reuteri releasing IL-22 (LR-IL-22) facilitates intestinal radioprotection for whole-abdomen irradiation (WAI) of ovarian cancer. Radiat Res 2022;198:89–105.

34 Hande V, Orita M, Matsunaga H et al. Comparison of quality of life between elderly and non-elderly adult residents in Okuma town, Japan, in a post-disaster setting. PLoS One 2023;18:e0281678.

35 Hauer-Jensen M, Denham JW, Andreyev HJ. Radiation enteropathy—pathogenesis, treatment and prevention. Nat Rev Gastroenterol Hepatol 2014;11:470–9.

36 Hayashi T, Morishita Y, Khattree R et al. Evaluation of systemic markers of inflammation in atomic-bomb survivors with special reference to radiation and age effects. FASEB J 2012;26:4765–73.

37 Hsu WL, Preston DL, Soda M et al. The incidence of leukemia, lymphoma and multiple myeloma among atomic bomb survivors: 1950–2001. Radiat Res 2013;179:361–82.

38 Hu L, Yin X, Zhang Y et al. Radiation-induced bystander effects impair transplanted human hematopoietic stem cells via oxidative DNA damage. Blood 2021;137:3339–50.

39 Janko M, Ontiveros F, Fitzgerald TJ et al. IL-1 generated subsequent to radiation-induced tissue injury contributes to the pathogenesis of radiodermatitis. Radiat Res 2012;178:166–72.

40 Jian YP, Yang G, Zhang LH et al. Lactobacillus plantarum alleviates irradiation-induced intestinal injury by activation of FXR-FGF15 signaling in intestinal epithelia. J Cell Physiol 2022;237:1845–56.

41 Jonak K, Kurpas M, Szoltysek K et al. A novel mathematical model of ATM/p53/NF-κB pathways points to the importance of the DDR switch-off mechanisms. BMC Syst Biol 2016;10:75.

42 Karaman B, Battal B, Sari S et al. Hepatocellular carcinoma review: current treatment, and evidence-based medicine. World J Gastroenterol 2014;20:18059–60.

43 Khanna S, Assi M, Lee C et al. Efficacy and safety of RBX2660 in PUNCH CD3, a Phase III, randomized, double-blind, placebo-controlled trial with a Bayesian primary analysis for the prevention of recurrent clostridioides difficile infection. Drugs 2022;82:1527–38.

44 Ki Y, Kim W, Cho H et al. The effect of probiotics for preventing radiation-induced morphological changes in intestinal mucosa of rats. J Korean Med Sci 2014;29:1372–8.

45 Kim YS, Kim J, Park SJ. High-throughput 16S rRNA gene sequencing reveals alterations of mouse intestinal microbiota after radiotherapy. Anaerobe 2015;33:1–7.

46 Kim JH, Kim K, Kim W. Gut microbiota restoration through fecal microbiota transplantation: a new atopic dermatitis therapy. Exp Mol Med 2021;53:907–16.

47 Klammer H, Mladenov E, Li F et al. Bystander effects as manifestation of intercellular communication of DNA damage and of the cellular oxidative status. Cancer Lett 2015;356:58–71.

48 Koay EJ, Owen D, Das P. Radiation-induced liver disease and modern radiotherapy. Semin Radiat Oncol 2018;28:321–31.

49 Kobashi Y, Shimazu Y, Sonoda Y et al. Maturing of public–private–people partnership (4P): lessons from 4P for triple disaster and subsequently COVID-19 pandemic in Fukushima. J Glob Health 2022;12:03028.

50 Kordahi MC, Chassaing B. The intestinal microbiota: our best frenemy in radiation-induced damages? Cell Host Microbe 2021;29:7–9.

51 Lapiere A, Geiger M, Robert V et al. Prophylactic Faecalibacterium prausnitzii treatment prevents the acute breakdown of colonic epithelial barrier in a preclinical model of pelvic radiation disease. Gut Microbes 2020;12:1–15.

52 Lee YS, Kim TY, Kim Y et al. Microbiota-derived lactate promotes hematopoiesis and erythropoiesis by inducing stem cell factor production from leptin receptor+ niche cells. Exp Mol Med 2021;53:1319–31.

53 Li Y, Dong J, Xiao H et al. Gut commensal derived-valeric acid protects against radiation injuries. Gut Microbes 2020;11:789–806.

