medsovetМедицинский СоветMeditsinskiy sovet = Medical Council2079-701X2658-5790REMEDIUM GROUP Ltd.10.21518/2079-701X-2017-9-108-115medsovet-1964Research ArticleАЛЛЕРГОЛОГИЯ И ИММУНОЛОГИЯALLERGOLOGY AND IMMUNOLOGYПРОБИОТИЧЕСКИЕ ШТАММЫ ЛАКТОБАЦИЛЛ КАК ИММУНОМОДУЛЯТОРЫ: В ФОКУСЕ — LACTOBACILLUS RHAMNOSUS GGPROBIOTIC STRAINS OF LACTOBACILLI AS IMMUNOMODULATORS: FOCUS ON LACTOBACILLUS RHAMNOSUS GGКАЛЮЖИНО. В.KALYUZHINO. V.

д.м.н., профессор

MD, Prof

Первый Московский государственный медицинский университет им. И.М. СеченоваРоссияFirst Moscow state University named after I.M. SechenovRussian Federation20172007201709108115Copyright © КАЛЮЖИН О.В., 20172017КАЛЮЖИН О.В.KALYUZHIN O.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.med-sovet.pro/jour/article/view/1964

Пробиотики уже давно рассматриваются не только как средства коррекции кишечного дисбиоза, но и перспективные инструменты иммуномодуляции. В последние годы существенно увеличилась доказательная база их эффективности в профилактике и лечении иммуноассоциированных заболеваний человека, уточнены ранее описанные и раскрыты новые механизмы иммунокорригирующего действия пробиотических бактерий, в том числе принадлежащих роду Lactobacillus. Выводы метаанализов и систематических обзоров не оставляют сомнений в целесообразности использования некоторых пробиотиков, в первую очередь Lactobacillus rhamnosus GG (LGG), у детей для лечения и предотвращения различных форм острой диареи, в том числе ассоциированной с приемом антибактериальных средств, а также для профилактики респираторных инфекций. Обнадеживающими являются результаты испытаний этого штамма как адъюванта вакцин и средства предотвращения атопического дерматита. В настоящем обзоре проанализированы особенности современных детей, делающие их более восприимчивыми к аллергическим и инфекционным заболеваниям, эффекторные молекулы лактобацилл и сигнальные пути, обеспечивающие их иммуномодулирующее действие, основные сферы лечебного и профилактического применения и безопасность пробиотиков с фокусом на LGG как один из наиболее изученных и апробированных штаммов. Кроме того, представлены данные о клинической эффективности разрешенного к применению в России синбиотика Нормобакт L, включающего комбинацию LGG (4 × 109) и фруктоолигосахаридов (800 мг), у детей с ротавирусной инфекцией на фоне атопического дерматита.

Probiotics have long been considered not only as a way of correcting intestinal dysbiosis but also as a promising immunomodulatory solution. Over the past years, the evidence base for their effectiveness in the prevention and treatment of immuneassociated human diseases has substantially increased, the previously described mechanisms were specified and new components of the immunocorrective effect of probiotic bacteria, including those belonging to the genus Lactobacillus, have been deciphered. The meta-analytical findings and systematic reviews leave no doubt about the advisability of using certain probiotics, primarily Lactobacillus rhamnosus GG (LGG), in children for the treatment and prevention of various forms of acute diarrhea, including those associated with the administration of antibacterial agents, as well as for the prevention of respiratory infections. The results of testing the strain to be used as an adjuvant vaccine and a way of preventing atopic dermatitis are encouraging. The review analyzes the specific characteristics of present-day children who are more susceptible to allergic and infectious diseases, effector molecules of lactobacilli and signaling pathways that ensure their immunomodulatory effect, the main areas of therapeutic and preventive application and safety of probiotics, with a focus on LGG as one of the most studied and tested strains. In addition, the clinical efficacy of the synbiotic Normobakt L, a combination of LGG (4 × 109) plus fructooligosaccharides (800 mg),which has been approved in Russia for use in children with rotavirus infection against a background of atopic dermatitis, is demonstrated

