Research progress on the mechanism of radiation enteritis

Jinjia Fan, Binwei Lin, Mi Fan, Tintin Niu, Feng Gao, Bangxian Tan, Xiaobo Du, Jinjia Fan, Binwei Lin, Mi Fan, Tintin Niu, Feng Gao, Bangxian Tan, Xiaobo Du

Abstract

Radiation enteritis (Re) is one of the most common complications of radiation therapy for abdominal tumors. The efficacy of cancer treatment by radiation is often limited by the side effects of Re. Re can be acute or chronic. Treatment of acute Re is essentially symptomatic. However, chronic Re usually requires surgical procedures. The underlying mechanisms of Re are complex and have not yet been elucidated. The purpose of this review is to provide an overview of the pathogenesis of Re. We reviewed the role of intestinal epithelial cells, intestinal stem cells (ISCs), vascular endothelial cells (ECs), intestinal microflora, and other mediators of Re, noting that a better understanding of the pathogenesis of Re may lead to better treatment modalities.

Keywords: Radiation enteritis; intestinal epithelial cells; intestinal microflora; intestinal stem cells; mechanism; vascular endothelial cell.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Fan, Lin, Fan, Niu, Gao, Tan and Du.

Figures

Figure 1
Figure 1
The mechanism of radiation enteritis.

