Epidemiology and Infectious DiseasesEpidemiology and Infectious DiseasesЭпидемиология и инфекционные болезни3034-20073034-2015Eco-Vector45102510.17816/EID451025ReviewsНаучные обзорыReview ArticleRole of microbiome in development of systemic inflammatory response syndrome and sepsis (review)Роль микробиома в развитии синдрома системного воспалительного ответа и сепсиса (научный обзор)https://orcid.org/0000-0003-3451-1952KhomyakovaTatyana I.ХомяковаТатьяна Ивановна
Russian Federation

MD, Cand. Sci. (Med.)

канд. мед. наук

tatkhom@yandex.ruhttps://orcid.org/0000-0003-0540-252X6602074139ACY-0748-2022KhomyakovYuri N.ХомяковЮрий Николаевич
Russian Federation

MD, Cand. Sci. (Med.), Dr. Sci. (Biol.)

канд. мед. наук, д-р биол. наук

khomyakovyuri@yandex.ruhttps://orcid.org/0000-0001-8581-107XMakarovaOlga V.МакароваОльга Васильевна
Russian Federation

MD, Dr. Sci. (Med.), Professor

д-р мед. наук, профессор

makarov.olga2013@yandex.ruAvtsyn Research Institute of Human MorphologyНаучно-исследовательский институт морфологии человека имени академика А.П. АвцынаAvtsyn Research Institute of Human MorphologyНаучно-исследовательский институт морфологии человека имени академика А.П. Авцына15062023300620232831671822205202330052023Copyright ©; 2023, Eco-vectorCopyright ©; 2023, Эко-вектор2023Eco-vectorЭко-векторhttps://creativecommons.org/licenses/by-nc-nd/4.0/https://rjeid.com/1560-9529/article/view/451025

Sepsis is a life-threatening organ dysfunction caused by a disturbed response to infection. Its development is preceded by systemic inflammatory response syndrome, which is the overall inflammatory response of the body to severe lesions. The role of opportunistic pathogens in the development of systemic inflammatory response syndrome and sepsis may be known, but the value of the intestinal microbiome remains underestimated in this context.

Experimental models are widely employed to study the role of the microbiome in the development of sepsis. Animal models of sepsis are created by disrupting the barrier function of the host intestine through cecal ligation/puncture, installation of an ascending bowel stent, and intraperitoneal feces injection. Toxemia is reproduced by the injection of lipopolysaccharides, peptidoglycans, lipoteichoic acid, CpG DNA, zymosan, and synthetic lipopeptides.

The review systematized data on the role of the cell wall or membrane components of gram-positive and gram-negative bacteria, which are representatives of the intestinal microbiome in the pathogenesis of systemic inflammatory response syndrome and sepsis.

Сепсис ― опасная для жизни органная дисфункция, вызванная нарушенной реакцией организма на инфекцию. Развитию сепсиса предшествует синдром системного воспалительного ответа, который представляет собой общую воспалительную реакцию организма в ответ на тяжёлое поражение. Роль условно-патогенных микроорганизмов в развитии синдрома системного воспалительного ответа и сепсиса может считаться доказанной, однако значение микробиома кишки остаётся недооценённой.

Для исследования роли микробиома в развитии сепсиса широко применяют экспериментальные модели. Методы, используемые для создания моделей сепсиса путём нарушения барьерной функции кишечника хозяина, включают перевязку/пункцию слепой кишки, установку стента восходящей кишки и внутрибрюшинную инъекцию фекалий. Токсемию воспроизводят путём инъекций липополисахаридов, пептидогликанов, липотейхоевой кислоты, ДНК CpG, зимозана и синтетических липопептидов.

В обзоре проведена систематизация данных, касающихся роли компонентов клеточной стенки или мембран грамположительных и грамотрицательных бактерий ― представителей кишечного микробиома в патогенезе синдрома системного воспалительного ответа и сепсиса.

