OncohematologyOncohematologyОнкогематология1818-83462413-4023Publishing House ABV Press47810.17650/1818-8346-2021-16-2-86-93SUPPORTIVE THERAPY ASPECTSАСПЕКТЫ ПОДДЕРЖИВАЮЩЕЙ ТЕРАПИИThe microbiome role in pathogenesis of inflammatory and immune alterations of gastrointestinal tract in pediatric patients with cancerРоль микробиома в патогенезе инфекционного и иммунологического повреждения желудочно-кишечного тракта у детей с онкогематологическими заболеваниямиhttps://orcid.org/0000-0001-9540-1162MorgachevaD. A.МоргачеваД. А.
Russian Federation

Dar’ya Andreevna Morgacheva

2 Akkuratova St., Saint-Petersburg 197341

Дарья Андреевна Моргачева

197341 Санкт-Петербург, ул. Аккуратова, 2

 

morgachevadarya483@gmail.comhttps://orcid.org/0000-0002-2003-0982DinikinaYu. V.ДиникинаЮ. В.
Russian Federation

2 Akkuratova St., Saint-Petersburg 197341

197341 Санкт-Петербург, ул. Аккуратова, 2

https://orcid.org/0000-0001-9753-9536ToshinaYu. K.ТошинаЮ. К.
Russian Federation

2 Akkuratova St., Saint-Petersburg 197341

197341 Санкт-Петербург, ул. Аккуратова, 2

https://orcid.org/0000-0002-7471-7181BelogurovaM. B.БелогуроваМ. Б.
Russian Federation

2 Akkuratova St., Saint-Petersburg 197341

197341 Санкт-Петербург, ул. Аккуратова, 2

V.A. Almazov National Medical Research Centre, Ministry of Health of RussiaФГБУ «Национальный медицинский исследовательский центр им. В.А. Алмазова» Минздрава России0706202116286930606202106062021https://oncohematology.abvpress.ru/ongm/article/view/478

Infectious complications remain one of the most significant problem associated with anticancer therapy in oncological patients. Cytotoxic, radiation and antibacterial therapy induce dysbiosis and gastrointestinal mucosal barrier injury. These changes lead to the mucositis, thereby increasing the risk of endogenous microflora translocation with following probable development of severe infectious and inflammatory diseases. In addition, current evidence suggests that there is a relationship between gut microbiome disturbances and post-transplant graft versus host disease development. The article presents the existing paradigms of determining the role of gastrointestinal tract functional condition in cancer patients in order to optimize prevention and antimicrobial treatment approaches.

Инфекционные осложнения остаются одной из наиболее значимых проблем, ассоциированных с противоопухолевой терапией у онкологических пациентов. В результате проводимой цитотоксической, лучевой, а также антибактериальной терапии возникают дисбиоз и повреждение слизистого барьера желудочно-кишечного тракта. Эти изменения приводят к развитию мукозита, тем самым повышая риск эндогенной транслокации микрофлоры с последующим вероятным развитием тяжелых инфекционно-воспалительных  заболеваний. Кроме этого, существующие на сегодняшний день данные свидетельствуют о наличии взаимосвязи между нарушениями в кишечном микробиоме и развитием посттрансплантационной реакции «трансплантат против хозяина». В статье приведены существующие парадигмы в отношении определения роли функционального состояния желудочно-кишечного тракта у онкологических пациентов в целях оптимизации подходов к профилактике и противомикробному лечению.