References

    1. Bhutta BS, Fatima R, Aziz M. Radiation enteritis. In: StatPearls. Treasure Island (FL: StatPearls Publishing LLC; (2022).
    1. Kountouras J, Zavos C. Recent advances in the management of radiation colitis. World J Gastroenterol (2008) 14(48):7289–301. doi: 10.3748/wjg.14.7289
    1. Hauer-Jensen M, Denham JW, Andreyev HJ. Radiation enteropathy–pathogenesis, treatment and prevention. Nat Rev Gastroenterol Hepatol (2014) 11(8):470–9. doi: 10.1038/nrgastro.2014.46
    1. Li Y, Yan H, Zhang Y, Li Q, Yu L, Li Q, et al. . Alterations of the gut microbiome composition and lipid metabolic profile in radiation enteritis. Front Cell Infect Microbiol (2020) 10:541178. doi: 10.3389/fcimb.2020.541178
    1. Keita AV, Söderholm JD. The intestinal barrier and its regulation by neuroimmune factors. Neurogastroenterol Motil (2010) 22(7):718–33. doi: 10.1111/j.1365-2982.2010.01498.x
    1. Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol (2009) 9(11):799–809. doi: 10.1038/nri2653
    1. Pelaseyed T, Bergström JH, Gustafsson JK, Ermund A, Birchenough GM, Schütte A, et al. . The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system. Immunol Rev (2014) 260(1):8–20. doi: 10.1111/imr.12182
    1. Van der Sluis M, De Koning BA, De Bruijn AC, Velcich A, Meijerink JP, Van Goudoever JB, et al. . Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology (2006) 131(1):117–29. doi: 10.1053/j.gastro.2006.04.020
    1. Wang K, Ding Y, Xu C, Hao M, Li H, Ding L. Cldn-7 deficiency promotes experimental colitis and associated carcinogenesis by regulating intestinal epithelial integrity. Oncoimmunology (2021) 10(1):1923910. doi: 10.1080/2162402X.2021.1923910
    1. Qu W, Zhang L, Ao J. Radiotherapy induces intestinal barrier dysfunction by inhibiting autophagy. ACS Omega (2020) 5(22):12955–63. doi: 10.1021/acsomega.0c00706
    1. Suzuki T. Regulation of the intestinal barrier by nutrients: The role of tight junctions. Anim Sci J (2020) 91(1):e13357. doi: 10.1111/asj.13357
    1. Du H, Yang X, Fan J, Du X. Claudin 6: Therapeutic prospects for tumours, and mechanisms of expression and regulation (Review). Mol Med Rep (2021) 24(3). doi: 10.3892/mmr.2021.12316
    1. Vancamelbeke M, Vermeire S. The intestinal barrier: a fundamental role in health and disease. Expert Rev Gastroenterol Hepatol (2017) 11(9):821–34. doi: 10.1080/17474124.2017.1343143
    1. Hou Q, Huang J, Ayansola H, Masatoshi H, Zhang B. Intestinal stem cells and immune cell relationships: Potential therapeutic targets for inflammatory bowel diseases. Front Immunol (2020) 11:623691. doi: 10.3389/fimmu.2020.623691
    1. Troy EB, Kasper DL. Beneficial effects of bacteroides fragilis polysaccharides on the immune system. Front Biosci (Landmark Ed) (2010) 15(1):25–34. doi: 10.2741/3603
    1. Morini J, Babini G, Barbieri S, Baiocco G, Ottolenghi A. The interplay between radioresistant caco-2 cells and the immune system increases epithelial layer permeability and alters signaling protein spectrum. Front Immunol (2017) 8:223. doi: 10.3389/fimmu.2017.00223
    1. Gupta R, Yin L, Grosche A, Lin S, Xu X, Guo J, et al. . An amino acid-based oral rehydration solution regulates radiation-induced intestinal barrier disruption in mice. J Nutr (2020) 150(5):1100–8. doi: 10.1093/jn/nxaa025
    1. Foerster EG, Mukherjee T, Cabral-Fernandes L, Rocha JDB, Girardin SE, Philpott DJ. How autophagy controls the intestinal epithelial barrier. Autophagy (2022) 18(1):86–103. doi: 10.1080/15548627.2021.1909406
    1. Asano J, Sato T, Ichinose S, Kajita M, Onai N, Shimizu S, et al. . Intrinsic autophagy is required for the maintenance of intestinal stem cells and for irradiation-induced intestinal regeneration. Cell Rep (2017) 20(5):1050–60. doi: 10.1016/j.celrep.2017.07.019
