Микробиом респираторного тракта: что известно сегодня?
Микробиом респираторного тракта: что известно сегодня?
Захарова И.Н., Касьянова А.Н., Климов Л.Я. и др. Микробиом респираторного тракта: что известно сегодня? Педиатрия (Прил. к журн. Consilium Medicum). 2018; 4: 10–17.
DOI: 10.26442/24138460.2018.4.180129
DOI: 10.26442/24138460.2018.4.180129
________________________________________________
DOI: 10.26442/24138460.2018.4.180129
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Аннотация
На сегодняшний день достаточно хорошо изучен микробиом кишечника, показана его роль в поддержании гомеостаза организма человека. Исторически сложилось врачебное мнение, что нижние отделы респираторного тракта здорового человека стерильны. В статье представлены данные современных исследований, доказывающих существование особого микробиома верхних и нижних отделов респираторного тракта. Некоторые микроорганизмы играют решающую роль в поддержании иммунитета. Известно, что снижение микробного разнообразия и возрастание численности патогенных микроорганизмов способствуют развитию острых и хронических воспалительных заболеваний легких, таких как бронхиальная астма и хроническая обструктивная болезнь легких, осложненному течению муковисцидоза. Восстановление нормального микробиома респираторного тракта с использованием пробиотических препаратов способно снизить риски развития респираторных инфекций.
Ключевые слова: микробиом, кишечник, респираторный тракт, защита от острых респираторных инфекций, микробиом респираторного тракта, пробиотики, дети.
Key words: microbiome, intestine, respiratory tract, protection from acute respiratory infections, respiratory tract microbiome, probiotics, children.
Ключевые слова: микробиом, кишечник, респираторный тракт, защита от острых респираторных инфекций, микробиом респираторного тракта, пробиотики, дети.
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Key words: microbiome, intestine, respiratory tract, protection from acute respiratory infections, respiratory tract microbiome, probiotics, children.
Список литературы
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16. Bosch AATM, Levin E, van Houten MA et al. Development of Upper Respiratory Tract Microbiota in Infancy is Affected by Mode of Delivery. E Bio Medicine 2016; 9: 336–45. DOI: 10.1016/j.ebiom.2016.05.031
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22. Prevaes SM, de Winter-de Groot KM, Janssens HM et al. Development of the Nasopharyngeal Microbiota in Infants with Cystic Fibrosis. Am J Respir Crit Care Med 2016; 193 (5): 504–15. DOI: 10.1164/rccm.201509-1759OC
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25. Forsythe P. Probiotics and lung diseases. Chest J 2011; 139: 901–8. DOI: 10.1378/chest.10-1861
26. Forsythe P. Probiotics and lung immune responses. Ann Am Thorac Soc 2014; 11: S33–S37.
27. Yoda K, He F, Miyazawa K et al. Orally administered heat-killed Lactobacillus gasseri TMC0356 alters respiratory immune responses and intestinal microbiota of diet-induced obese mice. J Appl Microbiol 2012; 113: 155–62. DOI: 10.1111/j.1365-2672.2012.05316.x
28. West CE. Gut microbiota and allergic disease: new findings. Curr Opin Clin Nutr Metab Care 2014; 17: 261–6. DOI: 10.1097/MCO.0000000000000044
29. Van den Broek MFL, De Boeck I, Claes IJJ et al. Multifactorial inhibition of lactobacilli against the respiratory tract pathogen Moraxella catarrhalis. Benef Microbes 2018; 9 (3): 429–39. DOI: 10.3920/BM2017.0101
30. Salva S, Villena J, Alvarez S. Immunomodulatory activity of Lactobacillus rhamnosusstrains isolated from goat milk: impact on intestinal and respiratory infections. Int J Food Microbiol 2010; 141: 82–9. 10.1016/j.ijfoodmicro.2010.03.013
31. Alvarez S, Herrero C, Bru E, Perdigon G. Effect of Lactobacillus casei and yogurt administration on prevention of Pseudomonas aeruginosa infection in young mice. J Food Prot 2001; 64: 1768–74.
32. Hori T, Kiyoshima J, Shida K, Yasui H. Effect of intranasal administration of Lactobacillus casei Shirota on influenza virus infection of upper respiratory tract in mice. Clin Diagn Lab Immunol 2001; 8: 593–7. DOI: 10.1128/cdli.8.3.593-597.2001
2. Dickson RP, Erb-Downward JR, Freeman CM et al. Spatial variation in the healthy human lung microbiome and the adapted island model of lung biogeography. Ann Am Thorac Soc 2015; 12: 821–30.
