mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-IVE-2622mimmun-2622Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESВлияние кишечных микросимбионтов на продукцию цитокинов в системе in vitroIn vitro effects of intestinal microsymbionts on the cytokine productionБухаринО. В.BukharinO. V.

Бухарин Олег В. – доктор медицинских наук, академик РАН, научный руководитель.

Оренбург

Oleg V. Bukharin - PhD, MD (Medicine), Full Member, Russian Academy of Sciences, Research Director, Institute of Cellular and Intracellular Symbiosis, Orenburg Federal Research Center, Ural Branch, Russian Academy of Sciences.

Orenburg

ofrc@list.ruИвановаЕ. В.IvanovaE. V.

Иванова Елена Валерьевна – доктор медицинских наук, доцент, ведущий научный сотрудник лаборатории инфекционной симбиологии.

460000, Оренбург, ул. Пионерская, 11

Тел.: 8 (3532) 77-26-19

Elena V. Ivanova - PhD, MD (Medicine), Associate Professor, Leading Research Associate, Laboratory of Infectious Symbiology, Institute of Cellular and Intracellular Symbiosis, Orenburg Federal Research Center, Ural Branch, Russian Academy of Sciences.

11 Pionerskaya St Orenburg 460000

Phone: +7 (3532) 77-26-19

walerewna13@gmail.comЧайниковаИ. Н.ChaynikovaI. N.

Чайникова Ирина Н. – доктор медицинских наук, профессор, ведущий научный сотрудник лаборатории инфекционной симбиологии.

Оренбург

Irina N. Chaynikova - PhD, MD (Medicine), Professor, Leading Research Associate, Laboratory of Infectious Symbiology, Institute of Cellular and Intracellular Symbiosis, Orenburg Federal Research Center, Ural Branch, Russian Academy of Sciences.

Orenburg

inchainicova@yandex.ruПеруноваН. Б.PerunovaN. B.

Перунова Наталья Б. – доктор медицинских наук, профессор РАН, ведущий научный сотрудник лаборатории инфекционной симбиологии.

Оренбург

Natalya B. Perunova - PhD, MD (Medicine), Professor, Russian Academy of Sciences, Leading Research Associate, Laboratory of Infectious Symbiology, Institute of Cellular and Intracellular Symbiosis, Orenburg Federal Research Center, Ural Branch, Russian Academy of Sciences.

Orenburg

perunovanb@gmail.comНикифоровИ. А.NikiforovI. A.

Никифоров Игорь А. – кандидат геолого-минералогических наук, ведущий научный сотрудник лаборатории инфекционной симбиологии.

Оренбург

Igor A. Nikiforov - PhD (Geology), Leading Research Associate, Laboratory of Infectious Symbiology, Institute of Cellular and Intracellular Symbiosis, Orenburg Federal Research Center, Ural Branch, Russian Academy of Sciences.

Orenburg

ofrc@list.ruЧелпаченкоО. Е.ChelpachenkoO. E.

Челпаченко Ольга Е. – доктор медицинских наук, профессор, ведущий научный сотрудник лаборатории инфекционной симбиологии.

Оренбург

Olga E. Chelpachenko - PhD, MD (Medicine), Professor, Leading Research Associate, Laboratory of Infectious Symbiology, Institute of Cellular and Intracellular Symbiosis, Orenburg Federal Research Center, Ural Branch, Russian Academy of Sciences.

Orenburg

oech57@gmail.comБондаренкоТ. А.BondarenkoT. A.

Бондаренко Таисия А. – научный сотрудник лаборатории инфекционной симбиологии.

Оренбург

Taisiya A. Bondarenko - Research Associate, Laboratory of Infectious Symbiology, Institute of Cellular and Intracellular Symbiosis, Orenburg Federal Research Center, Ural Branch, Russian Academy of Sciences.

Orenburg

semenovih88@mail.ruБекпергеноваА. В.BekpergenovaA. V.

Бекпергенова Анастасия В. – кандидат биологических наук, старший научный сотрудник лаборатории инфекционной симбиологии.

Оренбург

Anastasia V. Bekpergenova - PhD (Biology), Senior Research Associate, Laboratory of Infectious Symbiology, Institute of Cellular and Intracellular Symbiosis, Orenburg Federal Research Center, Ural Branch, Russian Academy of Sciences.

Orenburg

nsavasteeva@gmail.comИнститут клеточного и внутриклеточного симбиоза Уральского отделения Российской академии наук ФГБУН «Оренбургский федеральный исследовательский центр» Уральского отделения Российской академии наукРоссияInstitute of Cellular and Intracellular Symbiosis, Orenburg Federal Research Center, Ural Branch, Russian Academy of SciencesRussian Federation20231710202325613711388Copyright © Бухарин О.В., Иванова Е.В., Чайникова И.Н., Перунова Н.Б., Никифоров И.А., Челпаченко О.Е., Бондаренко Т.А., Бекпергенова А.В., 20232023Бухарин О.В., Иванова Е.В., Чайникова И.Н., Перунова Н.Б., Никифоров И.А., Челпаченко О.Е., Бондаренко Т.А., Бекпергенова А.В.Bukharin O.V., Ivanova E.V., Chaynikova I.N., Perunova N.B., Nikiforov I.A., Chelpachenko O.E., Bondarenko T.A., Bekpergenova A.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.mimmun.ru/mimmun/article/view/2622