    1. Datta K, Suman S, Fornace AJ., Jr. Radiation persistently promoted oxidative stress, activated mTOR via PI3K/Akt, and downregulated autophagy pathway in mouse intestine. Int J Biochem Cell Biol (2014) 57:167–76. doi: 10.1016/j.biocel.2014.10.022
    1. Galiniak S, Aebisher D, Bartusik-Aebisher D. Health benefits of resveratrol administration. Acta Biochim Pol (2019) 66(1):13–21. doi: 10.18388/abp.2018_2749
    1. Qin H, Zhang H, Zhang X, Zhang S, Zhu S, Wang H. Resveratrol protects intestinal epithelial cells against radiation-induced damage by promoting autophagy and inhibiting apoptosis through SIRT1 activation. J Radiat Res (2021) 62(4):574–81. doi: 10.1093/jrr/rrab035
    1. Rees WD, Sly LM, Steiner TS. How do immune and mesenchymal cells influence the intestinal epithelial cell compartment in inflammatory bowel disease? let’s crosstalk about it! J Leukoc Biol (2020) 108(1):309–21. doi: 10.1002/JLB.3MIR0120-567R
    1. Beumer J, Clevers H. Regulation and plasticity of intestinal stem cells during homeostasis and regeneration. Development (2016) 143(20):3639–49. doi: 10.1242/dev.133132
    1. Park M, Kwon J, Youk H, Shin US, Han YH, Kim Y. Valproic acid protects intestinal organoids against radiation via NOTCH signaling. Cell Biol Int (2021) 45(7):1523–32. doi: 10.1002/cbin.11591
    1. Saha S, Aranda E, Hayakawa Y, Bhanja P, Atay S, Brodin NP, et al. . Macrophage-derived extracellular vesicle-packaged WNTs rescue intestinal stem cells and enhance survival after radiation injury. Nat Commun (2016) 7:13096. doi: 10.1038/ncomms13096
    1. Wu J, Duan Y, Cui J, Dong Y, Li H, Wang M, et al. . Protective effects of zingerone derivate on ionizing radiation-induced intestinal injury. J Radiat Res (2019) 60(6):740–6. doi: 10.1093/jrr/rrz065
    1. Moussa L, Usunier B, Demarquay C, Benderitter M, Tamarat R, Sémont A, et al. . Bowel radiation injury: Complexity of the pathophysiology and promises of cell and tissue engineering. Cell Transplant (2016) 25(10):1723–46. doi: 10.3727/096368916X691664
    1. Nusse R, Clevers H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell (2017) 169(6):985–99. doi: 10.1016/j.cell.2017.05.016
    1. Huang P, Yan R, Zhang X, Wang L, Ke X, Qu Y. Activating wnt/β-catenin signaling pathway for disease therapy: Challenges and opportunities. Pharmacol Ther (2019) 196:79–90. doi: 10.1016/j.pharmthera.2018.11.008
    1. Young MA, Daly CS, Taylor E, James R, Clarke AR, Reed KR. Subtle deregulation of the wnt-signaling pathway through loss of Apc2 reduces the fitness of intestinal stem cells. Stem Cells (2018) 36(1):114–22. doi: 10.1002/stem.2712
    1. Bhanja P, Norris A, Gupta-Saraf P, Hoover A, Saha S. BCN057 induces intestinal stem cell repair and mitigates radiation-induced intestinal injury. Stem Cell Res Ther (2018) 9(1):26. doi: 10.1186/s13287-017-0763-3
    1. Li Y, Ma S, Zhang Y, Yao M, Zhu X, Guan F. (-)-Epicatechin mitigates radiation-induced intestinal injury and promotes intestinal regeneration via suppressing oxidative stress. Free Radic Res (2019) 53(8):851–64. doi: 10.1080/10715762.2019.1635692
    1. Kalita B, Ranjan R, Gupta ML. Combination treatment of podophyllotoxin and rutin promotes mouse Lgr5(+ ve) intestinal stem cells survival against lethal radiation injury through wnt signaling. Apoptosis (2019) 24(3-4):326–40. doi: 10.1007/s10495-019-01519-x
    1. Chen Y, Cao K, Liu H, Liu T, Liu L, Qin H, et al. . Heat killed salmonella typhimurium protects intestine against radiation injury through wnt signaling pathway. J Oncol (2021) 2021:5550956. doi: 10.1155/2021/5550956
    1. Hori K, Sen A, Artavanis-Tsakonas S. Notch signaling at a glance. J Cell Sci (2013) 126(Pt 10):2135–40. doi: 10.1242/jcs.127308
    1. Sancho R, Cremona CA, Behrens A. Stem cell and progenitor fate in the mammalian intestine: Notch and lateral inhibition in homeostasis and disease. EMBO Rep (2015) 16(5):571–81. doi: 10.15252/embr.201540188