54 Li X, Chen J, Yuan S et al. Activation of the P62-Keap1-NRF2 pathway protects against ferroptosis in radiation-induced lung injury. Oxid Med Cell Longev 2022;2022:8973509.

55 Linn YH, Thu KK, Win NHH. Effect of probiotics for the prevention of acute radiation-induced diarrhoea among cervical cancer patients: a randomized Double-Blind Placebo-Controlled Study. Probiotics Antimicrob Proteins 2019;11:638–47.

56 Liu X, Zhou Y, Wang S et al. Impact of low-dose ionising radiation on the composition of the gut microbiota of mice. Toxicol Sci 2019;171:258–68.

57 Liu L, Chen C, Liu X et al. Altered gut microbiota associated with hemorrhage in chronic radiation proctitis. Front Oncol 2021;11:637265.

58 Liu G, Yu Q, Tan B et al. Gut dysbiosis impairs hippocampal plasticity and behaviors by remodeling serum metabolome. Gut Microbes 2022a;14:2104089.

59 Liu Y, Yang M, Tang L et al. TLR4 regulates RORgammat(+) regulatory T-cell responses and susceptibility to colon inflammation through interaction with Akkermansia muciniphila. Microbiome 2022b;10:98.

60 Lu G, Wang W, Li P et al. Washed preparation of faecal microbiota changes the transplantation related safety, quantitative method and delivery. Microb Biotechnol 2022;15:2439–49.

61 Lucas S, Omata Y, Hofmann J et al. Short-chain fatty acids regulate systemic bone mass and protect from pathological bone loss. Nat Commun 2018;9:55.

62 Marcella C, Cui B, Kelly CR et al. Systematic review: the global incidence of faecal microbiota transplantation-related adverse events from 2000 to 2020. Aliment Pharmacol Ther 2021;53:33–42.

63 Melin N, Yarahmadov T, Sanchez-Taltavull D et al. A new mouse model of radiation-induced liver disease reveals mitochondrial dysfunction as an underlying fibrotic stimulus. JHEP Rep 2022;4:100508.

64 Miousse IR, Ewing LE, Skinner CM et al. Methionine dietary supplementation potentiates ionizing radiation-induced gastrointestinal syndrome. Am J Physiol Gastrointest Liver Physiol 2020;318:G439–50.

65 Mitchell JD, Cehic DA, Morgia M et al. Cardiovascular manifestations from therapeutic radiation: a multidisciplinary expert consensus statement from the International Cardio-Oncology Society. JACC CardioOncol 2021;3:360–80.

66 Morgan SE, Kastan MB. p53 and ATM: cell cycle, cell death, and cancer. Adv Cancer Res 1997;71:1–25.

67 Munoz-Schuffenegger P, Ng S, Dawson LA. Radiation-induced liver toxicity. Semin Radiat Oncol 2017;27:350–7.

68 Nie X, Li L, Yi M et al. The intestinal microbiota plays as a protective regulator against radiation pneumonitis. Radiat Res 2020;194:52–60.

69 Nishiyama Y, Morita A, Tatsuta S et al. Isorhamnetin promotes 53BP1 recruitment through the enhancement of ATM phosphorylation and protects mice from radiation gastrointestinal syndrome. Genes (Basel) 2021;12:1514.

70 Oscarsson N, Ny L, Molne J et al. Hyperbaric oxygen treatment reverses radiation induced pro-fibrotic and oxidative stress responses in a rat model. Free Radic Biol Med 2017;103:248–55.

71 Ramadan M, Hetta HF, Saleh MM et al. Alterations in skin microbiome mediated by radiotherapy and their potential roles in the prognosis of radiotherapy-induced dermatitis: a pilot study. Sci Rep 2021;11:5179.

72 Reiff C, Kelly D. Inflammatory bowel disease, gut bacteria and probiotic therapy. Int J Med Microbiol 2010;300:25–33.

73 Reis Ferreira M, Andreyev HJN, Mohammed K et al. Microbiotaand Radiotherapy-Induced Gastrointestinal Side-Effects (MARS) Study: a large pilot study of the microbiome in acute and late-radiation enteropathy. Clin Cancer Res 2019;25:6487–500.

74 Riehl TE, Alvarado D, Ee X et al. Lactobacillus rhamnosus GG protects the intestinal epithelium from radiation injury through release of lipoteichoic acid, macrophage activation and the migration of mesenchymal stem cells. Gut 2019;68:1003–13.