В сохранении иммунного гомеостаза кишечника важнейшая роль принадлежит иммунорегуляторным свойствам микробиоты, которая, взаимодействуя с образраспознающими рецепторами, активирует внутриклеточные сигнальные системы, экспрессию цитокинов, продукцию протективных факторов и ограничивает воспалительные реакции в кишечнике. Итог взаимодействий микробиоты и клеток хозяина (развитие воспалительного процесса или поддержание кишечного гомеостаза) зависит от многих факторов, включая потенциальную способность кишечных комменсалов влиять на цитокиновую сеть организма человека. При нарушении количественных и качественных характеристик микробиоты (дисбиоз) цитокиновый баланс, формируемый за счет влияния кишечных микросимбионтов и их метаболитов на иммунные и эпителиальные клетки кишечника, может изменяться, способствуя развитию различной патологии человека. Целью данного исследования явилась оценка иммунорегуляторных свойств эубиотических и дисбиотических кишечных микросимбионтов человека по влиянию их бесклеточных супернатантов на продукцию цитокинов в системе in vitro. Исследование было проведено на 49 эубиотических и 77 дисбиотических штаммах микроорганизмов, выделенных от условно здоровых пациентов, обследуемых на дисбиоз толстого кишечника. Для оценки иммунорегуляторных свойств кишечных микросимбионтов изучено влияние бесклеточных супернатантов исследуемых культур бактерий и грибов на продукцию про- (IFNγ, TNFα, IL-17, IL-8, IL-6) и противовоспалительных (IL-10, IL-1ra) цитокинов, секретируемых мононуклеарными клетками периферической крови здоровых людей. Микробиоту кишечника исследовали бактериологичеким методом. Идентификацию выделенных микробных культур проводили с помощью MALDI TOF MS серии Microflex LT (Bruker Daltoniсs, Германия). Уровень цитокинов определяли иммуноферментным методом с использованием коммерческих тест-систем («Цитокин», Россия). Статистический анализ включал: дискриминантный анализ, классификационное дерево решений и метод картирования равнодействующих. Применение многомерного статистического анализа позволило определить круг наиболее информативных показателей (среди цитокинов и микробных культур, изменяющих их продукцию) для оценки состояния гомеостаза при эу- и дисбиозе кишечника. Установлено, что супернатанты эубиотических культур кишечных симбионтов характеризовались выраженной способностью ингибировать уровень провоспалительных цитокинов: IFNγ, IL-8 и стимулировать секрецию противовоспалительного цитокина (IL-10), а дисбиотические культуры – преимущественно индуцировали провоспалительные цитокины IL-17, IFNγ, TNFα. В сохранение равномерного баланса между про- и противовоспалительными цитокинами при эубиозе вносили значимый вклад как ассоциации микросимбионтов (по мере убывания уровня факторных нагрузок: Bacteroides spp. > E. coli > Lactobacillus spp.), так и монокультуры (Bifidobacterium spp. и Lactobacillus spp.), через индукцию IL-10. При дисбиозе кишечника увеличивалось количество ассоциаций микросимбионтов, индуцирующих секрецию провоспалительных цитокинов. Провоспалительный профиль дисбиотических культур формировался через влияние на продукцию IFNγ (по мере убывания уровня факторных нагрузок) ассоциаций Bifidobacterium spp. > Enterococcus spp. > E. coli > Lactobacillus spp., а также ассоциации S. aureus > Candida spp. На секрецию IL-17 влияли монокультура Clostridium spp. и ассоциация C. acnes > S. aureus > Klebsiella spp., на TNFα – монокультуры бифидобактерий и эшерихий. Таким образом, при эубиозе нормобиота поддерживает равномерный баланс про- и противовоспалительных цитокинов, а при дисбиозе кишечника может происходить смещение баланса цитокинов в сторону провоспалительных за счет усиления уровня их секреции, расширения спектра данной группы цитокинов и увеличения количества моно- и ассоциаций микробных культур, влияющих на их продукцию.

The most important role in homeostasis of intestinal immune belongs to the immunoregulatory properties of the microbiota which activates intracellular signaling systems, cytokine expression, production of protective factors and limits inflammatory reactions in the intestine by interacting with the pattern recognition receptors. The outcome of interactions between the microbiota and host cells (development of an inflammatory process or maintenance of intestinal homeostasis) depends on many factors, including a potential ability of intestinal commensals to influence the cytokine network in human body. Due to disturbances of quantitative and qualitative microbiota profile (dysbiosis), the cytokine balance may be changed by the influence of intestinal microsymbionts and their metabolites on immune and epithelial cells of intestines, thus contributing to the development of various human disorders. The aim of this study was to evaluate the immunoregulatory properties of eubiotic and dysbiotic human intestinal microsymbionts by assessing the effects of their cell-free supernatants on cytokine production in the in vitro system. The study was conducted on 49 eubiotic and 77 dysbiotic strains of microorganisms isolated from conditionally healthy patients examined for colon dysbiosis. To assess immunoregulatory properties of intestinal microsymbionts, we studied the effects of cell-free supernatants from bacterial and fungal cultures up on production of proinflammatory (IFNγ, TNFα, IL-17, IL-8, IL-6) and anti-inflammatory (IL-10, IL-1ra) cytokines secreted by mononuclear cells isolated from peripheral blood of healthy persons. The intestinal microbiota was determined by bacteriological methods. Identification of isolated microbial cultures was performed using MALDI TOF MS Microflex LT series (Bruker Daltonics, Germany). The level of cytokines was determined by enzyme immunoassay using commercial test systems (“Cytokine”, Russia). Statistical evaluation included discriminant analysis, classification decision tree and resultant mapping method. The multivariate statistical analysis enabled us to determine the range of the most informative indexes among cytokines and microbial cultures that changing their production in order to assess the state of homeostasis in eubiosis and intestinal dysbiosis. It was found that the supernatants of eubiotic cultures of intestinal symbionts exhibited a pronounced ability to inhibit the level of pro-inflammatory cytokines (IFNγ, IL-8) and to stimulate the secretion of anti-inflammatory cytokine (IL-10), whereas the dysbiotic cultures predominantly induced pro-inflammatory cytokines (IL-17, IFNγ, TNFα). In maintaining a uniform balance between pro- and anti-inflammatory cytokines during eubiosis, both associations of microsymbionts (in descending order of factor loads): Bacteroides spp. > E. coli > Lactobacillus spp.), and monocultures (Bifidobacterium spp. and Lactobacillus spp.) made a significant contribution via IL-10 induction. In cases of intestinal dysbiosis, we found an increased number of associations between microsymbionts inducing secretion of pro-inflammatory cytokines was. The pro-inflammatory profile of dysbiotic cultures was determined by the influence on IFNγ production (ranged in descending order of factor loads) of Bifidobacterium spp. > Enterococcus spp. > E. coli > Lactobacillus spp. associations, as well as S. aureus > Candida spp associations. The secretion of IL-17 was influenced by the monoculture of Clostridium spp., and by association C. acnes > S. aureus > Klebsiella spp. Monocultures of Bifidobacteria and Escherichia exerted effects upon TNFα production. Thus, during eubiotic state, the normobiota maintains a uniform balance of pro- and anti-inflammatory cytokines, and, in presence of intestinal dysbiosis, a shift in the balance of cytokines towards pro-inflammatory ones may occur due to increased levels of their secretion, an expanded spectrum of cytokines from this group, and increased number of single bacteria and associations of microbial cultures affecting their production.