    1. Lv Y, Liang T, Wang G, Li Z. Ghrelin, a gastrointestinal hormone, regulates energy balance and lipid metabolism. Biosci Rep (2018) 38(5). doi: 10.1042/BSR20181061
    1. Kwak SY, Shim S, Park S, Kim H, Lee SJ, Kim MJ. Ghrelin reverts intestinal stem cell loss associated with radiation-induced enteropathy by activating notch signaling. Phytomedicine (2021) 81:153424. doi: 10.1016/j.phymed.2020.153424
    1. Auclair BA, Benoit YD, Rivard N, Mishina Y, Perreault N. Bone morphogenetic protein signaling is essential for terminal differentiation of the intestinal secretory cell lineage. Gastroenterology (2007) 133(3):887–96. doi: 10.1053/j.gastro.2007.06.066
    1. Hardwick JC, Van Den Brink GR, Bleuming SA, Ballester I, Van Den Brande JM, Keller JJ, et al. . Bone morphogenetic protein 2 is expressed by, and acts upon, mature epithelial cells in the colon. Gastroenterology (2004) 126(1):111–21. doi: 10.1053/j.gastro.2003.10.067
    1. Wang S, Chen YG. BMP signaling in homeostasis, transformation and inflammatory response of intestinal epithelium. Sci China Life Sci (2018) 61(7):800–7. doi: 10.1007/s11427-018-9310-7
    1. Feng XH, Derynck R. Specificity and versatility in tgf-beta signaling through smads. Annu Rev Cell Dev Biol (2005) 21:659–93. doi: 10.1146/annurev.cellbio.21.022404.142018
    1. He XC, Zhang J, Tong WG, Tawfik O, Ross J, Scoville DH, et al. . BMP signaling inhibits intestinal stem cell self-renewal through suppression of wnt-beta-catenin signaling. Nat Genet (2004) 36(10):1117–21. doi: 10.1038/ng1430
    1. Tian Y, Ma X, Lv C, Sheng X, Li X, Zhao R, et al. . Stress responsive miR-31 is a major modulator of mouse intestinal stem cells during regeneration and tumorigenesis. Elife (2017) 6. doi: 10.7554/eLife.29538
    1. Biswas S, Davis H, Irshad S, Sandberg T, Worthley D, Leedham S. Microenvironmental control of stem cell fate in intestinal homeostasis and disease. J Pathol (2015) 237(2):135–45. doi: 10.1002/path.4563
    1. McCarthy N, Manieri E, Storm EE, Saadatpour A, Luoma AM, Kapoor VN, et al. . Distinct mesenchymal cell populations generate the essential intestinal BMP signaling gradient. Cell Stem Cell (2020) 26(3):391–402.e5. doi: 10.1016/j.stem.2020.01.008
    1. Martín-Alonso M, Iqbal S, Vornewald PM, Lindholm HT, Damen MJ, Martínez F, et al. . Smooth muscle-specific MMP17 (MT4-MMP) regulates the intestinal stem cell niche and regeneration after damage. Nat Commun (2021) 12(1):6741. doi: 10.1038/s41467-021-26904-6
    1. Walton KD, Gumucio DL. Hedgehog signaling in intestinal development and homeostasis. Annu Rev Physiol (2021) 83:359–80. doi: 10.1146/annurev-physiol-031620-094324
    1. Büller NV, Rosekrans SL, Westerlund J, van den Brink GR. Hedgehog signaling and maintenance of homeostasis in the intestinal epithelium. Physiol (Bethesda) (2012) 27(3):148–55. doi: 10.1152/physiol.00003.2012
    1. Stewart FA, Akleyev AV, Hauer-Jensen M, Hendry JH, Kleiman NJ, Macvittie TJ, et al. . ICRP publication 118: ICRP statement on tissue reactions and early and late effects of radiation in normal tissues and organs–threshold doses for tissue reactions in a radiation protection context. Ann ICRP (2012) 41(1-2):1–322. doi: 10.1016/j.icrp.2012.02.001
    1. Ebrahimian T, Le Gallic C, Stefani J, Dublineau I, Yentrapalli R, Harms-Ringdahl M, et al. . Chronic gamma-irradiation induces a dose-Rate-Dependent pro-inflammatory response and associated loss of function in human umbilical vein endothelial cells. Radiat Res (2015) 183(4):447–54. doi: 10.1667/RR13732.1
    1. Wynn TA. Integrating mechanisms of pulmonary fibrosis. J Exp Med (2011) 208(7):1339–50. doi: 10.1084/jem.20110551
    1. Giblin JP, Hewlett LJ, Hannah MJ. Basal secretion of von willebrand factor from human endothelial cells. Blood (2008) 112(4):957–64. doi: 10.1182/blood-2007-12-130740
    1. Chang PY, Qu YQ, Wang J, Dong LH. The potential of mesenchymal stem cells in the management of radiation enteropathy. Cell Death Dis (2015) 6(8):e1840. doi: 10.1038/cddis.2015.189