75 Routy B, Le Chatelier E, Derosa L et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018;359:91–7.

76 Russo M, Guida F, Paparo L et al. The novel butyrate derivative phenylalanine-butyramide protects from doxorubicin- induced cardiotoxicity. Eur J Heart Fail 2019;21:519–28.

77 Scartoni D, Desideri I, Giacomelli I et al. Nutritional supplement based on zinc, prebiotics, probiotics and vitamins to prevent radiation-related gastrointestinal disorders. Anticancer Res 2015;35:5687–92.

78 Schuijt TJ, Lankelma JM, Scicluna BP et al. The gut microbiota plays a protective role in the host defence against pneumococcal pneumonia. Gut 2016;65:575–83.

79 Shao F, Xin FZ, Yang CG et al. The impact of microbial immune enteral nutrition on the patients with acute radiation enteritis in bowel function and immune status. Cell Biochem Biophys 2014;69:357–61.

80 Shen H, Yu H, Liang PH et al. An acute negative bystander effect of γ-irradiated recipients on transplanted hematopoietic stem cells. Blood 2012;119:3629–37.

81 Shibata A, Jeggo PA. Roles for 53BP1 in the repair of radiation-induced DNA double strand breaks. DNA Repair (Amst) 2020;93:102915.

82 Shuryak I, Matrosova VY, Gaidamakova EK et al. Microbial cells can cooperate to resist high-level chronic ionizing radiation. PLoS One 2017;12:e0189261.

83 Sittipo P, Pham HQ, Park CE et al. Irradiation-induced intestinal damage is recovered by the indigenous gut bacteria lactobacillus acidophilus. Front Cell Infect Microbiol 2020;10:415.

84 Song C, Duan F, Ju T et al. Eleutheroside E supplementation prevents radiation-induced cognitive impairment and activates PKA signaling via gut microbiota. Commun Biol 2022;5:680.

85 Soriano JL, Calpena AC, Souto EB et al. Therapy for prevention and treatment of skin ionizing radiation damage: a review. Int J Radiat Biol 2019;95:537–53.

86 Spyropoulos BG, Misiakos EP, Fotiadis C et al. Antioxidant properties of probiotics and their protective effects in the pathogenesis of radiation-induced enteritis and colitis. Dig Dis Sci 2011;56:285–294.

87 Su J, Zhao Q, Zheng Z et al. Prospective application of ferroptosis in hypoxic cells for tumor radiotherapy. Antioxidants (Basel) 2022;11:921.

88 Szczerbiec D, Piechocka J, Glowacki R et al. Organic acids secreted by Lactobacillus spp. isolated from urine and their antimicrobial activity against uropathogenic Proteus mirabilis. Molecules 2022;27:5557.

89 Thomsen M, Vitetta L. Adjunctive treatments for the prevention of chemotherapy- and radiotherapy-induced mucositis. Integr Cancer Ther 2018;17:1027–47.

90 Tian X, Wang F, Luo Y et al. Protective role of nuclear factor- erythroid 2-related factor 2 against radiation-induced lung injury and inflammation. Front Oncol 2018;8:542.

91 Tian T, Zhao Y, Yang Y et al. The protective role of short-chain fatty acids acting as signal molecules in chemotherapy- or radiation-induced intestinal inflammation. Am J Cancer Res 2020;10:3508–31.

92 Trompette A, Pernot J, Perdijk O et al. Gut-derived short-chain fatty acids modulate skin barrier integrity by promoting keratinocyte metabolism and differentiation. Mucosal Immunol 2022;15:908–26.

93 Turrens JF. Mitochondrial formation of reactive oxygen species. J Physiol 2003;552:335–44.

94 van der Laan HP, Van den Bosch L, Schuit E et al. Impact of radiation-induced toxicities on quality of life of patients treated for head and neck cancer. Radiother Oncol 2021;160:47–53.

95 Vozenin MC, Bourhis J, Durante M. Towards clinical translation of FLASH radiotherapy. Nat Rev Clin Oncol 2022;19:791–803.

96 Wang Y, Wiesnoski DH, Helmink BA et al. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat Med 2018;24:1804–08.

97 Wang Z, Wang Q, Wang X et al. Gut microbial dysbiosis is associated with development and progression of radiation enteritis during pelvic radiotherapy. J Cell Mol Med 2019;23:3747–56.

98 Wang L, Tang L, Feng Y et al. A purified membrane protein from Akkermansia muciniphila or the pasteurised bacterium blunts colitis associated tumourigenesis by modulation of CD8(+) T cells in mice. Gut 2020;69:1988–97.

99 Wang X, Undi RB, Ali N et al. It takes a village: microbiota, parainflammation, paligenosis and bystander effects in colorectal cancer initiation. Dis Model Mech 2021;14:dmm048793.

100 Wang Y, Zhang S, Borody TJ et al. Encyclopedia of fecal microbiota transplantation: a review of effectiveness in the treatment of 85 diseases. Chin Med J (Engl) 2022;135:1927–39.

101 Wang B, Chen X, Chen Z et al. Stable colonization of Akkermansia muciniphila educates host intestinal microecology and immunity to battle against inflammatory intestinal diseases. Exp Mol Med 2023a;55:55–68.

102 Wang W, Lu G, Wu X et al. Colonic transendoscopic enteral tubing is a new pathway to microbial therapy, colonic drainage, and host-microbiota interaction research. J Clin Med 2023b;12:780.

103 Wang Z, Xiao H, Dong J et al. Sexual dimorphism in gut microbiota dictates therapeutic efficacy of intravenous immunoglobulin on radiotherapy complications. J Adv Res 2023c;46:123–33.

104 Weng J, Tu M, Wang P et al. Amiodarone induces cell proliferation and myofibroblast differentiation via ERK1/2 and p38 MAPK signaling in fibroblasts. Biomed Pharmacother 2019;115:108889.

105 Xiao HW, Cui M, Li Y et al. Gut microbiota-derived indole 3-propionic acid protects against radiation toxicity via retaining acyl-CoA-binding protein. Microbiome 2020;8:69.

106 Xiao H, Fan Y, Li Y et al. Oral microbiota transplantation fights against head and neck radiotherapy-induced oral mucositis in mice. Comput Struct Biotechnol J 2021;19:5898–910.

107 Xu L, Huang H, Liu T et al. Exposure to X-rays causes depression- like behaviors in mice via HMGB1-mediated pyroptosis. Neuroscience 2022;481:99–110.

108 Zackular JP, Baxter NT, Iverson KD et al. The gut microbiome modulates colon tumorigenesis. mBio 2013;4:e00692–00613.

109 Zeng X, Li X, Li X et al. Fecal microbiota transplantation from young mice rejuvenates aged hematopoietic stem cells by suppressing inflammation. Blood 2023;141:1691–707.

110 Zhang F, Cui B, He X et al.; FMT-standardization Study Group. Microbiota transplantation: concept, methodology and strategy for its modernization. Protein Cell 2018;9:462–73.

111 Zhang T, Lu G, Zhao Z et al. Washed microbiota transplantation vs. manual fecal microbiota transplantation: clinical findings, animal studies and in vitro screening. Protein Cell 2020;11:251–66.

112 Zhang Y, Dong Y, Lu P et al. Gut metabolite Urolithin A mitigates ionizing radiation-induced intestinal damage. J Cell Mol Med 2021;25:10306–12.

113 Zhang F, Liu T, Huang HC et al. Activation of pyroptosis and ferroptosis is involved in radiation-induced intestinal injury in mice. Biochem Biophys Res Commun 2022;631:102–9.

114 Zhao TS, Xie LW, Cai S et al. Dysbiosis of gut microbiota is associated with the progression of radiation-induced intestinal injury and is alleviated by oral compound probiotics in mouse model. Front Cell Infect Microbiol 2021;11:717636.

115 Zheng YM, He XX, Xia HH et al. Multi-donor multi-course faecal microbiota transplantation relieves the symptoms of chronic hemorrhagic radiation proctitis: a case report. Medicine (Baltim) 2020;99:e22298.

116 Zhou L, Zhang M, Wang Y et al. Faecalibacterium prausnitzii produces butyrate to maintain Th17/Treg balance and to ameliorate colorectal colitis by inhibiting histone deacetylase 1. Inflamm Bowel Dis 2018;24:1926–40.

117 Zhu XX, Yang XJ, Chao YL et al. The potential effect of oral microbiota in the prediction of mucositis during radiotherapy for nasopharyngeal carcinoma. EBioMedicine 2017;18:23–31.

118 Zhang F, Wang W, Nie, Y et al. From microbial technology to microbiota medicine as a clinical discpline: Sustainable development goal. Microb Biotechnol 2023; online ahead of print.