pediatric oncologychemotherapymucositisfebrile neutropeniatranslocationintestinal microbiomeдетская онкологияхимиотерапиямукозитфебрильная нейтропениятранслокациякишечный микробиомVan Vliet M.J., Tissing W.J., Dun C.A. et al. Chemotherapy treatment in pediatric patients with acute myeloid leukemia receiving antimicrobial prophylaxis leads to a relative increase of colonization with potentially pathogenic bacteria in the gut. Clin Infect Dis 2009;49(2):262–70. DOI: 10.1086/599346.Kelly D.L., Lyon D.E., Yoon S.L., Horgas A.L. The Microbiome and cancer: implications for oncology nursing science. Cancer Nurs 2016;39(3):E56–62. DOI: 10.1097/NCC.0000000000000286.Malard F., Gasc C., Plantamura E. et al. High gastrointestinal microbial diversity and clinical outcome in graft-versus- host disease patients. Bone Marrow Transplant 2018;53(12):1493–7. DOI: 10.1038/s41409-018-0254-x.Tanaka M., Nakayama J. Development of the gut microbiota in infancy and its impact on health in later life. Allergol Int 2017;66(4):515–22. DOI: 10.1016/j.alit.2017.07.010.Okada H., Kuhn C., Feillet H., Bach J.F. The “hygiene hypothesis” for autoimmune and allergic diseases: an update. Clin Exp Immunol 2010;160(1):1–9. DOI: 10.1111/j.1365–2249.2010.04139.x.Alexander S., Pole J.D., Gibson P. et al. Classification of treatment-related mortality in children with cancer: a systematic assessment. Lancet Oncol 2015;16(16):e604–10. DOI: 10.1016/S1470–2045(15)00197–7.Gibson P., Pole J.D., Lazor T. et al. Treatment-related mortality in newly diagnosed pediatric cancer: a population-based analysis. Cancer Med 2018;7(3):707–15. DOI: 10.1002/cam4.1362.Van der Velden W.J., Herbers A.H., Netea M.G., Blijlevens N.M. Mucosal barrier injury, fever and infection in neutropenic patients with cancer: introducing the paradigm febrile mucositis. Br J Haematol 2014;167(4):441–52. DOI: 10.1111/bjh.13113.Clarke R.T., Jenyon T., van Hamel Parsons V., King A.J. Neutropenic sepsis: management and complications. Clin Med 2013;13(2):185–7. DOI: 10.7861/clinmedicine.13-2-185.Wright J.D., Neugut A.I., Ananth C.V. et al. Deviations from guideline-based therapy for febrile neutropenia in cancer patients and their effect on outcomes. JAMA Intern Med 2013;173(7):559–68. DOI: 10.1001/jamainternmed.2013.2921.Taur Y., Xavier J.B., Lipuma L. et al. Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation. Clin Infect Dis 2012;55(7):905–14. DOI: 10.1093/cid/cis580.Biagi E., Zama D., Nastasi C. et al. Gut microbiota trajectory in pediatric patients undergoing hematopoietic SCT. Bone Marrow Transplant 2015;50(7): 992–8. DOI: 10.1038/bmt.2015.16.Taur Y., Pamer E.G. Microbiome mediation of infections in the cancer setting. Genome Med 2016;8(1):40. DOI: 10.1186/s13073-016-0306-z.Petersen C., Round J.L. Defining dysbiosis and its influence on host immunity and disease. Cell Microbiol 2014;16(7):1024–33. DOI: 10.1111/cmi.12308.Miller M.M., Donald D.V., Hagemann T.M. Prevention and treatment of oral mucositis in children with cancer. J Pediatr Pharmacol Ther 2012;17(4): 340–50. DOI: 10.5863/1551-6776-17.4.340.Sonis S.T., Oster G., Fuchs H. et al. Oral mucositis and the clinical and economic outcomes of hematopoietic stem-cell transplantation. J Clin Oncol 2001;19(8):2201–5. DOI: 10.1200/JCO.2001.19.8.2201.Sonis S.T. The pathobiology of mucositis. Nat Rev Cancer 2004;4(4):277–84. DOI: 10.1038/nrc1318.Tsuji E., Hiki N., Nomura S. et al. Simultaneous onset of acute inflammatory response, sepsis-like symptoms and intestinal mucosal injury after cancer chemotherapy. Int J Cancer 2003;107(2):303–8. DOI: 10.1002/ijc.11196.Blijlevens N.M., van’t Land B., Donnelly J.P. et al. Measuring mucosal damage induced by cytotoxic therapy. Support Care Cancer 2004;12(4):227–33. DOI: 10.1007/s00520-003-0572-3.Herbers A.H., de Haan A.F., van der Velden W.J. et al. Mucositis not neutropenia determines bacteremia among hematopoietic stem cell transplant recipients. Transpl Infect Dis 2014;16(2):279–85. DOI: 10.1111/tid.12195.Van der Velden W.J., Herbers A.H., Feuth T. et al. Intestinal damage determines the inflammatory response and early complications in patients receiving conditioning for a stem cell transplantation. PLoS One 2010;5(12): e15156. DOI: 10.1371/journal.pone.0015156.Nagalingam N.A., Lynch S.V. Role of the microbiota in inflammatory bowel diseases. Inflamm Bowel Dis 2012;18(5):968–84. DOI: 