Lactobacillus rhamnosus GGиммуномодуляциядиареяатопический дерматитадъювантыреспираторные инфекцииНормобакт L.Lactobacillus rhamnosus GGimmunomodulationdiarrheaatopic dermatitisadjuvantsrespiratory infectionsNormobakt LReferencesКалюжин О.В. Безопасность и физиологичность действия пробиотиков как средств иммунокоррекции. Российский аллергологический журнал, 2013, 3: 45-56.Wells JM. Immunomodulatory mechanisms of lactobacilli. Microb Cell Fact, 2011, 10(Suppl 1): S17. doi: 10.1186/1475-2859-10-S1-S17.Калюжин О.В. Возможности использования пробиотиков для укрепления противоинфекционной защиты в свете иммуногомеостатической роли микробиоты. Эффективная фармакотерапия, 2013, 27-2: 12-25.Corr SC, Hill C, Gahan CG. Understanding the mechanisms by which probiotics inhibit gastrointestinal pathogens. Adv Food Nutr Res, 2009, 56: 1-15.Калюжин О.В. Пробиотики как современные средства укрепления противоинфекционной защиты: миф или реальность? РМЖ, 2012, 28: 1395-1401.Rao RK, Samak G. Protection and Restitution of Gut Barrier by Probiotics: Nutritional and Clinical Implications. Current nutrition and food science, 2013, 9(2): 99-107.Калюжин О.В., Афанасьев С.С., Быков А.С. Пероральные пробиотики как стимуляторы противоинфекционного иммунного ответа в респираторном тракте. Терапевтический архив, 2016, 88(5): 118-124.Del-Rio-Navarro BE, Espinosa Rosales F, Flenady V, Sienra-Monge JJ. Immunostimulants for preventing respiratory tract infection in children. Cochrane Database Syst Rev, 2006, 4: CD004974.Караулов А.В., Калюжин О.В. Иммунотерапия инфекционных болезней: проблемы и перспективы. Терапевтический архив, 2013, 85(11): 100-108.Treating infectious diseases in a microbial world: Report of two workshops on novel antimicrobial therapeutics. Washington: National Academies Press, 2006.Усенко Д.В. Влияние антибиотиков и пробиотиков на микробиом желудочно-кишечного тракта. Медицинский совет, 2016, 16: 52-56.Qin J, Li R, Raes J et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature, 2010, 464(7285): 59-65. doi: 10.1038/nature08821.Горелова Е.А., Олисова О.Ю., Усенко Д.В. Исходы и пути оптимизации лечения ротавирусной инфекции у детей с атопическим дерматитом. Инфекционные болезни, 2016, 14(1): 80-85. doi: 10.20953/1729-9225-2016-1-80-85.Smith PM, Garrett WS. The gut microbiota and mucosal T cells. Front Microbiol, 2011, 2: 111. doi: 10.3389/fmicb.2011.00111Taverniti V, Guglielmetti S. The immunomodulatory properties of probiotic microorganisms beyond their viability (ghost probiotics: proposal of paraprobiotic concept). Genes Nutr, 2011, 6(3): 261-274. doi: 10.1007/s12263-011-0218-x.Taverniti V, Guglielmetti S. The immunomodulatory properties of probiotic microorganisms beyond their viability (ghost probiotics: proposal of paraprobiotic concept). Genes Nutr, 2011, 6(3): 261-274. doi: 10.1007/s12263-011-0218-x.Cong Y, Feng T, Fujihashi K et al. A dominant, coordinated T regulatory cell-IgA response to the intestinal microbiota. Proc Natl Acad Sci USA, 2009, 106(46): 19256-19261. doi: 10.1073/pnas.0812681106.Cong Y, Feng T, Fujihashi K et al. A dominant, coordinated T regulatory cell-IgA response to the intestinal microbiota. Proc Natl Acad Sci USA, 2009, 106(46): 