systemic inflammatory response syndromeSIRSsepsispathobiomelipopolysaccharideglycoproteinsteichoic acidsсиндром системного воспалительного ответаССВОсепсиспатобиомлипополисахаридгликопротеинытейхоевые кислотыPAMPFleischmann C, Scherag A, Adhikari NK, et al. International forum of acute care trialists. Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations. Am J Respir Crit Care Med. 2016;193(3):259–272. doi: 10.1164/rccm.201504-0781OCFleischmann C., Scherag A., Adhikari N.K., et al. International forum of acute care trialists. Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations // Am J Respir Crit Care Med. 2016. Vol. 193, N 3. Р. 259–272. doi: 10.1164/rccm.201504-0781OCDugani S, Veillard J, Kissoon N. Reducing the global burden of sepsis. CMAJ. 2017;189(1):E2–E3. doi: 10.1503/cmaj.160798Dugani S., Veillard J., Kissoon N. Reducing the global burden of sepsis // CMAJ. 2017. Vol. 189, N 1. Р. E2–E3. doi: 10.1503/cmaj.160798Rybakova MG. Sepsis: From systemic inflammatory reaction syndrome to organ dysfunction. Arch Pathol. 2021;83(1):67–72. (In Russ). doi: 10.17116/patol20218301167Рыбакова М.Г. Сепсис: от синдрома системной воспалительной реакции до органной дисфункции // Архив патологии. 2021. Т. 83, № 1. C. 67–72. doi: 10.17116/patol20218301167Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315(8):801–810. doi: 10.1001/jama.2016.0287Singer M., Deutschman C.S., Seymour C.W., et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3) // JAMA. 2016. Vol. 315, N 8. Р. 801–810. doi: 10.1001/jama.2016.0287Mishnevo D, Grinberg LM, Zairatiants OV. Actual problems of sepsis pathology: 25 years in search of consensus. Arch Pathol. 2016;78(6):3–8. (In Russ). doi: 10.17116/patol20167863-8Мишнев О.Д., Гринберг Л.М., Зайратьянц О.В. Актуальные проблемы патологии сепсиса: 25 лет в поисках консенсуса // Архив патологии. 2016. Т. 78, № 6. C. 3–8. doi: 10.17116/patol20167863-8Ramachandran G. Gram-positive and gram-negative bacterial toxins in sepsis: A brief review. Virulence. 2014;5(1):213–218. doi: 10.4161/viru.27024Ramachandran G. Gram-positive and gram-negative bacterial toxins in sepsis: A brief review // Virulence. 2014. Vol. 5, N 1. Р. 213–218. doi: 10.4161/viru.27024Lilley E, Armstrong R, Clark N, et al. Refinement of animal models of sepsis and septic shock. Shock. 2015;43(4):304–316. doi: 10.1097/SHK.0000000000000318Lilley E., Armstrong R., Clark N., et al. Refinement of animal models of sepsis and septic shock // Shock. 2015. Vol. 43, N 4. Р. 304–316. doi: 10.1097/SHK.0000000000000318Osuchowski MF, Ayala A, Bahrami S, et al. Minimum quality threshold in pre-clinical sepsis studies (MQTiPSS): An International Expert Consensus Initiative for Improvement of Animal Modeling in Sepsis. Intensive Care Med Exp. 2018;6(1):26. doi: 10.1186/s40635-018-0189-yOsuchowski M.F., Ayala A., Bahrami S., et al. Minimum quality threshold in pre-clinical sepsis studies (MQTiPSS): An International Expert Consensus Initiative for Improvement of Animal Modeling in Sepsis // Intensive Care Med Exp. 2018. Vol. 6, N 1. Р. 26. doi: 10.1186/s40635-018-0189-yGutsmann T, Schromm AB, Brandenburg K. The physicochemistry of endotoxins in relation to bioactivity. Int J Med Microbiol. 2007;297(5):341–352. doi: 10.1016/j.ijmm.2007.03.004Gutsmann T., Schromm A.B., Brandenburg K. The physicochemistry of endotoxins in relation to bioactivity // Int J Med Microbiol. 2007. Vol. 297, N 5. Р. 341–352. doi: 10.1016/j.ijmm.2007.03.004Fink MP. Animal models of sepsis. Virulence. 2014;5(1):143–153. doi: 10.4161/viru.26083Fink M.P. Animal models of sepsis // Virulence. 2014. Vol. 5, N 1. Р. 143–153. doi: 10.4161/viru.26083Vogel SN, Moore RN, Sipe JD, Rosenstreich DL. BCG-induced enhancement of endotoxin sensitivity in C3H/HeJ mice. I. In vivo studies. J Immunol. 1980;124(4):2004–2009.Vogel S.N., Moore R.N., Sipe J.D., Rosenstreich D.L. BCG-induced enhancement of endotoxin sensitivity in C3H/HeJ mice. I. In vivo studies // J Immunol. 1980. Vol. 124, N 4. Р. 2004–2009.Khomyakova TI, Khomyakov YN. From the term «dysbiosis» to the concept of «pathobiom»: The evolution of views. Treatment Prevention. 2022;12(4):50–56. (In Russ).Хомякова Т.И., Хомяков Ю.Н. От термина «дисбактериоз» к понятию «патобиом»: эволюция взглядов // Лечение и профилактика. 