3. Bassis CM, Erb-Downward JR, Dickson RP et al. Analysis of the upper respiratory tract microbiotas as the source of the lung and gastric microbiotas in healthy individuals. MBio 2015; 6: e00037.
4. Charlson ES, Bittinger K, Haas AR et al. Topographical continuity of bacterial populations in the healthy human respiratory tract. Am J Respir Crit Care Med 2011; 184: 957–63.
5. Erb-Downward JR, Thompson DL, Han MK et al. Analysis of the lung microbiome in the “healthy” smoker and in COPD. PLoS One 2011; 6: e16384.
6. Charlson ES, Diamond JM, Bittinger K et al. Lung-enriched organisms and aberrant bacterial and fungal respiratory microbiota after lung transplant. Am J Respir Crit Care Med 2012; 186: 536–45.
7. Hilty M, Burke C, Pedro H et al. Disordered microbial communities in asthmatic airways. PLoS One 2010; 5: e8578. 10.1371/journal.pone.0008578
8. Sze MA, Dimitriu PA, Hayashi S et al. The lung tissue microbiome in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 185: 1073–80.
9. Madan JC, Koestler DC, Stanton BA et al. Serial analysis the gut and respiratory microbiome in cystic fibrosis in infancy: interaction between intestinal and respiratory tracts and impact of nutritional exposures. MBio 2012; 3 (4). pii: e00251-12. DOI: 10.1128/mBio.00251-12
10. Southam DS, Dolovich M, O'Byrne PM, Inman MD. Distribution of intranasal instillations in mice: effects of volume, time, body position, and anesthesia. Am J Physiol Lung Cell Mol Physiol 2002; 282: L833–L839. DOI: 10.1152/ajplung.00173.2001
11. Samuelson DR, Welsh DA, Shellito JE. Regulation of lung immunity and host defense by the intestinal microbiota. Front Microbiol 2015; 6: 1085.
12. Mathieu E, Escribano-Vazquez U, Descamps D et al. Paradigms of Lung Microbiota Functions in Health and Disease, Particularly, in Asthma. Front Physiol 2018; 9: 1168.
13. Statovci D, Aguilera M, MacSharry J, Melgar S. The Impact of Western Diet and Nutrients on the Microbiota and Immune Response at Mucosal Interfaces. Front Immunol 2017; 8: 838. DOI: 10.3389/fimmu.2017.00838
14. Dominguez-Bello MG, Costello EK, Contreras M et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci USA 2010; 107: 11971–5.
15. Cernadas M. It takes a microbiome: commensals, immune regulation, and allergy. Am J Respir Crit Care Med 2011; 184: 149–50.
16. Bosch AATM, Levin E, van Houten MA et al. Development of Upper Respiratory Tract Microbiota in Infancy is Affected by Mode of Delivery. E Bio Medicine 2016; 9: 336–45. DOI: 10.1016/j.ebiom.2016.05.031
17. Bosch AATM, de Steenhuijsen Piters WAA, van Houten MA et al. Maturation of the Infant Respiratory Microbiota, Environmental Drivers, and Health Consequences. A Prospective Cohort Study. Am J Respir Crit Care Med 2017; 196 (12): 1582–90. DOI: 10.1164/rccm.201703-0554OC
18. Bisgaard H, Hermansen MN, Buchvald F et al. Childhood asthma after bacterial colonization of the airway in neonates. N Engl J Med 2007; 357 (15): 1487–95.
19. Ong M-S, Umetsu DT, Mandl KD. Consequences of antibiotics and infections in infancy: bugs, drugs, and wheezing. Ann Allergy Asthma Immunol 2014; 112: 441–5.e441.
20. Ege MJ, Mayer M, Normand AC et al. Exposure to environmental microorganisms and childhood asthma. N Engl J Med 2011; 364: 701–9.