10.1002/ibd.21866.Chai L.Y., de Boer M.G., van der Velden W.J. et al. The Y238X stop codon polymorphism in the human β-glucan receptor dectin‑1 and susceptibility to invasive aspergillosis. J Infect Dis 2011;203(5):736–43. DOI: 10.1093/infdis/jiq102.Blijlevens N.M.A., Logan R.M., Netea M.G. Mucositis: from febrile neutropenia to febrile mucositis. J Antimicrob Chemother 2009;63(suppl_1):i36–40. DOI: 10.1093/jac/dkp081.Alyamkina E.A., Dolgova E.V., Proskurina A.S. et al. Intracellular systems for exogenous nucleic acids detection and triggering mechanisms of immune response to exogenous DNA internalization. Meditsinskaya immunologiya = Medical Immunology 2013;15(5):413‒30. (In Russ.). DOI: 10.15789/1563-0625-2013-5-413-430.Алямкина Е.А., Долгова Е.В., Проскурина А.С. и др. Внутриклеточные системы обнаружения экзогенных нуклеиновых кислот и механизмы запуска иммунных реакций в ответ на интернализацию экзогенной ДНК. Медицинская иммунология 2013;15(5):413–30.Palmblad J., Papadaki H.A. Chronic idiopathic neutropenias and severe congenital neutropenia. Curr Opin Hematol 2008;15(1):8–14. DOI: 10.1097/MOH.0b013e3282f172d3.Vinolo M.A., Rodrigues H.G., Nachbar R.T., Curi R. Regulation of inflammation by short chain fatty acids. Nutrients 2011;3(10):858–76. DOI: 10.3390/nu3100858.Mathewson N.D., Jenq R., Mathew A.V. et al. Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease. Nat Immunol 2016;17(5):505–13. DOI: 10.1038/ni.3400.Choi S.W., Gatza E., Hou G. et al. Histone deacetylase inhibition regulates inflammation and enhances Tregs after allogeneic hematopoietic cell transplantation in humans. Blood 2015;125(5):815–9. DOI: 10.1182/ blood-2014-10-605238.Taur Y., Jenq R.R., Perales M.A. et al. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood 2014;124(7):1174–82. DOI: 10.1182/blood‑2014-02-554725.Jenq R.R., Taur Y., Devlin S.M. et al. Intestinal blautia is associated with reduced death from graft-versus- host disease. Biol Blood Marrow Transplant 2015;21(8):1373–83. DOI: 10.1016/j.bbmt.2015.04.016.Sax H.C., Illig K.A., Ryan C.K., Hardy D. J. Low-dose enteral feeding is beneficial during total parenteral nutrition. Am J Surg 1996;171(6):587–90. DOI: 10.1016/s0002-9610(96)00039-6.Chen Y., Zhao Y., Cheng Q. et al. The role of intestinal microbiota in acute graft-versus- host disease. J Immunol Res 2015;2015:145859. DOI: 10.1155/2015/145859.Evans J.C., Hirani S.P., Needle J.J. Nutritional and post-transplantation outcomes of enteral versus parenteral nutrition in pediatric hematopoietic stem cell transplantation: a systematic review of randomized and nonrandomized studies. Biol Blood Marrow Transplant 2019;25(8):e252–9. DOI: 10.1016/j.bbmt.2019.02.023.Heubi J.E. Whenever possible, use the gut! J Pediatr Hematol Oncol 1999;21(2): 88–90. DOI: 10.1097/00043426-199903000-00003.Miedema K., te Poele E., Tissing W. et al. Association of polymorphisms in the TLR4 gene with the risk of developing neutropenia in children with leukemia. Leukemia 2011;25(6): 995–1000. DOI: 10.1038/leu.2011.27Holle E., Rogler G., Herfarth H. et al. Both donor and recipient NOD2/ CARD15 mutations associate with transplant-related mortality and GvHD following allogeneic stem cell transplantation. Blood 2004;104(3): 889–94. DOI: 10.1182/blood-2003-10-3543.Cunha C., Di Ianni M., Bozza S. et al. Dectin‑1 Y238X polymorphism associates with susceptibility to invasive aspergillosis in hematopoietic transplantation through impairment of both recipient- and donor-dependent mechanisms of antifungal immunity. Blood 2010;116(24):5394–402. DOI: 10.1182/blood‑2010-04-279307.Mazurok V.A., Golovkin A.S., Gorelov I.I. et al. Intestinal oxygenotherapy of critical conditions. Obshchaya reanimatologiya = General Reanimatology 2017;13(6):74–91. (In Russ.). DOI:10.15360/1813-9779-2017-6-74-91.Мазурок В.А., Головкин А.С., Горелов И.И. и др. Интестинальная оксигенотерапия критических состояний. Общая реаниматология 2017;13(6):74–91.Herbers A., van der Velden W., de Haan A. et al. Impact of palifermin on intestinal mucositis of HSCT recipients after BEAM. Bone Marrow Transplant 2014;49(1):8–10. DOI: 10.1038/bmt.2013.118.Blijlevens N.M., Donnelly J.P., DePauw B.E. Inflammatory response to mucosal barrier injury after myeloablative therapy in allogeneic stem cell transplant recipients. Bone Marrow Transplant 2005;36(8):703–7. DOI: 10.1038/sj.bmt.1705118.Noor F., Kaysen A., Wilmes P., Schneider J.G. The gut microbiota and hematopoietic stem cell transplantation: challenges and potentials. J Innate Immun 2019;11(5):405–15. DOI: 10.1159/000492943.Panek M., Čipčić Paljetak H., Barešić A. et al. Methodology challenges in studying human gut microbiota – effects of collection, storage, DNA extraction and next generation sequencing technologies. Sci Rep 2018;8:5143. DOI: 10.1038/s41598-018-23296-4.Gibson R.J., Keefe D.M., Lalla R.V. et al. Systematic review of agents for the management of gastrointestinal mucositis in cancer patients. Support Care Cancer 2013;21(1):313–26. DOI: 10.1007/s00520-012-1644-z.Kau A.L., Ahern P.P., Griffin N.W. et al. Human nutrition, the gut microbiome and the immune system. Nature 2011;474(7351):327–36. DOI: 10.1038/nature10213.Bhanja P., Saha S., Kabarriti R. et al. Protective role of R-spondin1, an intestinal stem cell growth factor, against radiation-induced gastrointestinal syndrome in mice. PLoS One 2009;4(11): e8014. DOI: 10.1371/journal.pone.0008014.Fort M.M., Mozaffarian A., Stöver A.G. et al. A synthetic TLR4 antagonist has anti-inflammatory effects in two murine models of inflammatory bowel disease. J Immunol 2005;174(10):6416–23. DOI: 10.4049/jimmunol.174.10.6416.Mookherjee N., Hancock R.E. Cationic host defence peptides: innate immune regulatory peptides as a novel approach for treating infections. Cell Mol Life Sci 2007;64(7–8):922–33. DOI: 10.1007/s00018-007-6475-6.Ellis M., Zwaan F., Hedström U. et al. Recombinant human interleukin 11 and bacterial infection in patients with [correction of] haematological malignant disease undergoing chemotherapy: a double-blind placebo-controlled randomised trial. Lancet 2003;361(9354):275–80. DOI: 10.1016/s0140-6736(03)12322-7.Bachanova V., Brunstein C.G., Burns L.J. et al. Fewer infections and lower infection-related mortality following non-myeloablative versus myeloablative conditioning for allotransplantation of patients with lymphoma. Bone Marrow Transplant 2009;43(3):237–44. DOI: 10.1038/bmt.2008.313.Ren Z.G., Liu H., Jiang J.W. et al. Protective effect of probiotics on intestinal barrier function in malnourished rats after liver transplantation. Hepatobiliary Pancreat Dis Int 2011;10(5):489–96. DOI: 10.1016/s1499-3872(11)60083-0.Yan F., Cao H., Cover T.L. et al. Soluble proteins produced by probiotic bacteria regulate intestinal epithelial cell survival and growth. Gastroenterology 2007;132(2):562–75. DOI: 10.1053/j.gastro.2006.11.022.Jones S.E., Versalovic J. Probiotic Lactobacillus reuteri biofilms produce antimicrobial and anti-inflammatory factors. BMC Microbiol 2009;9:35. DOI: 10.1186/1471-2180-9-35.Mehta A., Rangarajan S., Borate U. A cautionary tale for probiotic use in hematopoietic SCT patients-Lactobacillus acidophilus sepsis in a patient with mantle cell lymphoma undergoing hematopoietic SCT. Bone Marrow Transplant 2013;48(3):461–2. DOI: 10.1038/bmt.2012.153.Reyna-Figueroa J., Barrón-Calvillo E., García-Parra C. et al. Probiotic supplementation decreases chemotherapy-induced gastrointestinal side effects in patients with acute leukemia. J Pediatr Hematol Oncol 2019;41(6):468–72. DOI: 10.1097/MPH.0000000000001497.Ladas E.J., Bhatia M., Chen L. et al. The safety and feasibility of probiotics in children and adolescents undergoing hematopoietic cell transplantation. Bone Marrow Transplant 2016;51(2): 262–6. DOI: 10.1038/bmt.2015.275.Song Y., Garg S., Girotra M. et al. Microbiota dynamics in patients treated with fecal microbiota transplantation for recurrent Clostridium difficile infection. PLoS One 2013;8(11):e81330. DOI: 10.1371/journal.pone.0081330.Kakihana K., Fujioka Y., Suda W. et al. Fecal microbiota transplantation for patients with steroid- resistant acute graft-versus-host disease of the gut. Blood 2016;128(16):2083–8. DOI: 10.1182/blood‑2016-05-717652.Bilinski J., Grzesiowski P., Sorensen N. et al. Fecal microbiota transplantation in patients with blood disorders inhibits gut colonization with antibiotic-resistant bacteria: results of a prospective, single-center study. Clin Infect Dis 017;65(3): 364–70. DOI: 10.1093/cid/cix252.Taur Y., Coyte K., Schluter J. et al. Reconstitution of the gut microbiota of antibiotic-treated patients by autologous fecal microbiota transplant. Sci Transl Med 2018;10(460):eaap9489. DOI: 10.1126/scitranslmed.aap9489.