кишечные микросимбионтыпровоспалительные цитокиныпротивовоспалительные цитокиныэубиоздисбиозметоды многомерной статистикиintestinal microsymbiontspro-inflammatory cytokinesanti-inflammatory cytokineseubiosisdysbiosismultivariate statistical analysisReferencesАверина О.В., Ермоленко Е.И., Ратушный А.Ю., Тарасова Е.А., Борщев Ю.Ю., Леонтьева Г.Ф., Крамская Т.А., Котылева М.П., Даниленко В.Н., Суворов А.Н. Влияние пробиотиков на продукцию цитокинов в системах in vitro и in vivo // Медицинская иммунология, 2015. Т. 17, № 5. С. 443-454. doi:10.15789/1563-0625-2015-5-443-454.Averina O.V., Ermolenko E.I., Ratushniy A.Yu., Tarasova E.A., Borschev Yu.Yu., Leontieva G.F., Kramskaya T.A., Kotyleva M.P., Danilenko V.N., Suvorov A.N. Influence of probiotics on cytokine production in the in vitro and in vivo systems. Meditsinskaya immunologiya = Medical Immunology (Russia), 2015, Vol. 17, no. 5, pp. 443-454. (In Russ.) doi:10.15789/1563-0625-2015-5-443-454.Бухарин О.В., Перунова Н.Б. Микрoсимбиоценоз. Екатеринбург: УрО РАН, 2014. 257 с.Bukharin O.V., Perunova N.B. Microsymbiocenosis.Yekaterinburg: Ural Branch of the Russian Academy of Sciences, 2014. 257 p.Бухарин О.В., Лобакова Е.С., Немцева Н.В., Черкасов С.В. Ассоциативный симбиоз. Екатеринбург: УрО РАН, 2007. 264 с.Bukharin O.V., Lobakova E.S., Nemtseva N.V., Cherkasov S.V. Associative symbiosis Yekaterinburg: Ural Branch of the Russian Academy of Sciences, 2007. 264 p.Бухарин О.В., Иванова Е.В., Перунова Н.Б., Чайникова И.Н. Роль бифидобактерий в формировании иммунного гомеостаза человека // Журнал микробиологии, эпидемиологии и иммунобиологии, 2015.№ 6. С. 98-104.Bukharin O.V., Ivanova E.V., Perunova N.B., Chaynikova I.N. The role of bifidobacteria in the formation of human immune homeostasis. Zhurnal mikrobiologii, epidemiologii i immunobiologii = Journal of Microbiology, Epidemiology and Immunobiology, 2015, no. 6, pp. 98-104. (In Russ.)Бухарин О.В., Иванова Е.В., Перунова Н.Б., Чайникова И.Н., Андрющенко С.В. Метаболический профиль бифидофлоры при различных микроэкологических состояниях биотопа толстого кишечника человека // Журнал микробиологии, эпидемиологии и иммунобиологии, 2017.Т. 94, № 1. С. 3-11.Bukharin O.V., Ivanova E.V., Perunova N.B., Chaynikova I.N., Andryushchenko S.V. Metabolic profile of bifidoflora in various microecological conditions of human colon biotope. Zhurnal mikrobiologii, epidemiologii i immunobiologii = Journal of Microbiology, Epidemiology and Immunobiology, 2017, Vol. 94, no. 1, pp. 3-11. (In Russ.)Годовалов А.П., Карпунина Т.И. Влияние полиаминов бактериального происхождения на продукцию ключевых цитокинов в культуре мононуклеарных лейкоцитов человека // Медицинская иммунология, 2022. Т. 24, № 2. С. 257-262. doi: 10.15789/1563-0625-IOP-2399.Godovalov A.P., Karpunina T.I. Influence of polyamines of bacterial origin on the production of key cytokines in the culture of human mononuclear leukocytes. Meditsinskaya immunologiya = Medical Immunology (Russia), 2022, Vol. 24, no. 2, pp. 257-262. (In Russ.) doi: 10.15789/1563-0625-IOP-2399.Демидова Т.Ю., Лобанова К.Г., Ойноткинова О.Ш. Кишечная микробиота как фактор риска развития ожирения и сахарного диабета 2-го типа // Терапевтический архив, 2020. Т. 92, № 10. С. 97-104.Demidova T.Yu., Lobanova K.G., Oynotkinova O.Sh. Intestinal microbiota as a risk factor for the development of obesity and type 2 diabetes mellitus. Terapevticheskiy arkhiv = Therapeutic Archive, 2020, Vol. 92, no. 10, pp. 97-104. (In Russ.)Киселева Е.П. Акцептивный иммунитет – основа симбиотических взаимоотношений // Инфекция и иммунитет, 2015. Т. 5, № 2. C. 113-130. doi: 10.15789/2220-7619-2015-2-113-130.Kiseleva E.P. Acceptive immunity – a basis for symbiotic relationships. Infektsiya i immunitet = Russian Journal of Infection and Immunity, 2015, Vol. 5, no. 2. pp. 113-130. (In Russ.) doi: 10.15789/2220-7619-2015-2-113-130.Лукичев Б.Г., Румянцев А.Ш., Акименко В. Микробиота кишечника и хроническая болезнь почек. Сообщение первое // Нефрология, 2018. Т. 22, № 4. С. 57-73.Lukichev B.G., Rumyantsev A.S., Akimenko V. Colonic microbiota and chronic kidney disease. message one. Nefrologiya = Nephrology,2018, Vol. 22, no. 4, pp. 57-73. (In Russ.)Семинский И.Ж., Серебренникова С.Н., Гузовская Е.