2022. Т. 12, № 4. C. 50–56.Godovalov AP. Microbial associations of human biotopes as a factor determining the occurrence of polymicrobial infections. Epidemiol Inf Dis. 2023;28(2):110–117. (In Russ). doi: 10.17816/EID317442Годовалов А.П. Микробные ассоциации биотопов человека как фактор, определяющий возникновение полимикробных инфекций // Эпидемиология и инфекционные болезни. 2023. Т. 28, № 2. C. 110–117. doi: 10.17816/EID317442Martens EC, Neumann M, Desai MS. Interactions of commensal and pathogenic microorganisms with the intestinal mucosal barrier. Nat Rev Microbiol. 2018;16(8):457–470. doi: 10.1038/s41579-018-0036-xMartens E.C., Neumann M., Desai M.S. Interactions of commensal and pathogenic microorganisms with the intestinal mucosal barrier // Nat Rev Microbiol. 2018. Vol. 16, N 8. Р. 457–470. doi: 10.1038/s41579-018-0036-xMassey W, Brown JM. The gut microbial endocrine organ in type 2 diabetes. Endocrinology. 2021;162(2):bqaa235. doi: 10.1210/endocr/bqaa235Massey W., Brown J.M. The gut microbial endocrine organ in type 2 diabetes // Endocrinology. 2021. Vol. 162, N 2. Р. bqaa235. doi: 10.1210/endocr/bqaa235Wang L, Wang S, Zhang Q, et al. The role of the gut microbiota in health and cardiovascular diseases. Mol Biomed. 2022;3(1):30. doi: 10.1186/s43556-022-00091-2Wang L., Wang S., Zhang Q., et al. The role of the gut microbiota in health and cardiovascular diseases // Mol Biomed. 2022. Vol. 3, N 1. Р. 30. doi: 10.1186/s43556-022-00091-2Tilg H, Adolph TE, Trauner M. Gut-liver axis: Pathophysiological concepts and clinical implications. Cell Metab. 2022;34(11): 1700–1718. doi: 10.1016/j.cmet.2022.09.017Tilg H., Adolph T.E., Trauner M. Gut-liver axis: Pathophysiological concepts and clinical implications // Cell Metab. 2022. Vol. 34, N 11. Р. 1700–1718. doi: 10.1016/j.cmet.2022.09.017Beloborodova NI. Integration of human metabolism and its microbiome in critical States. General Reanimatol. 2012;8(4):42–54. (In Russ). doi: 10.15360/1813-9779-2012-4-42Белобородова Н.В. Интеграция метаболизма человека и его микробиома при критических состояниях // Общая реаниматология. 2012. Т. 8, № 4. C. 42–54. doi: 10.15360/1813-9779-2012-4-42Chernevskaya EA, Beloborodova NV. Gut microbiota in critical conditions (review). General Reanimatol. 2018;14(5):96–119. (In Russ). doi: 10.15360/1813-9779-2018-5-96-119Черневская Е.А., Белобородова Н.В. Микробиота кишечника при критических состояниях (обзор) // General Reanimatol. 2018. Т. 14, № 5. C. 96–119. doi: 10.15360/1813-9779-2018-5- 96-119Marshall JC. Gastrointestinal flora and its alterations in critical illness. Curr Opin Clin Nutr Metab Care. 1999;2(5):405–411. doi: 10.1097/00075197-199909000-00009Marshall J.C. Gastrointestinal flora and its alterations in critical illness // Curr Opin Clin Nutr Metab Care. 1999. Vol. 2, N 5. Р. 405–411. doi: 10.1097/00075197-199909000-00009Zhou A, Yuan Y, Yang M, et al. Crosstalk between the gut microbiota and epithelial cells under physiological and infectious conditions. Front Cell Infect Microbiol. 2022;(12):832672. doi: 10.3389/fcimb.2022.832672Zhou A., Yuan Y., Yang M., et al. Crosstalk between the gut microbiota and epithelial cells under physiological and infectious conditions // Front Cell Infect Microbiol. 2022. N 12. Р. 832672. doi: 10.3389/fcimb.2022.832672Chow J, Tang H, Mazmanian SK. Pathobionts of the gastrointestinal microbiota and inflammatory disease. Curr Opin Immunol. 2011;23(4):473–480. doi: 10.1016/j.coi.2011.07.010Chow J., Tang H., Mazmanian S.K. Pathobionts of the gastrointestinal microbiota and inflammatory disease // Curr Opin Immunol. 2011. Vol. 23, N 4. Р. 473–80. doi: 10.1016/j.coi.2011.07.010Ruff WE, Greiling TM, Kriegel MA. Host-microbiota interactions in immune-mediated diseases. Nat Rev Microbiol. 2020;18(9): 521–538. doi: 10.1038/s41579-020-0367-2Ruff W.E., Greiling T.M., Kriegel M.A. Host-microbiota interactions in immune-mediated diseases // Nat Rev Microbiol. 2020. Vol. 18, N 9. Р. 521–538. doi: 10.1038/s41579-020-0367-2Zhao S, Lieberman TD, Poyet M, et al. Adaptive evolution within gut microbiomes of healthy people. Cell Host Microbe. 2019;25(5):656–667.e8. doi: 10.1016/j.chom.2019.03.007Zhao S., Lieberman T.D., Poyet M., et al. Adaptive evolution within gut microbiomes of healthy people // Cell Host Microbe. 2019. Vol. 25, N 5. Р. 656–667.e8. doi: 10.1016/j.chom.2019.03.007Faith JJ, Guruge JL, Charbonneau M, et al. The long-term stability of the human gut microbiota. Science. 2013;341(6141):1237439. doi: 10.1126/science.1237439Faith J.J., Guruge J.L., Charbonneau M., et al. The long-term stability of the human gut microbiota // Science. 2013. Vol. 341, N 6141. Р. 1237439. doi: 10.1126/science.1237439Feliziani S, Marvig RL, Luján AM, et al. Coexistence and within-host evolution of diversified lineages of hypermutable Pseudomonas aeruginosa in long-term cystic fibrosis infections. PLoS Genet. 2014;10(10):e1004651. doi: 10.1371/journal.pgen.1004651Feliziani S., Marvig R.L, Luján A.M., et al. Coexistence and within-host evolution of diversified lineages of hypermutable Pseudomonas aeruginosa in long-term cystic fibrosis infections // PLoS Genet. 2014. Vol. 10, N 10. Р. e1004651. doi: 10.1371/journal.pgen.1004651Rice TA, Bielecka AA, Nguyen MT, et al. Interspecies commensal interactions have nonlinear impacts on host immunity. Cell Host Microbe. 2022;30(7):988–1002.e6. doi: 10.1016/j.chom.2022.05.004Rice T.A., Bielecka A.A., Nguyen M.T., et al. Interspecies commensal interactions have nonlinear impacts on host immunity // Cell Host Microbe. 2022. Vol. 30, N 7. Р. 988–1002.e6. doi: 10.1016/j.chom.2022.05.004Ohanyan KA, Arzhanova ON, Zamorskaya L, Savicheva AM. Enterococci and their role in perinatal pathology. J Art Women’s Dis. 2015;(5):49–54. (In Russ).Оганян К.А., Аржанова О.Н., Зациорская С.Л., Савичева А.М. Энтерококки и их роль в перинатальной патологии // Журнал акушерство и женские болезни. 2015. № 5. C. 49–54.Griffith SJ, Nathan C, Selander RK, et al. The epidemiology of Pseudomonas aeruginosa in oncology patients in a general hospital. J Infect Dis. 1989;160(6):1030–1036. doi: 10.1093/infdis/160.6.1030Griffith S.J., Nathan C., Selander R.K., et al. The epidemiology of Pseudomonas aeruginosa in oncology patients in a general hospital // J Infect Dis. 1989. Vol. 160, N 6. Р. 1030–1036. doi: 10.1093/infdis/160.6.1030Hansen F, Johansen HK, Østergaard C, et al. Characterization of carbapenem nonsusceptible Pseudomonas aeruginosa in Denmark: A nationwide, prospective study. Microb Drug Resist. 2014;20(1): 22–29. doi: 10.1089/mdr.2013.0085Hansen F., Johansen H.K., Østergaard C., et al. Characterization of carbapenem nonsusceptible Pseudomonas aeruginosa in Denmark: A nationwide, prospective study // Microb Drug Resist. 2014. Vol. 20, N 1. Р. 22–29. doi: 10.1089/mdr.2013.0085Laughlin RS, Musch MW, Hollbrook CJ, et al. The key role of Pseudomonas aeruginosa PA-I lectin on experimental gut-derived sepsis. Ann Surg. 2000;232(1):133–142. doi: 10.1097/00000658-200007000-00019Laughlin R.S., Musch M.W., Hollbrook C.J., et al. The key role of Pseudomonas aeruginosa PA-I lectin on experimental gut-derived sepsis // Ann Surg. 2000. Vol. 232, N 1. Р. 133–42. doi: 10.1097/00000658-200007000-00019Zhao S, Lieberman TD, Poyet M, et al. Adaptive evolution within gut microbiomes of healthy people. Cell Host Microbe. 2019;25(5): 656–667.e8. doi: 10.1016/j.chom.2019.03.007Zhao S., Lieberman T.D., Poyet M., et al. Adaptive evolution within gut microbiomes of healthy people // Cell Host Microbe. 2019. Vol. 25, N 5. Р. 656–667.e8. doi: 10.1016/j.chom.2019.03.007Yelin I, Flett KB, Merakou C, et al. Genomic and epidemiological evidence of bacterial transmission from probiotic capsule to blood in ICU patients. Nat Med. 2019;25(11):1728–1732. doi: 10.1038/s41591-019-0626-9Yelin I., Flett K.B., Merakou C., et al. Genomic and epidemiological evidence of bacterial transmission from probiotic capsule to blood in ICU patients // Nat Med. 2019. Vol. 25, N 11. Р. 1728–1732. doi: 10.1038/s41591-019-0626-9Zhu XX, Zhang WW, Wu CH, et al. The novel role of metabolism-associated molecular patterns in sepsis. Front Cell Infect Microbiol. 2022;(12):915099. doi: 10.3389/fcimb.2022.915099Zhu X.X., Zhang W.W., Wu C.H., et al. The novel role of metabolism-associated molecular patterns in sepsis // Front Cell Infect Microbiol. 2022. N 12. Р. 915099. doi: 10.3389/fcimb.2022.915099Dammermann W, Wollenberg L, Bentzien F, et al. Toll-like receptor 2 agonists lipoteichoic acid and peptidoglycan are able to enhance antigen specific IFNγ release in whole blood during recall antigen responses. J Immunol Methods. 2013;396(1-2):107–115. doi: 10.1016/j.jim.2013.08.004Dammermann W., Wollenberg L., Bentzien F., et al. Toll-like receptor 2 agonists lipoteichoic acid and peptidoglycan are able to enhance antigen specific IFNγ release in whole blood during recall antigen responses // J Immunol Methods. 2013. Vol. 396, N 1-2. Р. 107–15. doi: 10.1016/j.jim.2013.08.004Augusto LA, Bourgeois-Nicolaos N, Breton A, et al. Presence of 2-hydroxymyristate on endotoxins is associated with death in neonates with Enterobacter cloacae complex septic shock. Science. 2021;24(8):102916. doi: 10.1016/j.isci.2021.102916Augusto L.A., Bourgeois-Nicolaos N., Breton A., et al. Presence of 2-hydroxymyristate on endotoxins is associated with death in neonates with Enterobacter cloacaecomplex septic shock // Science. 2021. Vol. 24, N 8. Р. 102916. doi: 10.1016/j.isci.2021.102916Schumann RR, Zweigner J. A novel acute-phase marker: Lipopolysaccharide binding protein (LBP). Clin Chem Lab Med. 1999;37(3):271–274. doi: 10.1515/CCLM.1999.047Schumann R.R., Zweigner J. A novel acute-phase marker: lipopolysaccharide binding protein (LBP) // Clin Chem Lab Med. 1999. Vol. 37, N 3. Р. 271–274. doi: 10.1515/CCLM.1999.047Wegscheider K, Schumann RR. High concentrations of lipopolysaccharide-binding protein in serum of patients with severe sepsis or septic shock inhibit the lipopolysaccharide response in human monocytes. Blood. 2001;98(13):3800–3808. doi: 10.1182/blood.v98.13.3800Wegscheider K., Schumann R.R. High concentrations of lipopolysaccharide-binding protein in serum of patients with severe sepsis or septic shock inhibit the lipopolysaccharide response in human monocytes // Blood. 2001. Vol. 98, N 13. Р. 3800–3808. doi: 10.1182/blood.v98.13.3800Zvyagin AA, Demidova VS, Smirnov GV. Biological markers in the diagnosis and treatment of sepsis (literature review). Wounds and wound infections. The prof. B.M. Kostyuchenok journal. 2016; 3(2):20–23. (In Russ). doi: 10.17650/2408-9613-2016-3-2-19-23Звягин А.А., Демидова В.С., Смирнов Г.В. Биологические маркеры в диагностике и лечении сепсиса (обзор литературы) // Раны и раневые инфекции. Журнал имени профессора Б.М. Костючёнка. 2016.Т. 3, № 2. С. 20–23. doi: 10.17650/2408-9613-2016-3-2-19-23Brown S, Santa Maria JP, Walker S. Wall teichoic acids of gram-positive bacteria. Annu Rev Microbiol. 2013;(67):313–336. doi: 10.1146/annurev-micro-092412-155620Brown S., Santa Maria J.P., Walker S. Wall teichoic acids of gram-positive bacteria // Annu Rev Microbiol. 2013. N 67. Р. 313–336. doi: 10.1146/annurev-micro-092412-155620Percy MG, Gründling A. Lipoteichoic acid synthesis and function in gram-positive bacteria. Annu Rev Microbiol. 2014;(68):81–100. doi: 10.1146/annurev-micro-091213-112949Percy M.G., Gründling A. Lipoteichoic acid synthesis and function in gram-positive bacteria // Annu Rev Microbiol. 2014. N 68. Р. 81–100. doi: 10.1146/annurev-micro-091213-112949Chee Wezen X, Chandran A, Eapen RS, et al. Structure-Based discovery of lipoteichoic acid synthase inhibitors. J Chem Inf Model. 2022;62(10):2586–2599. doi: 10.1021/acs.jcim.2c00300Wezen C.X., Chandran A., Eapen R.S., et al. Structure-based discovery of lipoteichoic acid synthase inhibitors // J Chem Inf Model. 2022. Vol. 62, N 10. Р. 2586–2599. doi: 10.1021/acs.jcim.2c00300Dickson K, Lehmann C. Inflammatory response to different toxins in experimental sepsis models. Int J Mol Sci. 2019;20(18):4341. doi: 10.3390/ijms20184341Dickson K., Lehmann C. Inflammatory response to different toxins in experimental sepsis models // Int J Mol Sci. 2019. Vol. 20, N 18. Р. 4341. doi: 10.3390/ijms20184341Ginsburg I. Role of lipoteichoic acid in infection and inflammation. Lancet Infect Dis. 2002;2(3):171–179. doi: 10.1016/s1473-3099(02)00226-8Ginsburg I. Role of lipoteichoic acid in infection and inflammation // Lancet Infect Dis. 2002. Vol. 2, N 3. Р. 171–179. doi: 10.1016/s1473-3099(02)00226-8Richter SG, Elli D, Kim HK, et al. Small molecule inhibitor of lipoteichoic acid synthesis is an antibiotic for Gram-positive bacteria. Proc Natl Acad Sci USA. 2013;110(9):3531–3536. doi: 10.1073/pnas.1217337110Richter S.G., Elli D., Kim H.K., et al. Small molecule inhibitor of lipoteichoic acid synthesis is an antibiotic for Gram-positive bacteria // Proc Natl Acad Sci USA. 2013. Vol. 110, N 9. Р. 3531–3536. doi: 10.1073/pnas.1217337110Schneewind O, Missiakas D. Lipoteichoic acids, phosphate-containing polymers in the envelope of gram-positive bacteria. J Bacteriol. 2014;196(6):1133–1142. doi: 10.1128/JB.01155-13Schneewind O., Missiakas D. Lipoteichoic acids, phosphate-containing polymers in the envelope of gram-positive bacteria // J Bacteriology. 2014. Vol. 196, N 6. P. 1133–1142. doi: 10.1128/ JB.01155-13Szentirmai É, Massie AR, Kapás L. Lipoteichoic acid, a cell wall component of Gram-positive bacteria, induces sleep and fever and suppresses feeding. Brain Behav Immun. 2021;(92):184–192. doi: 10.1016/j.bbi.2020.12.008Szentirmai É., Massie A.R., Kapás L. Lipoteichoic acid, a cell wall component of Gram-positive bacteria, induces sleep and fever and suppresses feeding // Brain Behav Immun. 2021. N 92. Р. 184–192. doi: 10.1016/j.bbi.2020.12.008Kubicek-Sutherland JZ, Vu DM, Mendez HM, et al. Detection of lipid and amphiphilic biomarkers for disease diagnostics. Biosensors (Basel). 2017;7(3):25. doi: 10.3390/bios7030025Kubicek-Sutherland J.Z., Vu D.M., Mendez H.M., et al. Detection of lipid and amphiphilic biomarkers for disease diagnostics // Biosensors (Basel). 2017. Vol. 7, N 3. Р. 25. doi: 10.3390/bios7030025Middelveld RJ, Alving K. Synergistic septicemic action of the gram-positive bacterial cell wall components peptidoglycan and lipoteichoic acid in the pig in vivo. Shock. 2000;13(4):297–306. doi: 10.1097/00024382-200004000-00008Middelveld R.J., Alving K. Synergistic septicemic action of the gram-positive bacterial cell wall components peptidoglycan and lipoteichoic acid in the pig in vivo // Shock. 2000. Vol. 13, N 4. Р. 297–306. doi: 10.1097/00024382-200004000-00008Schneewind O, Missiakas D. Lipoteichoic acids, phosphate-containing polymers in the envelope of gram-positive bacteria. J Bacteriol. 2014;196(6):1133–1142. doi: 10.1128/JB.01155-13Schneewind O., Missiakas D. Lipoteichoic acids, phosphate-containing polymers in the envelope of gram-positive bacteria // J Bacteriol. 2014. Vol. 196, N 6. Р. 1133–1142. doi: 10.1128/JB.01155-13Zhong Y, Kinio A, Saleh M. Functions of NOD-like receptors in human diseases. Front Immunol. 2013;(4):333. doi: 10.3389/fimmu.2013.00333Zhong Y., Kinio A., Saleh M. Functions of NOD-like receptors in human diseases // Front Immunol. 2013. N 4. Р. 333. doi: 10.3389/fimmu.2013.00333Said-Sadier N, Ojcius DM. Alarmins, inflammasomes and immunity. Biomed J. 2012;35(6):437–449. doi: 10.4103/2319-4170.104408Said-Sadier N., Ojcius D.M. Alarmins, inflammasomes and immunity // Biomed J. 2012. Vol. 35, N 6. Р. 437–449. doi: 10.4103/2319-4170.104408Wolf AJ, Underhill DM. Peptidoglycan recognition by the innate immune system. Nat Rev Immunol. 2018;18(4):243–254. doi: 10.1038/nri.2017.136Wolf A.J., Underhill D.M. Peptidoglycan recognition by the innate immune system // Nat Rev Immunol. 2018. Vol. 18, N 4. Р. 243–254. doi: 10.1038/nri.2017.136Wolf AJ, Reyes CN, Liang W, et al. Hexokinase is an innate immune receptor for the detection of bacterial peptidoglycan. Cell. 2016;166(3):624–636. doi: 10.1016/j.cell.2016.05.076Wolf A.J., Reyes C.N., Liang W., et al. Hexokinase Is an innate immune receptor for the detection of bacterial peptidoglycan // Cell. 2016. Vol. 166, N 3. Р. 624–636. doi: 10.1016/j.cell.2016.05.076Jeong JH, Jang S, Jung BJ, et al. Differential immune-stimulatory effects of LTAs from different lactic acid bacteria via MAPK signaling pathway in RAW 264.7 cells. Immunobiology. 2015;220(4):460–466. doi: 10.1016/j.imbio.2014.11.002Jeong J.H., Jang S., Jung B.J., et al. Differential immune-stimulatory effects of LTAs from different lactic acid bacteria via MAPK signaling pathway in RAW 264.7 cells // Immunobiology. 2015. Vol. 220, N 4. Р. 460–466. doi: 10.1016/j.imbio.2014.11.002Cox KH, Cox ME, Woo-Rasberry V, Hasty DL. Pathways involved in the synergistic activation of macrophages by lipoteichoic acid and hemoglobin. PLoS One. 2012;7(10):e47333. doi: 10.1371/journal.pone.0047333Cox K.H., Cox M.E., Woo-Rasberry V., Hasty D.L. Pathways involved in the synergistic activation of macrophages by lipoteichoic acid and hemoglobin // PLoS One. 2012. Vol. 7, N 10. Р. e47333. doi: 10.1371/journal.pone.0047333Kim HG, Kim NR, Gim MG, et al. Lipoteichoic acid isolated from Lactobacillus plantarum inhibits lipopolysaccharide-induced TNF-production in THP-1 cells and endotoxin shock in mice. J Immunol. 2008;180(4):2553–2561. doi: 10.4049/jimmunol.180.4.2553Kim H.G., Kim N.R., Gim M.G., et al. Lipoteichoic acid isolated from Lactobacillus plantarum inhibits lipopolysaccharide-induced TNF- production in THP-1 cells and endotoxin shock in mice // J Immunol. 2008. Vol. 180, N 4. Р. 2553–2561. doi: 10.4049/jimmunol.180.4.2553Yipp BG, Andonegui G, Howlett CJ. Profound differences in leukocyte-endothelial cell responses to lipopolysaccharide versuslipoteichoic acid. J Immunol. 2002;168(9):4650–4658. doi: 10.4049/jimmunol.168.9.4650Yipp B.G., Andonegui G., Howlett C.J. Profound differences in leukocyte-endothelial cell responses to lipopolysaccharide versuslipoteichoic acid // J Immunol. 2002. Vol. 168, N 9. Р. 4650–4658. doi: 10.4049/jimmunol.168.9.4650Sharma P, Dube D, Sinha M, et al. Structural insights into the dual strategy of recognition by peptidoglycan recognition protein, PGRP-S: Structure of the ternary complex of PGRP-S with lipopolysaccharide and stearic acid. PLoS One. 2013;8(1):e53756. doi: 10.1371/journal.pone.0053756Sharma P., Dube D., Sinha M., et al. Structural insights into the dual strategy of recognition by peptidoglycan recognition protein, PGRP-S: Structure of the ternary complex of PGRP-S with lipopolysaccharide and stearic acid // PLoS One. 2013. Vol. 8, N 1. Р. e53756. doi: 10.1371/journal.pone.0053756Van Langevelde P, van Dissel JT, Ravensbergen E, et al. Antibiotic-induced release of lipoteichoic acid and peptidoglycan from staphylococcus aureus: Quantitative measurements and biological reactivities. Agents Chemother. 1998;42(12):3073–3078. doi: 10.1128/AAC.42.12.3073Van Langevelde P., van Dissel J.T., Ravensbergen E., et al. Antibiotic-induced release of lipoteichoic acid and peptidoglycan from staphylococcus aureus: Quantitative measurements and biological reactivities // Agents Chemother. 1998. Vol. 42, N 12. Р. 3073–3078. doi: 10.1128/AAC.42.12.3073Imai J, Kitamoto S, Sugihara K, et al. Flagellin-mediated activation of IL-33-ST2 signaling by a pathobiont promotes intestinal fibrosis. Mucosal Immunol. 2019;12(3):632–643. doi: 10.1038/s41385-019-0138-4Imai J., Kitamoto S., Sugihara K., et al. Flagellin-mediated activation of IL-33-ST2 signaling by a pathobiont promotes intestinal fibrosis // Mucosal Immunol. 2019. Vol. 12, N 3. Р. 632–643. doi: 10.1038/s41385-019-0138-4Naseer N, Egan MS, Ruiz VM, et al. Human NAIP/NLRC4 and NLRP3 inflammasomes detect Salmonella type III secretion system activities to restrict intracellular bacterial replication. PLoS Pathog. 2022;18(1):e1009718. doi: 10.1371/journal.ppat.1009718Naseer N., Egan M.S., Ruiz V.M., et al. Human NAIP/NLRC4 and NLRP3 inflammasomes detect Salmonella type III secretion system activities to restrict intracellular bacterial replication // PLoS Pathog. 2022. Vol. 18, N 1. Р. e1009718. doi: 10.1371/journal.ppat.1009718Xue Y, Tuipulotu ED, Tan WH, et al. Emerging activators and regulators ofinflammasomes and pyroptosis. Trends Immunol. 2019;40(11):1035–1052. doi: 10.1016/j.it.2019.09.005Xue Y., Tuipulotu E.D., Tan W.H., et al. Emerging activators and regulators of inflammasomes and pyroptosis // Trends Immunol. 2019. Vol. 40, N 11. Р. 1035–1052. doi: 10.1016/j.it.2019.09.005Grimaldi E, Donnarumma G, Perfetto B, et al. Proinflammatory signal transduction pathway induced by Shigella flexneri porins in caco-2 cells. Braz J Microbiol. 2009;40(3):701–713. doi: 10.1590/S1517-838220090003000036Grimaldi E., Donnarumma G., Perfetto B., et al. Proinflammatory signal transduction pathway induced by Shigella flexneri porins in caco-2 cells // Braz J Microbiol. 2009. Vol. 40, N 3. Р. 701–713. doi: 10.1590/S1517-838220090003000036Mukhopadhaya A, Mahalanabis D, Chakrabarti MK. Role of Shigella flexneri 2a 34 kDa outer membrane protein in induction of protective immune response. Vaccine. 2006;24(33-34):6028–6036. doi: 10.1016/j.vaccine.2006.03.026Mukhopadhaya A., Mahalanabis D., Chakrabarti M.K. Role of Shigella flexneri 2a 34 kDa outer membrane protein in induction of protective immune response // Vaccine. 