19256-19261. doi: 10.1073/pnas.0812681106.Doron S, Snydman DR, Gorbach SL. Lactobacillus GG: Bacteriology and clinical applications. Gastroenterology Clinics of North America, 2005, 34: 483-498. doi: 10.1016/j.gtc.2005.05.011.Doron S, Snydman DR, Gorbach SL. Lactobacillus GG: Bacteriology and clinical applications. Gastroenterology Clinics of North America, 2005, 34: 483-498. doi: 10.1016/j.gtc.2005.05.011.Goldin BR, Gorbach SL, Saxelin M, Barakat S, Gualtieri L, Salminen S. Survival of Lactobacillus species (strain GG) in human gastrointestinal tract. Dig Dis Sci, 1992, 37(1): 121-128.Goldin BR, Gorbach SL, Saxelin M, Barakat S, Gualtieri L, Salminen S. Survival of Lactobacillus species (strain GG) in human gastrointestinal tract. Dig Dis Sci, 1992, 37(1): 121-128.Collado MC, Grzeskowiak L, Salminen S.Probiotic strains and their combination inhibit in vitro adhesion of pathogens to pig intestinal mucosa. Curr. Microbiol., 2007, 55: 260-265.Collado MC, Grzeskowiak L, Salminen S.Probiotic strains and their combination inhibit in vitro adhesion of pathogens to pig intestinal mucosa. Curr. Microbiol., 2007, 55: 260-265.Segers ME, Lebeer S. Towards a better understanding of Lactobacillus rhamnosus GG - host interactions. Microbial Cell Factories, 2014, 13(Suppl 1): S7. doi: 10.1186/1475-2859-13-S1-S7.Segers ME, Lebeer S. Towards a better understanding of Lactobacillus rhamnosus GG - host interactions. Microbial Cell Factories, 2014, 13(Suppl 1): S7. doi: 10.1186/1475-2859-13-S1-S7.Kang JY, Nan X, Jin MS et al. Recognition of lipopeptide patterns by Toll-like receptor 2-Toll-like receptor 6 heterodimer. Immunity, 2009, 31: 873-884. doi: 10.1016/j.immuni.2009.09.018.Kang JY, Nan X, Jin MS et al. Recognition of lipopeptide patterns by Toll-like receptor 2-Toll-like receptor 6 heterodimer. Immunity, 2009, 31: 873-884. doi: 10.1016/j.immuni.2009.09.018.Nilsen NJ, Deininger S, Nonstad U et al. Cellular trafficking of lipoteichoic acid and Toll-like receptor 2 in relation to signaling; role of CD14 and CD36. Journal of Leukocyte Biology, 2008, 84(1): 280-291. doi:10.1189/jlb.0907656.Nilsen NJ, Deininger S, Nonstad U et al. Cellular trafficking of lipoteichoic acid and Toll-like receptor 2 in relation to signaling; role of CD14 and CD36. Journal of Leukocyte Biology, 2008, 84(1): 280-291. doi:10.1189/jlb.0907656.Claes IJ, Segers ME, Verhoeven TL et al. Lipoteichoic acid is an important microbeassociated molecular pattern of Lactobacillus rhamnosus GG. Microb Cell Fact, 2012, 11: 161. doi: 10.1186/1475-2859-11-161.Claes IJ, Segers ME, Verhoeven TL et al. Lipoteichoic acid is an important microbeassociated molecular pattern of Lactobacillus rhamnosus GG. Microb Cell Fact, 2012, 11: 161. doi: 10.1186/1475-2859-11-161.Claes IJJ, Lebeer S, Shen C et al. Impact of lipoteichoic acid modification on the performance of the probiotic Lactobacillus rhamnosus GG in experimental colitis. Clinical and Experimental Immunology, 2010, 162(2): 306-314. doi:10.1111/j.1365-2249.2010.04228.x.Claes IJJ, Lebeer S, Shen C et al. Impact of lipoteichoic acid modification on the performance of the probiotic Lactobacillus rhamnosus GG in experimental colitis. Clinical and Experimental Immunology, 2010, 162(2): 306-314. doi:10.1111/j.1365-2249.2010.04228.x.Reunanen J, von Ossowski I, Hendrickx APA, Palva A, de Vos WM. Characterization of the SpaCBA Pilus Fibers in the Probiotic Lactobacillus rhamnosus GG. Applied and Environmental Microbiology, 2012, 78(7): 2337-2344. doi: 10.1128/AEM.07047-11.Reunanen J, von Ossowski I, Hendrickx APA, Palva A, de Vos WM. Characterization of the