В. Роль цитокинов в патогенезе заболеваний // Сибирский медицинский журнал (Иркутск), 2015. Т. 132, № 1. С. 14-17.Seminsky I.Zh., Serebrennikova S.N., Guzovskaya E.V. The role of cytokines in the pathogenesis of diseases. Sibirskiy meditsinskiy zhurnal (Irkutsk) = Siberian Medical Journal (Irkutsk), 2014, Vol. 131, no. 8, pp. 30-33. (In Russ.)Симбирцев А.С. Цитокины в патогенезе и лечении заболеваний человека. СПб.: Фолиант, 2018. 512 с.Simbirtsev A.S. Cytokines in the pathogenesis and treatment of human diseases. St. Petersburg: Foliant, 2018. 512 p.Abe K., Takahashi A., Fujita M., Imaizumi H., Hayashi M., Okai K., Ohira H. Dysbiosis of oral microbiota and its association with salivary immunological biomarkers in autoimmune liver disease. PLoS One, 2018, Vol. 13, no. 7, e0198757. doi: 10.1371/journal.pone.0198757.Abe K., Takahashi A., Fujita M., Imaizumi H., Hayashi M., Okai K., Ohira H. Dysbiosis of oral microbiota and its association with salivary immunological biomarkers in autoimmune liver disease. PLoS One, 2018, Vol. 13, no. 7, e0198757. doi: 10.1371/journal.pone.0198757.Al Bander Z., Nitert M.D., Mousa A., Naderpoor N. The gut microbiota and inflammation: An overview. Int. J. Environ. Res. Public Health, 2020, Vol. 17, no. 20, 7618. doi: 10.3390/ijerph17207618.Al Bander Z., Nitert M.D., Mousa A., Naderpoor N. The gut microbiota and inflammation: An overview. Int. J. Environ. Res. Public Health, 2020, Vol. 17, no. 20, 7618. doi: 10.3390/ijerph17207618.Allaire J.M., Crowley S.M., Law H.T., Chang S.Y., Ko H.J., Vallance B.A. The intestinal epithelium: central coordinator of mucosal immunity. Trends Immunol., 2018, Vol. 39, no. 9, pp. 677-696.Allaire J.M., Crowley S.M., Law H.T., Chang S.Y., Ko H.J., Vallance B.A. The intestinal epithelium: central coordinator of mucosal immunity. Trends Immunol., 2018, Vol. 39, no. 9, pp. 677-696.Andrews C., McLean M.H., Durum S.K. Cytokine tuning of intestinal epithelial function. Front. Immunol., 2018, Vol. 9, 1270. doi: 10.3389/fimmu.2018.01270.Andrews C., McLean M.H., Durum S.K. Cytokine tuning of intestinal epithelial function. Front. Immunol., 2018, Vol. 9, 1270. doi: 10.3389/fimmu.2018.01270.Badi S.A., Khatami S.H., Irani S.H., Siadat S.D. Induction Effects of bacteroides fragilis derived outer membrane vesicles on Toll like receptor 2, Toll like receptor 4 genes expression and cytokines concentration in human intestinal epithelial cells. Cell J., 2019, Vol. 21, no. 1, pp. 57-61.Badi S.A., Khatami S.H., Irani S.H., Siadat S.D. Induction Effects of bacteroides fragilis derived outer membrane vesicles on Toll like receptor 2, Toll like receptor 4 genes expression and cytokines concentration in human intestinal epithelial cells. Cell J., 2019, Vol. 21, no. 1, pp. 57-61.Caffaratti C., Plazy C., Mery G., Tidjani A.R., Fiorini F., Thiroux S., Toussaint B., Hannani D., le Gouellec A. What we know so far about the metabolite-mediated microbiota-intestinal immunity dialogue and how to hear the sound of this crosstalk. Metabolites, 2021, Vol. 11, no. 6, 406. doi: 10.3390/metabo11060406.Caffaratti C., Plazy C., Mery G., Tidjani A.R., Fiorini F., Thiroux S., Toussaint B., Hannani D., le Gouellec A. What we know so far about the metabolite-mediated microbiota-intestinal immunity dialogue and how to hear the sound of this crosstalk. Metabolites, 2021, Vol. 11, no. 6, 406. doi: 10.3390/metabo11060406.Ciesielska A. TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling. Cell Mol. Life Sci., 2021, Vol. 78, no. 4, pp. 1233-1261.Ciesielska A. TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling. Cell Mol. Life Sci., 2021, Vol. 78, no. 4, pp. 1233-1261.Coquant G., Aguanno D., Brot L., Belloir C., Delugeard J., Roger N., Pham H.P., Briand L., Moreau M., de Sordi L., Carrière V., Grill J.P., Thenet S., Seksik P. 3-oxo-C12:2-HSL, quorum sensing molecule from human intestinal microbiota, inhibits pro-inflammatory pathways in immune cells via bitter taste receptors. Sci. Rep., 2022, Vol. 12, no. 1, 9440. doi: 10.1038/s41598-022-13451-3.Coquant G., Aguanno D., Brot L., Belloir C., Delugeard J., Roger N., Pham H.P., Briand L., Moreau M., de Sordi L., Carrière V., Grill J.P., Thenet S., Seksik P. 3-oxo-C12:2-HSL, quorum sensing molecule from human intestinal microbiota, inhibits pro-inflammatory pathways in immune cells via bitter taste receptors. Sci. Rep., 2022, Vol. 12, no. 1, 9440. doi: 10.1038/s41598-022-13451-3.Duary R.K., Batish V.K., Grover S. Immunomodulatory activity of two potential probiotic strains in LPS-stimulated HT-29 cells. Genes Nutr., 2014, Vol. 9, no. 3, 398. doi: 10.1007/s12263-014-0398-2.Duary R.K., Batish V.K., Grover S. Immunomodulatory activity of two potential probiotic strains in LPS-stimulated HT-29 cells. Genes Nutr., 2014, Vol. 9, no. 3, 398. doi: 10.1007/s12263-014-0398-2.Dyakov I.N., Mavletova D.A., Chernyshova I.N., Snegireva N.A., Gavrilova M.V., Bushkova K.K., Dyachkova M.S., Alekseeva M.G., Danilenko V.N. FN3 protein fragment containing two type III fibronectin domains from B. longum GT15 binds to human tumor necrosis factor alpha in vitro. Anaerobe, 2020, Vol. 65, 102247. doi: 10.1016/j.anaerobe.2020.102247.Dyakov I.N., Mavletova D.A., Chernyshova I.N., Snegireva N.A., Gavrilova M.V., Bushkova K.K., Dyachkova M.S., Alekseeva M.G., Danilenko V.N. FN3 protein fragment containing two type III fibronectin domains from B. longum GT15 binds to human tumor necrosis factor alpha in vitro. Anaerobe, 2020, Vol. 65, 102247. doi: 10.1016/j.anaerobe.2020.102247.Gao J., Xu K., Liu H., Liu G., Bai M., Peng C., Li T., Yin Y. Impact of the gut microbiota on intestinal immunity mediated by tryptophan metabolism. Front. Cell. Infect. Microbiol., 2018, Vol. 8, 13. doi: 10.3389/fcimb.2018.00013.Gao J., Xu K., Liu H., Liu G., Bai M., Peng C., Li T., Yin Y. Impact of the gut microbiota on intestinal immunity mediated by tryptophan metabolism. Front. Cell. Infect. Microbiol., 2018, Vol. 8, 13. doi: 10.3389/fcimb.2018.00013.Guzmán-Mejía F., Godínez-Victoria M., Vega-Bautista A., Pacheco-Yépez J., Drago-Serrano M.E. Intestinal homeostasis under stress siege. Int. J. Mol. Sci., 2021, Vol.22, no. 10, 5095. doi: 10.3390/ijms22105095.Guzmán-Mejía F., Godínez-Victoria M., Vega-Bautista A., Pacheco-Yépez J., Drago-Serrano M.E. Intestinal homeostasis under stress siege. Int. J. Mol. Sci., 2021, Vol.22, no. 10, 5095. doi: 10.3390/ijms22105095.Harrison O.J., Powrie F.M. Regulatory T cells and immune tolerance in the intestine. Cold Spring Harb. Perspect. Biol., 2013, Vol. 5, no. 7, a018341. doi: 10.1101/cshperspect.a018341.Harrison O.J., Powrie F.M. Regulatory T cells and immune tolerance in the intestine. Cold Spring Harb. Perspect. Biol., 2013, Vol. 5, no. 7, a018341. doi: 10.1101/cshperspect.a018341.Hills R.D. Jr, Pontefract B.A., Mishcon H.R., Black C.A., Sutton S.C., Theberge C.R. Gut microbiome: profound implications for diet and disease. Nutrients, 2019, Vol. 11, no. 7, 1613. doi: 10.3390/nu11071613.Hills R.D. Jr, Pontefract B.A., Mishcon H.R., Black C.A., Sutton S.C., Theberge C.R. Gut microbiome: profound implications for diet and disease. Nutrients, 2019, Vol. 11, no. 7, 1613. doi: 10.3390/nu11071613.Holden V.I., Breen P., Houle S., Dozois C.M., Bachman M.A. Klebsiella pneumoniae siderophores induce inflammation, bacterial dissemination, and HIF-1α stabilization during pneumonia. mBio, 2016, Vol. 7, no. 5, e01397-16. doi: 10.1128/mBio.01397-16.Holden V.I., Breen P., Houle S., Dozois C.M., Bachman M.A. Klebsiella pneumoniae siderophores induce inflammation, bacterial dissemination, and HIF-1α stabilization during pneumonia. mBio, 2016, Vol. 7, no. 5, e01397-16. doi: 10.1128/mBio.01397-16.Hsieh C.Y., Osaka T., Moriyama E., Date Y., Kikuchi J., Tsuneda S. Strengthening of the intestinal epithelial tight junction by bifidobacterium bifidum. Physiol. Rep., 2015, Vol. 3, e12327. doi: 10.14814/phy2.12327.Hsieh C.Y., Osaka T., Moriyama E., Date Y., Kikuchi J., Tsuneda S. Strengthening of the intestinal epithelial tight junction by bifidobacterium bifidum. Physiol. Rep., 2015, Vol. 3, e12327. doi: 10.14814/phy2.12327.Iacob S., Iacob D.G. Infectious threats, the intestinal barrier, and its trojan horse: dysbiosis. Front Microbiol., 2019, Vol. 10, 1676. doi: 10.3389/fmicb.2019.01676.Iacob S., Iacob D.G. Infectious threats, the intestinal barrier, and its trojan horse: dysbiosis. Front Microbiol., 2019, Vol. 10, 1676. doi: 10.3389/fmicb.2019.01676.Kayama H., Takeda K. Manipulation of epithelial integrity and mucosal immunity by host and microbiota-derived metabolites. Eur. J. Immunol., 2020, Vol. 50, no. 7, pp. 