    1. Wang Y, Boerma M, Zhou D. Ionizing radiation-induced endothelial cell senescence and cardiovascular diseases. Radiat Res (2016) 186(2):153–61. doi: 10.1667/RR14445.1
    1. Shao S, Gao Y, Liu J, Tian M, Gou Q, Su X, et al. . Ferulic acid mitigates radiation injury in human umbilical vein endothelial cells In vitro via the thrombomodulin pathway. Radiat Res (2018) 190(3):298–308. doi: 10.1667/RR14696.1
    1. Rotolo J, Stancevic B, Zhang J, Hua G, Fuller J, Yin X, et al. . Anti-ceramide antibody prevents the radiation gastrointestinal syndrome in mice. J Clin Invest (2012) 122(5):1786–90. doi: 10.1172/JCI59920
    1. Ito T, Maruyama I. Thrombomodulin: protectorate God of the vasculature in thrombosis and inflammation. J Thromb Haemost (2011) 9(Suppl)1:168–73. doi: 10.1111/j.1538-7836.2011.04319.x
    1. Kruse JJ, Floot BG, te Poele JA, Russell NS, Stewart FA. Radiation-induced activation of TGF-beta signaling pathways in relation to vascular damage in mouse kidneys. Radiat Res (2009) 171(2):188–97. doi: 10.1667/RR1526.1
    1. Feng W, Ying WZ, Aaron KJ, Sanders PW. Transforming growth factor-β mediates endothelial dysfunction in rats during high salt intake. Am J Physiol Renal Physiol (2015) 309(12):F1018–25. doi: 10.1152/ajprenal.00328.2015
    1. Shang L, Jia SS, Jiang HM, Wang H, Xu WH, Lv CJ. Simvastatin downregulates expression of TGF-βRII and inhibits proliferation of A549 cells via ERK. Tumour Biol (2015) 36(6):4819–24. doi: 10.1007/s13277-015-3134-7
    1. Pathak R, Wang J, Garg S, Aykin-Burns N, Petersen KU, Hauer-Jensen M. Recombinant thrombomodulin (Solulin) ameliorates early intestinal radiation toxicity in a preclinical rat model. Radiat Res (2016) 186(2):112–20. doi: 10.1667/RR14408.1
    1. Yan T, Zhang T, Mu W, Qi Y, Guo S, Hu N, et al. . Ionizing radiation induces BH(4) deficiency by downregulating GTP-cyclohydrolase 1, a novel target for preventing and treating radiation enteritis. Biochem Pharmacol (2020) 180:114102. doi: 10.1016/j.bcp.2020.114102
    1. Yan T, Guo S, Zhang T, Zhang Z, Liu A, Zhang S, et al. . Ligustilide prevents radiation enteritis by targeting Gch1/BH(4)/eNOS to improve intestinal ischemia. Front Pharmacol (2021) 12:629125. doi: 10.3389/fphar.2021.629125
    1. Singh RK, Chang HW, Yan D, Lee KM, Ucmak D, Wong K, et al. . Influence of diet on the gut microbiome and implications for human health. J Transl Med (2017) 15(1):73. doi: 10.1186/s12967-017-1175-y
    1. Crawford PA, Gordon JI. Microbial regulation of intestinal radiosensitivity. Proc Natl Acad Sci U.S.A. (2005) 102(37):13254–9. doi: 10.1073/pnas.0504830102
    1. Li Y, Zhang Y, Wei K, He J, Ding N, Hua J, et al. . Review: Effect of gut microbiota and its metabolite SCFAs on radiation-induced intestinal injury. Front Cell Infect Microbiol (2021) 11:577236. doi: 10.3389/fcimb.2021.577236
    1. Visich KL, Yeo TP. The prophylactic use of probiotics in the prevention of radiation therapy-induced diarrhea. Clin J Oncol Nurs (2010) 14(4):467–73. doi: 10.1188/10.CJON.467-473
    1. Touchefeu Y, Montassier E, Nieman K, Gastinne T, Potel G, Bruley des Varannes S, et al. . Systematic review: the role of the gut microbiota in chemotherapy- or radiation-induced gastrointestinal mucositis - current evidence and potential clinical applications. Aliment Pharmacol Ther (2014) 40(5):409–21. doi: 10.1111/apt.12878
    1. Johnson LB, Riaz AA, Adawi D, Wittgren L, Bäck S, Thornberg C, et al. . Radiation enteropathy and leucocyte-endothelial cell reactions in a refined small bowel model. BMC Surg (2004) 4:10. doi: 10.1186/1471-2482-4-10
    1. Zhang Y, Dong Y, Lu P, Wang X, Li W, Dong H, et al. . Gut metabolite urolithin a mitigates ionizing radiation-induced intestinal damage. J Cell Mol Med (2021) 25(21):10306–12. doi: 10.1111/jcmm.16951

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir