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Полифакториальные эффекты Lactobacillus paracasei DG в регуляции микробно-тканевого комплекса
Захаренко С.М. Полифакториальные эффекты Lactobacillus paracasei DG в регуляции микробно-тканевого комплекса. Терапевтический архив. 2024;96(2):168–175. DOI: 10.26442/00403660.2024.02.202649
© ООО «КОНСИЛИУМ МЕДИКУМ», 2024 г.
© ООО «КОНСИЛИУМ МЕДИКУМ», 2024 г.
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Zakharenko SM. Multifactorial effects of Lactobacillus paracasei DG in the regulation of the microbial-tissue complex: A review. Terapevticheskii Arkhiv (Ter. Arkh.). 2024;96(2):168–175.
DOI: 10.26442/00403660.2024.02.202649
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Аннотация
Микробиом кишечника человека представляет собой сложную биологическую систему, функции и метаболические процессы которой являются результатом множественных взаимодействий между микробными группами. Внутри этих групп и между ними формируются специфические взаимосвязи, позволяющие дублировать и резервировать отдельные функции, системно управлять их реализацией и в целом обеспечивать надежное функционирование всего микробиома, в том числе в интересах макроорганизма-хозяина. Решающая роль в функционировании микробиоценоза как цельной системы принадлежит функционально-метаболическому микробному ядру. Современный пробиотик Lactobacillus paracasei DG благодаря природным свойствам выполняет функцию «дирижера» микробиоценоза желудочно-кишечного тракта, регулируя метаболическую активность нормофлоры кишечника, реализуя иммунотропные эффекты благодаря продукции экзополисахаридов, в том числе неизвестного ранее экзополисахарида b, поддерживая целостность кишечного эпителиального барьера, оказывая противовирусное действие, дистантные эффекты в отношении микробиоценозов других экологических ниш.
Ключевые слова: микробиом, Lactobacillus paracasei DG, микробиоценоз-ориентированная терапия, микробно-тканевой комплекс
Ключевые слова: микробиом, Lactobacillus paracasei DG, микробиоценоз-ориентированная терапия, микробно-тканевой комплекс
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The human gut microbiome is a complex biological system whose functions and metabolic processes are the result of multiple interactions between microbial groups. Within these groups and between them, specific relationships are formed that allow duplicating and reserving individual functions, systematically managing their implementation and, in general, ensuring the reliable functioning of the entire microbiome, including in the interests of the host macroorganism. The functional and metabolic microbial nucleus plays a crucial role in the functioning of microbiocenosis as a whole system. Due to its natural properties, the modern probiotic Lactobacillus paracasei DG performs the function of a conductor of the microbiocenosis of the gastrointestinal tract, regulating the metabolic activity of the intestinal normoflora, realizing immunotropic effects due to the production of exopolysaccharides, including previously unknown exopolysaccharides b, maintaining the integrity of the intestinal epithelial barrier, exerting antiviral action, exerting distant effects against microbiocenoses of other ecological niches.
Keywords: microbiome, Lactobacillus paracasei DG, microbiocenosis-oriented therapy, microbial-tissue complex
Полный текст
Список литературы
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21. Moya A, Ferrer M. Functional redundancy-induced stability of gut microbiota subjected to disturbance. Trends Microbiol. 2016;24(5):402-13. DOI:10.1016/j.tim.2016.02.002
22. Qin J, Li R, Raes J, Arumugam M, et al.; MetaHIT Consortium; Bork P, Ehrlich SD, Wang J. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464(7285):59-65. DOI:10.1038/nature08821
23. Forster SC, Kumar N, Anonye BO, et al. A human gut bacterial genome and culture collection for improved metagenomic analyses. Nat Biotechnol. 2019;37(2):186-92. DOI:10.1038/s41587-018-0009-7
24. Zelezniak A, Andrejev S, Ponomarova O, et al. Metabolic dependencies drive species co-occurrence in diverse microbial communities. Proc Natl Acad Sci USA. 2015;112(20):6449-54. DOI:10.1073/pnas.1421834112
25. Hall CV, Lord A, Betzel R, et al. Co-existence of network architectures supporting the human gut microbiome. iScience. 2019;22:380-91. DOI:10.1016/j.isci.2019.11.032
26. Haffner JJ, Katemauswa M, Kagone TS, et al. The core human fecal metabolome. bioRxiv. 2021.05.08.442269. DOI:10.1101/2021.05.08.442269
27. Human Microbiome Market Size & Share, by Product (Probiotics, Prebiotics, Diagnostic Tests, Drugs); Disease Type (Infectious Disease, Obesity, Diabetes, Gastrointestinal Diseases, Cancer, Cardiovascular Diseases); Organism Type (Aerobic Organisms, Obligate & Facultative Anaerobes, Genetically Engineered Strains, BSL-2 & Spore-Forming Species); Application (Therapeutics, Diagnostics) – Global Supply & Demand Analysis, Growth Forecasts, Statistics Report 2023–2035. Available at: https://www.researchnester.com/reports/human-microbiome-market/4062. Accessed: 16.12.2023.