921-931.Kayama H., Takeda K. Manipulation of epithelial integrity and mucosal immunity by host and microbiota-derived metabolites. Eur. J. Immunol., 2020, Vol. 50, no. 7, pp. 921-931.Laffont S., Siddiqui K.R., Powrie F. Intestinal inflammation abrogates the tolerogenic properties of MLN CD103+ dendritic cells. Eur. J. Immunol., 2010, Vol. 40, no. 7, pp. 1877-1883.Laffont S., Siddiqui K.R., Powrie F. Intestinal inflammation abrogates the tolerogenic properties of MLN CD103+ dendritic cells. Eur. J. Immunol., 2010, Vol. 40, no. 7, pp. 1877-1883.Lederberg J. Infectious history. Science, 2000, Vol. 288, no. 5464, pp. 287-293.Lederberg J. Infectious history. Science, 2000, Vol. 288, no. 5464, pp. 287-293.Liu T., Wang S., Wornow M., Altman R.B. Construction of disease-specific cytokine profiles by associating disease genes with immune responses. PLoS Comput. Biol., 2022, Vol. 18, no. 4, e1009497. doi: 10.1371/journal.pcbi.1009497.Liu T., Wang S., Wornow M., Altman R.B. Construction of disease-specific cytokine profiles by associating disease genes with immune responses. PLoS Comput. Biol., 2022, Vol. 18, no. 4, e1009497. doi: 10.1371/journal.pcbi.1009497.Liu M., Nieuwdorp M., de Vos W.M., Rampanelli E. Microbial tryptophan metabolism tunes host immunity, metabolism, and extraintestinal disorders. Metabolites, 2022, Vol. 12, no. 9, 834. doi: 10.3390/metabo12090834.Liu M., Nieuwdorp M., de Vos W.M., Rampanelli E. Microbial tryptophan metabolism tunes host immunity, metabolism, and extraintestinal disorders. Metabolites, 2022, Vol. 12, no. 9, 834. doi: 10.3390/metabo12090834.Lo B.C., Chen G.Y., Núñez G., Caruso R. Gut microbiota and systemic immunity in health and disease. Int. Immunol., 2021, Vol. 33, no. 4, pp. 197-209.Lo B.C., Chen G.Y., Núñez G., Caruso R. Gut microbiota and systemic immunity in health and disease. Int. Immunol., 2021, Vol. 33, no. 4, pp. 197-209.Martin-Gallausiaux C., Béguet-Crespel F., Marinelli L., Jamet A., Ledue F., Blottière H.M., Lapaque N. Butyrate produced by gut commensal bacteria activates TGF-beta1 expression through the transcription factor SP1 in human intestinal epithelial cells. Sci Rep., 2018, Vol. 8, no. 1, 9742. doi: 10.1038/s41598-018-28048-y.Martin-Gallausiaux C., Béguet-Crespel F., Marinelli L., Jamet A., Ledue F., Blottière H.M., Lapaque N. Butyrate produced by gut commensal bacteria activates TGF-beta1 expression through the transcription factor SP1 in human intestinal epithelial cells. Sci Rep., 2018, Vol. 8, no. 1, 9742. doi: 10.1038/s41598-018-28048-y.Martin-Gallausiaux C., Marinelli L., Blottière H.M., Larraufie P., Lapaque N. SCFA: mechanisms and functional importance in the gut. Proc. Nutr. Soc., 2021, Vol. 80, no. 1, pp. 37-49.Martin-Gallausiaux C., Marinelli L., Blottière H.M., Larraufie P., Lapaque N. SCFA: mechanisms and functional importance in the gut. Proc. Nutr. Soc., 2021, Vol. 80, no. 1, pp. 37-49.Nezametdinova V.Z., Mavletova D.A., Alekseeva M.G., Chekalina M.S., Zakharevich N.V., Danilenko V.N. Species-specific ser-ine-threonine protein kinase Pkb2 of bifidobacterium longum subsp. Longum: genetic environment and substrate specificity. Anaerobe, 2018, Vol. 51, pp. 26-35.Nezametdinova V.Z., Mavletova D.A., Alekseeva M.G., Chekalina M.S., Zakharevich N.V., Danilenko V.N. Species-specific ser-ine-threonine protein kinase Pkb2 of bifidobacterium longum subsp. Longum: genetic environment and substrate specificity. Anaerobe, 2018, Vol. 51, pp. 26-35.Nezametdinova V.Z., Yunes R.A., Dukhinova M.S., Alekseeva M.G., Danilenko V.N. The role of the PFNA operon of bifidobacteria in the recognition of host’s immune signals: prospects for the use of the FN3 protein in the treatment of COVID-19. Int. J. Mol. Sci., 2021, Vol. 22, no. 17, 9219. doi: 10.3390/ijms22179219.Nezametdinova V.Z., Yunes R.A., Dukhinova M.S., Alekseeva M.G., Danilenko V.N. The role of the PFNA operon of bifidobacteria in the recognition of host’s immune signals: prospects for the use of the FN3 protein in the treatment of COVID-19. Int. J. Mol. Sci., 2021, Vol. 22, no. 17, 9219. doi: 10.3390/ijms22179219.Nicolas G.R., Chang P.V. Deciphering the chemical lexicon of host-gut microbiota interactions. Trends Pharmacol. Sci., 2019, Vol. 40, no. 6, pp. 430-445.Nicolas G.R., Chang P.V. Deciphering the