2006. Vol. 24, N 33-34. Р. 6028–6036. doi: 10.1016/j.vaccine.2006.03.026Sugimoto N, Leu H, Inoue N, et al. The critical role of lipopolysaccharide in the upregulation of aquaporin 4 in glial cells treated with Shiga toxin. J Biomed Sci. 2015;22(1):78. doi: 10.1186/s12929-015-0184-5Sugimoto N., Leu H., Inoue N., et al. The critical role of lipopolysaccharide in the upregulation of aquaporin 4 in glial cells treated with Shiga toxin // J Biomed Sci. 2015. Vol. 22, N 1. Р. 78. doi: 10.1186/s12929-015-0184-5Keskinidou C, Lotsios NS, Vassiliou AG, et al. The interplay between aquaporin-1 and the hypoxia-inducible factor 1α in a lipopolysaccharide-induced lung injury model in human pulmonary microvascular endothelial cells. Int J Mol Sci. 2022;23(18):10588. doi: 10.3390/ijms231810588Keskinidou C., Lotsios N.S., Vassiliou A.G., et al. The interplay between aquaporin-1 and the hypoxia-inducible factor 1α in a lipopolysaccharide-induced lung injury model in human pulmonary microvascular endothelial cells // Int J Mol Sci. 2022. Vol. 23, N 18. Р. 10588. doi: 10.3390/ijms231810588Zhu Y, Wang Y, Teng W, et al. Role of Aquaporin-3 in intestinal injury induced by sepsis. Biol Pharm Bull. 2019;42(10):1641–1650. doi: 10.1248/bpb.b19-00073Zhu Y., Wang Y., Teng W., et al. Role of Aquaporin-3 in intestinal injury induced by sepsis // Biol Pharm Bull. 2019. Vol. 42, N 10. Р. 1641–1650. doi: 10.1248/bpb.b19-00073Takeuchi O, Kawai T, Mühlradt PF, et al. Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int Immunol. 2001;13(7):933–940. doi: 10.1093/intimm/13.7.933Takeuchi O., Kawai T., Mühlradt P.F., et al. Discrimination of bacterial lipoproteins by Toll-like receptor 6 // Int Immunol. 2001. Vol. 13, N 7. Р. 933–940. doi: 10.1093/intimm/13.7.933Fang H, Wang Y, Deng J, et al. Sepsis-induced gut dysbiosis mediates the susceptibility to sepsis-associated encephalopathy in mice. Systems. 2022;7(3):e0139921. doi: 10.1128/msystems.01399-21Fang H., Wang Y., Deng J., et al. Sepsis-Induced gut dysbiosis mediates the susceptibility to sepsis-associated encephalopathy in mice // Systems. 2022. Vol. 7, N 3. Р. e0139921. doi: 10.1128/msystems.01399-21Wang L, Lin F, Ren M, et al. The PICK1/TLR4 complex on microglia is involved in the regulation of LPS-induced sepsis-associated encephalopathy. Int Immunopharmacol. 2021;(100):108116. doi: 10.1016/j.intimp.2021.108116Wang L., Lin F., Ren M., et al. The PICK1/TLR4 complex on microglia is involved in the regulation of LPS-induced sepsis-associated encephalopathy // Int Immunopharmacol. 2021. N 100.Р. 108116. doi: 10.1016/j.intimp.2021.108116Johannes HM, Abraham PR, van Barreveld E, et al., Distribution and kinetics of lipoprotein-bound lipoteichoic acid. Infect Immun. 2003;71(6):3280–3284. doi: 10.1128/IAI.71.6.3280-3284.2003Johannes H.M., Abraham P.R., van Barreveld E., et al. Distribution and kinetics of lipoprotein-bound lipoteichoic acid // Infect Immun. 2003. Vol. 71, N 6. P. 3280–3284. doi: 10.1128/IAI.71.6.3280-3284.2003Levine DM, Parker TS, Donnelly TM, et al. In vivo protection against endotoxin by plasma high density lipoprotein. Proc Natl Acad Sci USA. 1993;90(24):12040–12044. doi: 10.1073/pnas.90.24.12040Levine D.M., Parker T.S., Donnelly T.M., et al. In vivo protection against endotoxin by plasma high density lipoprotein // Proc Natl Acad Sci USA. 1993. Vol. 90, N 24. Р. 12040–12044. doi: 10.1073/pnas.90.24.12040Vreugdenhil AC, Snoek AM, van Veer C, et al. LPS-binding protein circulates in association with apoB-containing lipoproteins and enhances endotoxin-LDL/VLDL interaction. J Clin Invest. 2001;107(2):225–234. doi: 10.1172/JCI10832Vreugdenhil A.C., Snoek A.M., van Veer C., et al. LPS-binding protein circulates in association with apoB-containing lipoproteins and enhances endotoxin-LDL/VLDL interaction // J Clin Invest. 2001. Vol. 107, N 2. Р. 225–234. doi: 10.1172/JCI10832Leung AK, Genga KR, Topchiy E, et al. Reduced proprotein convertase subtilisin/kexin 9 (PCSK9) function increases lipoteichoic acid clearance and improves outcomes in Gram positive septic shock patients. Sci Rep. 2019;9(1):10588. doi: 10.1038/s41598-019-46745-0Leung A.K., Genga K.R., Topchiy E., et al. Reduced Proprotein convertase subtilisin/kexin 9 (PCSK9) function increases lipoteichoic acid clearance and improves outcomes in Gram positive septic shock patients // Sci Rep. 2019. Vol. 9, N 1. Р. 10588. doi: 10.1038/s41598-019-46745-0Ursell LK, Metcalf JL, Parfrey LW, Knight R. Defining the human microbiome. Nutr Rev. 2012;70(Suppl 1):S38–S44. doi: 10.1111/j.1753-4887.2012.00493.xUrsell L.K., Metcalf J.L., Parfrey L.W., Knight R. Defining the human microbiome // Nutr Rev. 2012. Vol. 70, Suppl. 1. Р. S38–S44. doi: 10.1111/j.1753-4887.2012.00493.x