SpaCBA Pilus Fibers in the Probiotic Lactobacillus rhamnosus GG. Applied and Environmental Microbiology, 2012, 78(7): 2337-2344. doi: 10.1128/AEM.07047-11.Von Ossowski I, Satokari R, Reunanen J et al. Functional characterization of a mucus-specific LPXTG surface adhesin from probiotic Lactobacillus rhamnosus GG. Appl Environ Microbiol, 2011, 77: 4465-4472. doi: 10.1128/AEM.02497-10.Von Ossowski I, Satokari R, Reunanen J et al. Functional characterization of a mucus-specific LPXTG surface adhesin from probiotic Lactobacillus rhamnosus GG. Appl Environ Microbiol, 2011, 77: 4465-4472. doi: 10.1128/AEM.02497-10.Velez MP, Petrova MI, Lebeer S et al. Characterization of MabA, a modulator of Lactobacillus rhamnosus GG adhesion and biofilm formation. FEMS Immunol Med Microbiol, 2010, 59: 386-398.Velez MP, Petrova MI, Lebeer S et al. Characterization of MabA, a modulator of Lactobacillus rhamnosus GG adhesion and biofilm formation. FEMS Immunol Med Microbiol, 2010, 59: 386-398.Von Ossowski I, Pietilä TE, Rintahaka J et al. Using Recombinant Lactococci as an Approach to Dissect the Immunomodulating Capacity of Surface Piliation in Probiotic Lactobacillus rhamnosus GG. Foligne B, ed. PLoS ONE, 2013, 8(5): e64416. doi:10.1371/journal.pone.0064416.Von Ossowski I, Pietilä TE, Rintahaka J et al. Using Recombinant Lactococci as an Approach to Dissect the Immunomodulating Capacity of Surface Piliation in Probiotic Lactobacillus rhamnosus GG. Foligne B, ed. PLoS ONE, 2013, 8(5): e64416. doi:10.1371/journal.pone.0064416.Lebeer S, Claes I, Tytgat HLP et al. Functional Analysis of Lactobacillus rhamnosus GG Pili in Relation to Adhesion and Immunomodulatory Interactions with Intestinal Epithelial Cells. Applied and Environmental Microbiology, 2012, 78(1): 185-193. doi:10.1128/AEM.06192-11.Lebeer S, Claes I, Tytgat HLP et al. Functional Analysis of Lactobacillus rhamnosus GG Pili in Relation to Adhesion and Immunomodulatory Interactions with Intestinal Epithelial Cells. Applied and Environmental Microbiology, 2012, 78(1): 185-193. doi:10.1128/AEM.06192-11.Ghadimi D, Folster-Holst R, de Vrese M, Winkler P, Heller KJ, Schrezenmeir J. Effects of probiotic bacteria and their genomic DNA on TH1/TH2-cytokine production by peripheral blood mononuclear cells (PBMCs) of healthy and allergic subjects. Immunobiology, 2008, 213: 677-692. doi: 10.1016/j.imbio.2008.02.001.Ghadimi D, Folster-Holst R, de Vrese M, Winkler P, Heller KJ, Schrezenmeir J. Effects of probiotic bacteria and their genomic DNA on TH1/TH2-cytokine production by peripheral blood mononuclear cells (PBMCs) of healthy and allergic subjects. Immunobiology, 2008, 213: 677-692. doi: 10.1016/j.imbio.2008.02.001.Lee J, Mo JH, Katakura K, Alkalay I et al. Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells. Nat Cell Biol, 2006, 8(12): 1327-1336.Lee J, Mo JH, Katakura K, Alkalay I et al. Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells. Nat Cell Biol, 2006, 8(12): 1327-1336.Yan F, Polk DB. Probiotic bacterium prevents cytokine-induced apoptosis in intestinal epithelial cells. J Biol Chem, 2002, 277: 50959-50965. doi: 10.1074/jbc.M207050200.Yan F, Polk DB. Probiotic bacterium prevents cytokine-induced apoptosis in intestinal epithelial cells. J Biol Chem, 2002, 277: 50959-50965. doi: 10.1074/jbc.M207050200.Claes IJ, Schoofs G, Regulski K et al. Genetic and Biochemical Characterization of the Cell Wall Hydrolase Activity of the Major Secreted Protein of Lactobacillus rhamnosus GG. PLoS One, 2012, 7: e31588. doi: 10.1371/journal.pone.0031588.Claes IJ, Schoofs G, Regulski K et al. Genetic and Biochemical Characterization of the Cell Wall Hydrolase Activity of the Major Secreted Protein of Lactobacillus rhamnosus GG. PLoS One, 2012, 7: e31588. doi: 10.1371/journal.pone.0031588.Yan F, Cao H, Cover TL, Whitehead R, Washington MK, Polk DB. Soluble Proteins Produced by Probiotic Bacteria Regulate Intestinal Epithelial Cell Survival and Growth. Gastroenterology, 2007, 132: 562-575. doi:10.1053/j.gastro.2006.11.022.Yan F, Cao H, Cover TL, Whitehead R, Washington MK, Polk DB. Soluble Proteins Produced by Probiotic Bacteria Regulate Intestinal Epithelial Cell Survival and Growth. Gastroenterology, 2007, 132: 562-575. doi:10.1053/j.gastro.2006.11.022.Seth A, Yan F, Polk DB, Rao RK. Probiotics ameliorate the hydrogen peroxide- induced epithelial barrier disruption by a PKC- and MAP kinase-dependent mechanism. American Journal of Physiology-Gastrointestinal and Liver Physiology, 2008, 294: G1060-G1069. doi:10.1152/ajpgi.00202.2007.Seth A, Yan F, Polk DB, Rao RK. Probiotics ameliorate the hydrogen peroxide- induced epithelial barrier disruption by a PKC- and MAP kinase-dependent mechanism. American Journal of Physiology-Gastrointestinal and Liver Physiology, 2008, 294: G1060-G1069. doi:10.1152/ajpgi.00202.2007.Yan F, Liu L, Dempsey PJ, Tsai YH et al. A Lactobacillus rhamnosus GG-derived soluble protein, p40, stimulates ligand release from intestinal epithelial cells to transactivate epidermal growth factor receptor. J Biol Chem, 2013, 288: 30742-30751. doi: 10.1074/jbc.M113.492397.Yan F, Liu L, Dempsey PJ, Tsai YH et al. A Lactobacillus rhamnosus GG-derived soluble protein, p40, stimulates ligand release from intestinal epithelial cells to transactivate epidermal growth factor receptor. J Biol Chem, 2013, 288: 30742-30751. doi: 10.1074/jbc.M113.492397.Marianelli C, Cifani N, Pasquali P. Evaluation of antimicrobial activity of probiotic bacteria against Salmonella enterica subsp. enterica serovar typhimurium 1344 in a common medium under different environmental conditions. Res Microbiol, 2010, 161: 673-680. doi:10.1016/j.resmic.2010.06.007.Marianelli C, Cifani N, Pasquali P. Evaluation of antimicrobial activity of probiotic bacteria against Salmonella enterica subsp. enterica serovar typhimurium 1344 in a common medium under different environmental conditions. Res Microbiol, 2010, 161: 673-680. doi:10.1016/j.resmic.2010.06.007.Lu R, Fasano S, Madayiputhiya N, Morin NP, Nataro J, Fasano A. Isolation, identification, and characterization of small bioactive peptides from Lactobacillus GG conditional media that exert both anti-Gram-negative and Gram-positive bactericidal activity. J Pediatr Gastroenterol Nutr, 2009, 49: 23-30. doi: 10.1097/MPG.0b013e3181924d1e.Lu R, Fasano S, Madayiputhiya N, Morin NP, Nataro J, Fasano A. Isolation, identification, and characterization of small bioactive peptides from Lactobacillus GG conditional media that exert both anti-Gram-negative and Gram-positive bactericidal activity. J Pediatr Gastroenterol Nutr, 2009, 49: 23-30. doi: 10.1097/MPG.0b013e3181924d1e.De Keersmaecker SC1, Sonck K, Vanderleyden J.Let LuxS speak up in AI-2 signaling. Trends Microbiol, 2006, 14(3): 114-119. doi: 10.1016/j.tim.2006.01.003.De Keersmaecker SC1, Sonck K, Vanderleyden J.Let LuxS speak up in AI-2 signaling. Trends Microbiol, 2006, 14(3): 114-119. doi: 10.1016/j.tim.2006.01.003.Kalliomaki M, Salminen S, Poussa T, Isolauri E. Probiotics during the first 7 years of life: a cumulative risk reduction of eczema in a randomized, placebo- controlled trial. J Allergy Clin Immunol, 2007, 119: 1019-1021. doi: 10.1016/j.jaci.2006.12.608.Kalliomaki M, Salminen S, Poussa T, Isolauri E. Probiotics during the first 7 years of life: a cumulative risk reduction of eczema in a randomized, placebo- controlled trial. J Allergy Clin Immunol, 2007, 119: 1019-1021. doi: 10.1016/j.jaci.2006.12.608.Kalliomaki M, Salminen S, Poussa T, Arvilommi H, Isolauri E. Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial. Lancet, 2003, 361: 1869-1871. doi: 10.1016/S0140-6736(03)13490-3.Kalliomaki M, Salminen S, Poussa T, Arvilommi H, Isolauri E. Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial. Lancet, 2003, 361: 1869-1871. doi: 10.1016/S0140-6736(03)13490-3.Kalliomaki M, Salminen S, Arvilommi H, Kero P, Koskinen P, Isolauri E. Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet, 2001, 357: 1076-1079.doi: 10.1016/S0140-6736(00)04259-8.Kalliomaki M, Salminen S, Arvilommi H, Kero P, Koskinen P, Isolauri E. Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet, 2001, 357: 1076-1079.doi: 10.1016/S0140-6736(00)04259-8.Kopp MV, Hennemuth I, Heinzmann A, Urbanek R. Randomized, double-blind, placebo-controlled trial of probiotics for primary prevention: no clinical effects of Lactobacillus GG supplementation. Pediatrics, 2008, 121: e850-856. doi: 10.1542/peds.2007-1492.Kopp MV, Hennemuth I, Heinzmann A, Urbanek R. Randomized, double-blind, placebo-controlled trial of probiotics for primary prevention: no clinical effects of Lactobacillus GG supplementation. Pediatrics, 2008, 121: e850-856. doi: 10.1542/peds.2007-1492.Viljanen M, Savilahti E, Haahtela T et al. Probiotics in the treatment of atopic eczema/dermatitis syndrome in infants: a double-blind placebo-controlled trial. Allergy, 2005, 60: 494-500. doi: 10.1111/j.1398-9995.2004.00514.x.Viljanen M, Savilahti E, Haahtela T et al. Probiotics in the treatment of atopic eczema/dermatitis syndrome in infants: a double-blind placebo-controlled trial. Allergy, 2005, 60: 494-500. doi: 10.1111/j.1398-9995.2004.00514.x.Pohjavuori E, Viljanen M, Korpela R et al. Lactobacillus GG effect in increasing IFNgamma production in infants with cow’s milk allergy. J Allergy Clin Immunol, 2004, 114: 131-136. doi: 10.1016/j.jaci.2004.03.036.Pohjavuori E, Viljanen M, Korpela R et al. Lactobacillus GG effect in increasing IFNgamma production in infants with cow’s milk allergy. J Allergy Clin Immunol, 2004, 114: 131-136. doi: 10.1016/j.jaci.2004.03.036.Pelto L, Isolauri E, Lilius EM, Nuutila J, Salminen S. Probiotic bacteria down- regulate the milk-induced inflammatory response in milk-hypersensitive subjects but have an immunostimulatory effect in healthy subjects. Clin Exp Allergy, 1998, 28: 1474-1479. doi: 10.1046/j.1365-2222.1998.00449.x.Pelto L, Isolauri E, Lilius EM, Nuutila J, Salminen S. Probiotic bacteria down- regulate the milk-induced inflammatory response in milk-hypersensitive subjects but have an immunostimulatory effect in healthy subjects. Clin Exp Allergy, 1998, 28: 1474-1479. doi: 10.1046/j.1365-2222.1998.00449.x.Szajewska H, Skórka A, Ruszczyński M, Gieruszczak-Białek D. Meta-analysis: Lacto bacillus GG for treating acute diarrhoea in children. Aliment Pharmacol Ther, 2007, 25(8): 871-881.Szajewska H, Skórka A, Ruszczyński M, Gieruszczak-Białek D. Meta-analysis: Lacto bacillus GG for treating acute diarrhoea in children. Aliment Pharmacol Ther, 2007, 25(8): 871-881.Szajewska H, Skórka A, Ruszczyński M, Gieruszczak-Białek D. Meta-analysis: Lactobacillus GG for treating acute gastroenteritis in children–updated analysis of randomised controlled trials. Aliment Pharmacol Ther, 2013, 38(5): 467-476. doi: 10.1111/apt.12403.Szajewska H, Skórka A, Ruszczyński M, Gieruszczak-Białek D. Meta-analysis: Lactobacillus GG for treating acute gastroenteritis in children–updated analysis of randomised controlled trials. Aliment Pharmacol Ther, 2013, 38(5): 467-476. doi: 10.1111/apt.12403.Szajewska H, Guarino A, Hojsak I et al. Use of probiotics for management of acute gastroenteritis: a position paper by the ESPGHAN Working Group for Probiotics and Prebiotics. J Pediatr Gastroenterol Nutr, 2014, 58(4): 531-539. doi: 10.1097/MPG.0000000000000320.Szajewska H, Guarino A, Hojsak I et al. Use of probiotics for management of acute gastroenteritis: a position paper by the ESPGHAN Working Group for Probiotics and Prebiotics. J Pediatr Gastroenterol Nutr, 2014, 58(4): 531-539. doi: 10.1097/MPG.0000000000000320.Diarrhoea and Vomiting Caused by Gastroenteritis: Diagnosis, Assessment and Management in Children Younger than 5 Years. NICE Clinical Guidelines, No. 84. National Collaborating Centre for Women’s and Children’s Health (UK). London: RCOG Press, 2009.Diarrhoea and Vomiting Caused by Gastroenteritis: Diagnosis, Assessment and Management in Children Younger than 5 Years. NICE Clinical Guidelines, No. 84. National Collaborating Centre for Women’s and Children’s Health (UK). London: RCOG Press, 2009.Guarner F, Khan AG, Garisch J et al. World Gastroenterology Organisation Global Guidelines: probiotics and prebiotics October 2011. J Clin Gastroenterol, 2012, 46(6): 468-481. doi: 10.1097/MCG.0b013e3182549092.Guarner F, Khan AG, Garisch J et al. World Gastroenterology Organisation Global Guidelines: probiotics and prebiotics October 2011. J Clin Gastroenterol, 2012, 46(6): 468-481. doi: 10.1097/MCG.0b013e3182549092.Johnston BC, Goldenberg JZ, Vandvik PO, Sun X, Guyatt GH. Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst Rev, 2011, 11: CD004827. doi: 10.1002/14651858.CD004827.pub3.Johnston BC, Goldenberg JZ, Vandvik PO, Sun X, Guyatt GH. Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst Rev, 2011, 11: CD004827. doi: 10.1002/14651858.CD004827.pub3.Goldenberg JZ1, Lytvyn L, Steurich J, Parkin P, Mahant S, Johnston BC. Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst Rev, 2015, 12: CD004827. doi: 10.1002/14651858.CD004827.pub4.Goldenberg JZ1, Lytvyn L, Steurich J, Parkin P, Mahant S, Johnston BC. Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst Rev, 2015, 12: CD004827. doi: 10.1002/14651858.CD004827.pub4.Wang Y, Li X, Ge T et al. Probiotics for prevention and treatment of respiratory tract infections in children: A systematic review and meta-analysis of randomized controlled trials. S. Daoud. S, ed. Medicine, 2016, 95(31): e4509. doi: 10.1097/MD.0000000000004509.Wang Y, Li X, Ge T et al. Probiotics for prevention and treatment of respiratory tract infections in children: A systematic review and meta-analysis of randomized controlled trials. S. Daoud. S, ed. Medicine, 2016, 95(31): e4509. doi: 10.1097/MD.0000000000004509.Isolauri E, Joensuu J, Suomalainen H, Luomala M, Vesikari T. Improved immunogenicity of oral D × RRV reassortant rotavirus vaccine by Lactobacillus casei GG. Vaccine, 1995, 13: 310-312. doi: 10.1016/0264-410X(95)93319-5.Isolauri E, Joensuu J, Suomalainen H, Luomala M, Vesikari T. Improved immunogenicity of oral D × RRV reassortant rotavirus vaccine by Lactobacillus casei GG. Vaccine, 1995, 13: 310-312. doi: 10.1016/0264-410X(95)93319-5.de Vrese M, Rautenberg P, Laue C, Koopmans M, Herremans T, Schrezenmeir J. Probiotic bacteria stimulate virus-specific neutralizing antibodies following a booster polio vaccination. European Journal of Nutrition, 2005, 44: 406-413. doi: 10.1007/s00394-004-0541-8.de Vrese M, Rautenberg P, Laue C, Koopmans M, Herremans T, Schrezenmeir J. Probiotic bacteria stimulate virus-specific neutralizing antibodies following a booster polio vaccination. European Journal of Nutrition, 2005, 44: 406-413. doi: 10.1007/s00394-004-0541-8.Davidson LE, Fiorino AM, Snydman DR, Hibberd PL. Lactobacillus GG as an immune adjuvant for live-attenuated influenza vaccine in healthy adults: a randomized double-blind placebocontrolled trial. Eur J Clin Nutr, 2011, 65: 501-507. doi: 10.1038/ejcn.2010.289.Davidson LE, Fiorino AM, Snydman DR, Hibberd PL. Lactobacillus GG as an immune adjuvant for live-attenuated influenza vaccine in healthy adults: a randomized double-blind placebocontrolled trial. Eur J Clin Nutr, 2011, 65: 501-507. doi: 10.1038/ejcn.2010.289.Ouwehand AC, Saxelin M, Salminen S.Phenotypic differences between commercial Lactobacillus rhamnosus GG and L. rhamnosus strains recovered from blood. Clin Infect Dis, 2004, 39: 1858-1860. doi: 10.1086/425741.Ouwehand AC, Saxelin M, Salminen S.Phenotypic differences between commercial Lactobacillus rhamnosus GG and L. rhamnosus strains recovered from blood. Clin Infect Dis, 2004, 39: 1858-1860. doi: 10.1086/425741.Sullivan A, Nord CE. Probiotic lactobacilli and bacteraemia in Stockholm. Scand J Infect Dis, 2006, 38: 327-331. doi: 10.1080/00365540500449826.Sullivan A, Nord CE. Probiotic lactobacilli and bacteraemia in Stockholm. Scand J Infect Dis, 2006, 38: 327-331. doi: 10.1080/00365540500449826.Luoto R, Isolauri E, Lehtonen L. Safety of Lactobacillus GG probiotic in infants with very low birth weight: twelve years of experience. Clin Infect Dis, 2010, 50: 1327-1328. doi: 10.1086/651694.Luoto R, Isolauri E, Lehtonen L. Safety of Lactobacillus GG probiotic in infants with very low birth weight: twelve years of experience. Clin Infect Dis, 2010, 50: 1327-1328. doi: 10.1086/651694.Boyle RJ, Mah LJ, Chen A, Kivivuori S, Robins-Browne RM, Tang ML. Effects of Lactobacillus GG treatment during pregnancy on the development of fetal antigen-specific immune responses. Clin Exp Allergy, 2008, 38: 1882-1890. doi: 10.1111/j.1365-2222.2008.03100.x.Boyle RJ, Mah LJ, Chen A, Kivivuori S, Robins-Browne RM, Tang ML. Effects of Lactobacillus GG treatment during pregnancy on the development of fetal antigen-specific immune responses. Clin Exp Allergy, 2008, 38: 1882-1890. doi: 10.1111/j.1365-2222.2008.03100.x.Salminen MK, Tynkkynen S, Rautelin H et al. The efficacy and safety of probiotic Lactobacillus rhamnosus GG on prolonged, noninfectious diarrhea in HIV Patients on antiretroviral therapy: a randomized, placebo-controlled, crossover study. HIV Clin Trials, 2004, 5: 183-191. doi: 10.1310/6F83-N39Q-9PPP-LMVV.Salminen MK, Tynkkynen S, Rautelin H et al. The efficacy and safety of probiotic Lactobacillus rhamnosus GG on prolonged, noninfectious diarrhea in HIV Patients on antiretroviral therapy: a randomized, placebo-controlled, crossover study. HIV Clin Trials, 2004, 5: 183-191. doi: 10.1310/6F83-N39Q-9PPP-LMVV.Nissilä E, Douillard FP, Ritari J et al. Genotypic and phenotypic diversity of Lactobacillus rhamnosus clinical isolates, their comparison with strain GG and their recognition by complement system. PLoS ONE, 2017, 12(5): e0176739. https://doi.org/10.1371/journal.pone.0176739.Nissilä E, Douillard FP, Ritari J et al. Genotypic and phenotypic diversity of Lactobacillus rhamnosus clinical isolates, their comparison with strain GG and their recognition by complement system. PLoS ONE, 2017, 12(5): e0176739. https://doi.org/10.1371/journal.pone.0176739.

The authors declare that there are no conflicts of interest present.