chemical lexicon of host-gut microbiota interactions. Trends Pharmacol. Sci., 2019, Vol. 40, no. 6, pp. 430-445.Nikiforov I.A. Geochemical classification by means of mapping resultants. Geochem. Int., 2014, Vol. 52, no. 4, pp. 325-332.Nikiforov I.A. Geochemical classification by means of mapping resultants. Geochem. Int., 2014, Vol. 52, no. 4, pp. 325-332.Nogacka A.M., Oddi S., Salazar N., Reinheimer J.A., Gueimonde M., Vinderola G., de Los Reyes-Gavilán C.G. Intestinal immunomodulation and shifts on the gut microbiota of BALB/c mice promoted by two bifidobacterium and lactobacillus strains isolated from human samples. Biomed Res. Int., 2019, Vol. 2019, 323540. doi: 10.1155/2019/2323540.Nogacka A.M., Oddi S., Salazar N., Reinheimer J.A., Gueimonde M., Vinderola G., de Los Reyes-Gavilán C.G. Intestinal immunomodulation and shifts on the gut microbiota of BALB/c mice promoted by two bifidobacterium and lactobacillus strains isolated from human samples. Biomed Res. Int., 2019, Vol. 2019, 323540. doi: 10.1155/2019/2323540.Perrotta G. The intestinal microbiota: Towards a multifactorial integrative model. Eubiosis and dysbiosis in morbid physical and psychological conditions. Arch. Clin. Gastroenterol., 2021, Vol. 7, no. 2, pp. 024-035.Perrotta G. The intestinal microbiota: Towards a multifactorial integrative model. Eubiosis and dysbiosis in morbid physical and psychological conditions. Arch. Clin. Gastroenterol., 2021, Vol. 7, no. 2, pp. 024-035.Rabe H., Lundell A.-C., Sjöberg F., Ljung A., Strömbeck A., Gio-Batta M., Maglio C., Nordström I., Andersson K., Nookaew I., Wold A.E., Adlerberth I., Rudin A. Neonatal gut colonization by Bifidobacterium is associated with higher childhood cytokine responses. Gut Microbes, 2020, Vol. 12, no.1, pp. 1-14.Rabe H., Lundell A.-C., Sjöberg F., Ljung A., Strömbeck A., Gio-Batta M., Maglio C., Nordström I., Andersson K., Nookaew I., Wold A.E., Adlerberth I., Rudin A. Neonatal gut colonization by Bifidobacterium is associated with higher childhood cytokine responses. Gut Microbes, 2020, Vol. 12, no.1, pp. 1-14.Rivière A., Selak M., Lantin D., Leroy F., de Vuyst L. Bifidobacteria and butyrate-producing colon bacteria: importance and strategies for their stimulation in the human gut. Front. Microbiol., 2016, Vol. 7, 979. doi: 10.3389/fmicb.2016.00979.Rivière A., Selak M., Lantin D., Leroy F., de Vuyst L. Bifidobacteria and butyrate-producing colon bacteria: importance and strategies for their stimulation in the human gut. Front. Microbiol., 2016, Vol. 7, 979. doi: 10.3389/fmicb.2016.00979.Sharon G., Garg N., Debelius J., Knight R., Dorrestein P.C., Mazmanian S.K. Specialized metabolites from the microbiome in health and disease. Cell Metab., 2014, Vol. 20, no. 5, pp. 719-730.Sharon G., Garg N., Debelius J., Knight R., Dorrestein P.C., Mazmanian S.K. Specialized metabolites from the microbiome in health and disease. Cell Metab., 2014, Vol. 20, no. 5, pp. 719-730.Shehata E., Parker A., Suzuki T., Swann J.R., Suez J., Kroon P.A., Day-Walsh P. Microbiomes in physiology: insights into 21st-century global medical challenges. Exp. Physiol., 2022, Vol. 107, no. 4, pp. 257-264.Shehata E., Parker A., Suzuki T., Swann J.R., Suez J., Kroon P.A., Day-Walsh P. Microbiomes in physiology: insights into 21st-century global medical challenges. Exp. Physiol., 2022, Vol. 107, no. 4, pp. 257-264.Silva Y.P., Bernardi A., Frozza R.L. The Role of short-chain fatty acids from gut microbiota in gut-brain communication. Front. Endocrinol., 2020, Vol. 1, 25. doi: 10.3389/fendo.2020.00025.Silva Y.P., Bernardi A., Frozza R.L. The Role of short-chain fatty acids from gut microbiota in gut-brain communication. Front. Endocrinol., 2020, Vol. 1, 25. doi: 10.3389/fendo.2020.00025.Sonnenburg J.L., Bäckhed F. Diet-microbiota interactions as moderators of human metabolism. Nature, 2016, Vol. 535, pp. 56-64.Sonnenburg J.L., Bäckhed F. Diet-microbiota interactions as moderators of human metabolism. Nature, 2016, Vol. 535, pp. 56-64.Spari D., Beldi G. Extracellular ATP as an inter-kingdom signaling molecule: release mechanisms by bacteria and its implication on the host. Int. J. Mol. Sci.,2020, Vol. 21, no. 15, 5590. doi: 10.3390/ijms21155590.Spari D., Beldi G. Extracellular ATP as an inter-kingdom signaling molecule: release mechanisms by bacteria and its implication on the host. Int. J. Mol. Sci.,2020, Vol. 21, no. 15, 5590. doi: 10.3390/ijms21155590.Sun M., Wu W., Liu Z., Cong Y. Microbiota metabolite short chain fatty acids, GPCR, and inflammatory bowel diseases. J. Gastroenterol., 2017, Vol. 52, no. 1, pp. 1-8.Sun M., Wu W., Liu Z., Cong Y. Microbiota metabolite short chain fatty acids, GPCR, and inflammatory bowel diseases. J. Gastroenterol., 2017, Vol. 52, no. 1, pp. 1-8.Telesford K.M., Yan W., Ochoa-Reparaz J., Pant A., Kircher C., Christy M. A., Begum-Haque S., Kasper D.L., Kasper L.H. A commensal symbiotic factor derived from Bacteroides fragilis promotes human CD39(+)Foxp3(+) T cells and Treg function. Gut Microbes, 2015, Vol. 6, no. 4, pp. 234-242.Telesford K.M., Yan W., Ochoa-Reparaz J., Pant A., Kircher C., Christy M. A., Begum-Haque S., Kasper D.L., Kasper L.H. A commensal symbiotic factor derived from Bacteroides fragilis promotes human CD39(+)Foxp3(+) T cells and Treg function. Gut Microbes, 2015, Vol. 6, no. 4, pp. 234-242.Thaiss C.A., Levy M., Suez J., Elinav E. The interplay between the innate immune system and the microbiota. Curr. Opin. Immunol., 2014, Vol. 26, pp. 41-48.Thaiss C.A., Levy M., Suez J., Elinav E. The interplay between the innate immune system and the microbiota. Curr. Opin. Immunol., 2014, Vol. 26, pp. 41-48.Turkina M.V., Vikström E. Bacteria-host crosstalk: sensing of the quorum in the context of pseudomonas aeruginosa infections. J. Innate Immun., 2019, Vol. 11, no. 3, pp. 263-279.Turkina M.V., Vikström E. Bacteria-host crosstalk: sensing of the quorum in the context of pseudomonas aeruginosa infections. J. Innate Immun., 2019, Vol. 11, no. 3, pp. 263-279.Winter S.E. Lopez C.A., Bäumler A.J. The dynamics of gut-associated microbial communities during inflammation. EMBO Rep., 2013, Vol. 14, no. 4, pp. 319-327.Winter S.E. Lopez C.A., Bäumler A.J. The dynamics of gut-associated microbial communities during inflammation. EMBO Rep., 2013, Vol. 14, no. 4, pp. 319-327.Yadav A.K., Tyagi A., Kumar A., Panwar S., Grover S., Saklani A.C., Hemalatha R., Batish V.K. Adhesion of lactobacilli and their anti-infectivity potential. Crit. Rev. Food Sci. Nutr., 2017, Vol. 57, no. 10, pp. 2042-2056.Yadav A.K., Tyagi A., Kumar A., Panwar S., Grover S., Saklani A.C., Hemalatha R., Batish V.K. Adhesion of lactobacilli and their anti-infectivity potential. Crit. Rev. Food Sci. Nutr., 2017, Vol. 57, no. 10, pp. 2042-2056.Yang Y.H., Qian W., Hou X.H., Dai C.B. Bifidobacterium bifidum and Bacteroides fragilis induced differential immune regulation of enteric glial cells subjected to exogenous inflammatory stimulation. Inflammation, 2022. doi: 10.1007/s10753-022-01700-6.Yang Y.H., Qian W., Hou X.H., Dai C.B. Bifidobacterium bifidum and Bacteroides fragilis induced differential immune regulation of enteric glial cells subjected to exogenous inflammatory stimulation. Inflammation, 2022. doi: 10.1007/s10753-022-01700-6.Yu R., Zuo F., Ma H., Chen S. Exopolysaccharide-producing Bifidobacterium adolescentis Strains with similar adhesion property induce differential regulation of inflammatory immune response in Treg/Th17 Axis of DSS-Colitis Mice. Nutrients, 2019, Vol. 11, no. 4, 782. doi: 10.3390/nu11040782.Yu R., Zuo F., Ma H., Chen S. Exopolysaccharide-producing Bifidobacterium adolescentis Strains with similar adhesion property induce differential regulation of inflammatory immune response in Treg/Th17 Axis of DSS-Colitis Mice. Nutrients, 2019, Vol. 11, no. 4, 782. doi: 10.3390/nu11040782.Zhao L., Xie Q., Etareri Evivie S., Liu D., Dong J., Ping L., Liu F., Li B., Huo G. Bifidobacterium dentium N8 with potential probiotic characteristics prevents LPS-Induced intestinal barrier injury by alleviating the inflammatory response and regulating the tight junction in Caco-2 cell monolayers. Food Funct., 2021, Vol. 12, pp. 7171-7184.Zhao L., Xie Q., Etareri Evivie S., Liu D., Dong J., Ping L., Liu F., Li B., Huo G. Bifidobacterium dentium N8 with potential probiotic characteristics prevents LPS-Induced intestinal barrier injury by alleviating the inflammatory response and regulating the tight junction in Caco-2 cell monolayers. Food Funct., 2021, Vol. 12, pp. 7171-7184.

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