21. Trompette A, Gollwitzer ES, Yadava K et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med 2014; 20: 159–66.
22. Prevaes SM, de Winter-de Groot KM, Janssens HM et al. Development of the Nasopharyngeal Microbiota in Infants with Cystic Fibrosis. Am J Respir Crit Care Med 2016; 193 (5): 504–15. DOI: 10.1164/rccm.201509-1759OC
23. Hoen AG, Li J, Moulton LA et al. Associations between gut microbial colonization in early life and respiratory outcomes in cystic fibrosis. J Pediatr 2015; 167: 138–47, e131–133.
24. Schippa S, Iebba V, Santangelo F et al. Cystic fibrosis transmembrane conductance regulator (CFTR) allelic variants relate to shifts in faecal microbiota of cystic fibrosis patients. PLoS ONE 2013; 8: e61176.
25. Forsythe P. Probiotics and lung diseases. Chest J 2011; 139: 901–8. DOI: 10.1378/chest.10-1861
26. Forsythe P. Probiotics and lung immune responses. Ann Am Thorac Soc 2014; 11: S33–S37.
27. Yoda K, He F, Miyazawa K et al. Orally administered heat-killed Lactobacillus gasseri TMC0356 alters respiratory immune responses and intestinal microbiota of diet-induced obese mice. J Appl Microbiol 2012; 113: 155–62. DOI: 10.1111/j.1365-2672.2012.05316.x
28. West CE. Gut microbiota and allergic disease: new findings. Curr Opin Clin Nutr Metab Care 2014; 17: 261–6. DOI: 10.1097/MCO.0000000000000044
29. Van den Broek MFL, De Boeck I, Claes IJJ et al. Multifactorial inhibition of lactobacilli against the respiratory tract pathogen Moraxella catarrhalis. Benef Microbes 2018; 9 (3): 429–39. DOI: 10.3920/BM2017.0101
30. Salva S, Villena J, Alvarez S. Immunomodulatory activity of Lactobacillus rhamnosusstrains isolated from goat milk: impact on intestinal and respiratory infections. Int J Food Microbiol 2010; 141: 82–9. 10.1016/j.ijfoodmicro.2010.03.013
31. Alvarez S, Herrero C, Bru E, Perdigon G. Effect of Lactobacillus casei and yogurt administration on prevention of Pseudomonas aeruginosa infection in young mice. J Food Prot 2001; 64: 1768–74.
32. Hori T, Kiyoshima J, Shida K, Yasui H. Effect of intranasal administration of Lactobacillus casei Shirota on influenza virus infection of upper respiratory tract in mice. Clin Diagn Lab Immunol 2001; 8: 593–7. DOI: 10.1128/cdli.8.3.593-597.2001
2. Dickson RP, Erb-Downward JR, Freeman CM et al. Spatial variation in the healthy human lung microbiome and the adapted island model of lung biogeography. Ann Am Thorac Soc 2015; 12: 821–30.
3. Bassis CM, Erb-Downward JR, Dickson RP et al. Analysis of the upper respiratory tract microbiotas as the source of the lung and gastric microbiotas in healthy individuals. MBio 2015; 6: e00037.
4. Charlson ES, Bittinger K, Haas AR et al. Topographical continuity of bacterial populations in the healthy human respiratory tract. Am J Respir Crit Care Med 2011; 184: 957–63.
5. Erb-Downward JR, Thompson DL, Han MK et al. Analysis of the lung microbiome in the “healthy” smoker and in COPD. PLoS One 2011; 6: e16384.
6. Charlson ES, Diamond JM, Bittinger K et al. Lung-enriched organisms and aberrant bacterial and fungal respiratory microbiota after lung transplant. Am J Respir Crit Care Med 2012; 186: 536–45.
7. Hilty M, Burke C, Pedro H et al. Disordered microbial communities in asthmatic airways. PLoS One 2010; 5: e8578. 10.1371/journal.pone.0008578
8. Sze MA, Dimitriu PA, Hayashi S et al. The lung tissue microbiome in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 185: 1073–80.
9. Madan JC, Koestler DC, Stanton BA et al. Serial analysis the gut and respiratory microbiome in cystic fibrosis in infancy: interaction between intestinal and respiratory tracts and impact of nutritional exposures. MBio 2012; 3 (4). pii: e00251-12. DOI: 10.1128/mBio.00251-12
10. Southam DS, Dolovich M, O'Byrne PM, Inman MD. Distribution of intranasal instillations in mice: effects of volume, time, body position, and anesthesia. Am J Physiol Lung Cell Mol Physiol 2002; 282: L833–L839. DOI: 10.1152/ajplung.00173.2001
11. Samuelson DR, Welsh DA, Shellito JE. Regulation of lung immunity and host defense by the intestinal microbiota. Front Microbiol 2015; 6: 1085.
12. Mathieu E, Escribano-Vazquez U, Descamps D et al. Paradigms of Lung Microbiota Functions in Health and Disease, Particularly, in Asthma. Front Physiol 2018; 9: 1168.
13. Statovci D, Aguilera M, MacSharry J, Melgar S. The Impact of Western Diet and Nutrients on the Microbiota and Immune Response at Mucosal Interfaces. Front Immunol 2017; 8: 838. DOI: 10.3389/fimmu.2017.00838
14. Dominguez-Bello MG, Costello EK, Contreras M et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci USA 2010; 107: 11971–5.
15. Cernadas M. It takes a microbiome: commensals, immune regulation, and allergy. Am J Respir Crit Care Med 2011; 184: 149–50.
16. Bosch AATM, Levin E, van Houten MA et al. Development of Upper Respiratory Tract Microbiota in Infancy is Affected by Mode of Delivery. E Bio Medicine 2016; 9: 336–45. DOI: 10.1016/j.ebiom.2016.05.031
17. Bosch AATM, de Steenhuijsen Piters WAA, van Houten MA et al. Maturation of the Infant Respiratory Microbiota, Environmental Drivers, and Health Consequences. A Prospective Cohort Study. Am J Respir Crit Care Med 2017; 196 (12): 1582–90. DOI: 10.1164/rccm.201703-0554OC
18. Bisgaard H, Hermansen MN, Buchvald F et al. Childhood asthma after bacterial colonization of the airway in neonates. N Engl J Med 2007; 357 (15): 1487–95.
19. Ong M-S, Umetsu DT, Mandl KD. Consequences of antibiotics and infections in infancy: bugs, drugs, and wheezing. Ann Allergy Asthma Immunol 2014; 112: 441–5.e441.
20. Ege MJ, Mayer M, Normand AC et al. Exposure to environmental microorganisms and childhood asthma. N Engl J Med 2011; 364: 701–9.
21. Trompette A, Gollwitzer ES, Yadava K et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med 2014; 20: 159–66.
22. Prevaes SM, de Winter-de Groot KM, Janssens HM et al. Development of the Nasopharyngeal Microbiota in Infants with Cystic Fibrosis. Am J Respir Crit Care Med 2016; 193 (5): 504–15. DOI: 10.1164/rccm.201509-1759OC
23. Hoen AG, Li J, Moulton LA et al. Associations between gut microbial colonization in early life and respiratory outcomes in cystic fibrosis. J Pediatr 2015; 167: 138–47, e131–133.
24. Schippa S, Iebba V, Santangelo F et al. Cystic fibrosis transmembrane conductance regulator (CFTR) allelic variants relate to shifts in faecal microbiota of cystic fibrosis patients. PLoS ONE 2013; 8: e61176.
25. Forsythe P. Probiotics and lung diseases. Chest J 2011; 139: 901–8. DOI: 10.1378/chest.10-1861
26. Forsythe P. Probiotics and lung immune responses. Ann Am Thorac Soc 2014; 11: S33–S37.
27. Yoda K, He F, Miyazawa K et al. Orally administered heat-killed Lactobacillus gasseri TMC0356 alters respiratory immune responses and intestinal microbiota of diet-induced obese mice. J Appl Microbiol 2012; 113: 155–62. DOI: 10.1111/j.1365-2672.2012.05316.x
28. West CE. Gut microbiota and allergic disease: new findings. Curr Opin Clin Nutr Metab Care 2014; 17: 261–6. DOI: 10.1097/MCO.0000000000000044
29. Van den Broek MFL, De Boeck I, Claes IJJ et al. Multifactorial inhibition of lactobacilli against the respiratory tract pathogen Moraxella catarrhalis. Benef Microbes 2018; 9 (3): 429–39. DOI: 10.3920/BM2017.0101
30. Salva S, Villena J, Alvarez S. Immunomodulatory activity of Lactobacillus rhamnosusstrains isolated from goat milk: impact on intestinal and respiratory infections. Int J Food Microbiol 2010; 141: 82–9. 10.1016/j.ijfoodmicro.2010.03.013
31. Alvarez S, Herrero C, Bru E, Perdigon G. Effect of Lactobacillus casei and yogurt administration on prevention of Pseudomonas aeruginosa infection in young mice. J Food Prot 2001; 64: 1768–74.
32. Hori T, Kiyoshima J, Shida K, Yasui H. Effect of intranasal administration of Lactobacillus casei Shirota on influenza virus infection of upper respiratory tract in mice. Clin Diagn Lab Immunol 2001; 8: 593–7. DOI: 10.1128/cdli.8.3.593-597.2001
________________________________________________
2. Dickson RP, Erb-Downward JR, Freeman CM et al. Spatial variation in the healthy human lung microbiome and the adapted island model of lung biogeography. Ann Am Thorac Soc 2015; 12: 821–30.
3. Bassis CM, Erb-Downward JR, Dickson RP et al. Analysis of the upper respiratory tract microbiotas as the source of the lung and gastric microbiotas in healthy individuals. MBio 2015; 6: e00037.
4. Charlson ES, Bittinger K, Haas AR et al. Topographical continuity of bacterial populations in the healthy human respiratory tract. Am J Respir Crit Care Med 2011; 184: 957–63.
5. Erb-Downward JR, Thompson DL, Han MK et al. Analysis of the lung microbiome in the “healthy” smoker and in COPD. PLoS One 2011; 6: e16384.
6. Charlson ES, Diamond JM, Bittinger K et al. Lung-enriched organisms and aberrant bacterial and fungal respiratory microbiota after lung transplant. Am J Respir Crit Care Med 2012; 186: 536–45.
7. Hilty M, Burke C, Pedro H et al. Disordered microbial communities in asthmatic airways. PLoS One 2010; 5: e8578. 10.1371/journal.pone.0008578
8. Sze MA, Dimitriu PA, Hayashi S et al. The lung tissue microbiome in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 185: 1073–80.
9. Madan JC, Koestler DC, Stanton BA et al. Serial analysis the gut and respiratory microbiome in cystic fibrosis in infancy: interaction between intestinal and respiratory tracts and impact of nutritional exposures. MBio 2012; 3 (4). pii: e00251-12. DOI: 10.1128/mBio.00251-12
10. Southam DS, Dolovich M, O'Byrne PM, Inman MD. Distribution of intranasal instillations in mice: effects of volume, time, body position, and anesthesia. Am J Physiol Lung Cell Mol Physiol 2002; 282: L833–L839. DOI: 10.1152/ajplung.00173.2001
11. Samuelson DR, Welsh DA, Shellito JE. Regulation of lung immunity and host defense by the intestinal microbiota. Front Microbiol 2015; 6: 1085.
12. Mathieu E, Escribano-Vazquez U, Descamps D et al. Paradigms of Lung Microbiota Functions in Health and Disease, Particularly, in Asthma. Front Physiol 2018; 9: 1168.
13. Statovci D, Aguilera M, MacSharry J, Melgar S. The Impact of Western Diet and Nutrients on the Microbiota and Immune Response at Mucosal Interfaces. Front Immunol 2017; 8: 838. DOI: 10.3389/fimmu.2017.00838
14. Dominguez-Bello MG, Costello EK, Contreras M et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci USA 2010; 107: 11971–5.
15. Cernadas M. It takes a microbiome: commensals, immune regulation, and allergy. Am J Respir Crit Care Med 2011; 184: 149–50.
16. Bosch AATM, Levin E, van Houten MA et al. Development of Upper Respiratory Tract Microbiota in Infancy is Affected by Mode of Delivery. E Bio Medicine 2016; 9: 336–45. DOI: 10.1016/j.ebiom.2016.05.031
17. Bosch AATM, de Steenhuijsen Piters WAA, van Houten MA et al. Maturation of the Infant Respiratory Microbiota, Environmental Drivers, and Health Consequences. A Prospective Cohort Study. Am J Respir Crit Care Med 2017; 196 (12): 1582–90. DOI: 10.1164/rccm.201703-0554OC
18. Bisgaard H, Hermansen MN, Buchvald F et al. Childhood asthma after bacterial colonization of the airway in neonates. N Engl J Med 2007; 357 (15): 1487–95.
19. Ong M-S, Umetsu DT, Mandl KD. Consequences of antibiotics and infections in infancy: bugs, drugs, and wheezing. Ann Allergy Asthma Immunol 2014; 112: 441–5.e441.
20. Ege MJ, Mayer M, Normand AC et al. Exposure to environmental microorganisms and childhood asthma. N Engl J Med 2011; 364: 701–9.
21. Trompette A, Gollwitzer ES, Yadava K et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med 2014; 20: 159–66.
22. Prevaes SM, de Winter-de Groot KM, Janssens HM et al. Development of the Nasopharyngeal Microbiota in Infants with Cystic Fibrosis. Am J Respir Crit Care Med 2016; 193 (5): 504–15. DOI: 10.1164/rccm.201509-1759OC
23. Hoen AG, Li J, Moulton LA et al. Associations between gut microbial colonization in early life and respiratory outcomes in cystic fibrosis. J Pediatr 2015; 167: 138–47, e131–133.
24. Schippa S, Iebba V, Santangelo F et al. Cystic fibrosis transmembrane conductance regulator (CFTR) allelic variants relate to shifts in faecal microbiota of cystic fibrosis patients. PLoS ONE 2013; 8: e61176.
25. Forsythe P. Probiotics and lung diseases. Chest J 2011; 139: 901–8. DOI: 10.1378/chest.10-1861
26. Forsythe P. Probiotics and lung immune responses. Ann Am Thorac Soc 2014; 11: S33–S37.
27. Yoda K, He F, Miyazawa K et al. Orally administered heat-killed Lactobacillus gasseri TMC0356 alters respiratory immune responses and intestinal microbiota of diet-induced obese mice. J Appl Microbiol 2012; 113: 155–62. DOI: 10.1111/j.1365-2672.2012.05316.x
28. West CE. Gut microbiota and allergic disease: new findings. Curr Opin Clin Nutr Metab Care 2014; 17: 261–6. DOI: 10.1097/MCO.0000000000000044
29. Van den Broek MFL, De Boeck I, Claes IJJ et al. Multifactorial inhibition of lactobacilli against the respiratory tract pathogen Moraxella catarrhalis. Benef Microbes 2018; 9 (3): 429–39. DOI: 10.3920/BM2017.0101
30. Salva S, Villena J, Alvarez S. Immunomodulatory activity of Lactobacillus rhamnosusstrains isolated from goat milk: impact on intestinal and respiratory infections. Int J Food Microbiol 2010; 141: 82–9. 10.1016/j.ijfoodmicro.2010.03.013
31. Alvarez S, Herrero C, Bru E, Perdigon G. Effect of Lactobacillus casei and yogurt administration on prevention of Pseudomonas aeruginosa infection in young mice. J Food Prot 2001; 64: 1768–74.
32. Hori T, Kiyoshima J, Shida K, Yasui H. Effect of intranasal administration of Lactobacillus casei Shirota on influenza virus infection of upper respiratory tract in mice. Clin Diagn Lab Immunol 2001; 8: 593–7. DOI: 10.1128/cdli.8.3.593-597.2001
Авторы
И.Н.Захарова*1, А.Н.Касьянова1, Л.Я.Климов2, В.А.Курьянинова2, М.А.Симакова1, О.В.Дедикова1, К.А.Кольцов1
1 ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава России. 125993, Россия, Москва, ул. Баррикадная, д. 2/1;
2 ФГБОУ ВО «Ставропольский государственный медицинский университет» Минздрава России. 355017, Россия, Ставрополь, ул. Мира, д. 310
*zakharova-rmapo@yandex.ru
1 Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation. 125993, Russian Federation, Moscow, ul. Barrikadnaia, d. 2/1;
2 Stavropol State Medical University of the Ministry of Health of the Russian Federation. 355017, Russian Federation, Stavropol, ul. Mira, d. 310
*zakharova-rmapo@yandex.ru
1 ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава России. 125993, Россия, Москва, ул. Баррикадная, д. 2/1;
2 ФГБОУ ВО «Ставропольский государственный медицинский университет» Минздрава России. 355017, Россия, Ставрополь, ул. Мира, д. 310
*zakharova-rmapo@yandex.ru
________________________________________________
1 Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation. 125993, Russian Federation, Moscow, ul. Barrikadnaia, d. 2/1;
2 Stavropol State Medical University of the Ministry of Health of the Russian Federation. 355017, Russian Federation, Stavropol, ul. Mira, d. 310
*zakharova-rmapo@yandex.ru
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