28. Human Microbiome Market (4th Edition): Focus on Therapeutics, Diagnostics and Fecal Microbiota Therapy: Distribution by Type of Molecule (Small Molecule and Biologic), Type of Product (Probiotic Drugs and Other Drugs), Target Indication. Industry Trends and Global Forecasts, 2022–2035. Available at: https://www.giiresearch.com/report/root1071905-human-microbiome-market-4th-edition-focus-on.html. Accessed: 16.12.2023.
29. Balzaretti S, Taverniti V, Guglielmetti S, et al. A novel rhamnose-rich hetero-exopolysaccharide isolated from Lactobacillus paracasei DG activates THP-1 human monocytic cells. Appl Environ Microbiol. 2017;83(3):e02702-16. DOI:10.1128/AEM.02702-16
30. Radicioni M, Koirala R, Fiore W, et al. Survival of L. casei DG® (Lactobacillus paracasei CNCMI1572) in the gastrointestinal tract of a healthy paediatric population. Eur J Nutr. 2019;58(8):3161-70. DOI:10.1007/s00394-018-1860-5
31. Arioli S, Koirala R, Taverniti V, et al. Quantitative recovery of viable Lactobacillus paracasei CNCM I-1572 (L. casei DG®) after gastrointestinal passage in healthy adults. Front Microbiol. 2018;9:1720. DOI:10.3389/fmicb.2018.01720
32. Altaha BM, Wadi J, Shehabi AA. Detection probiotic's DNA of Lactobacillus paracasei in healthy human faeces. J Pharm Res Int. 2018;23:44636. DOI:10.9734/JPRI/2018/44636
33. Drago L, De Vecchi E, Valli M, Gismondo MR. Colonizzazione intestinale di Lactobacillus casei subsp. casei I-1572 CNCM (L. casei DG) in volontari sani e in topi germ-free. Farmaci e Terapia. 2002;19(1/2):72-6.
34. Ferrario C, Taverniti V, Milani C, et al. Modulation of fecal Clostridiales bacteria and butyrate by probiotic intervention with Lactobacillus paracasei DG varies among healthy adults. J Nutr. 2014;144(11):1787-96. DOI:10.3945/jn.114.197723
35. Торшин И.Ю., Громова О.А., Максимов В.А., и др. Анализ штамм-специфичных эффектов лактобацилл L. casei DG (L. paracasei CNCM I-1572) и возможность их применения в клинической практике. Экспериментальная и клиническая гастроэнтерология. 2019;162(2):151-8 [Torshin IYu, Gromova OA, Maksimov VA, et al. Analysis of the strain-specific effects of lactobacilli L. casei DG (L. paracasei CNCM I-1572) and the possibility of their use in clinical practice. Experimental and Clinical Gastroenterology. 2019;162(2):151-8 (in Russian)]. DOI:10.31146/1682-8658-ecg-162-2-151-158
36. Taverniti V, Cesari V, Gargari G, et al. Probiotics modulate mouse gut microbiota and influence intestinal immune and serotonergic gene expression in a site-specific fashion. Front Microbiol. 2021;12:706135. DOI:10.3389/fmicb.2021.706135
37. Zambori C, Morvay AA, Sala C, et al. Antimicrobial effect of probiotics on bacterial species from dental plaque. J Infect Dev Ctries. 2016;10(3):214-21. DOI:10.3855/jidc.6800
38. Cremon C, Guglielmetti S, Gargari G, et al. Effect of Lactobacillus paracasei CNCM I-1572 on symptoms, gut microbiota, short chain fatty acids, and immune activation in patients with irritable bowel syndrome: A pilot randomized clinical trial. United European Gastroenterol J. 2018;6(4):604-13. DOI:10.1177/2050640617736478
39. Хлынов И.Б., Хлынова Р.И., Воронова Е.И., и др. Эффективность и безопасность Lactobacillus paracasei CNCM I-1572 и фруктоолигосахаридов в лечении больных СРК с запором. Экспериментальная и клиническая гастроэнтерология. 2021;190(6):57-62 [Khlinov IB, Khlynova RI, Voronova EI, et al. Efficacy and safety of Lactobacillus paracasei CNCM I-1572 and fructo-oligosaccharides in the treatment of patients with irritable bowel syndrome with constipation. Experimental and Clinical Gastroenterology. 2021;1(6):57-62 (in Russian)]. DOI:10.31146/1682-8658-ecg-190-6-57-62
40. Compare D, Rocco A, Coccoli P, et al. Lactobacillus casei DG and its postbiotic reduce the inflammatory mucosal response: An ex-vivo organ culture model of post-infectious irritable bowel syndrome. BMC Gastroenterol. 2017;17(1):53. DOI:10.1186/s12876-017-0605-x
41. Turco F, Andreozzi P, Palumbo I, et al. Bacterial stimuli activate nitric oxide colonic mucosal production in diverticular disease. Protective effects of L. casei DG® (Lactobacillus paracasei CNCM I-1572). United European Gastroenterol J. 2017;5(5):715-24. DOI:10.1177/2050640616684398
42. Tursi A, Brandimarte G, Giorgetti GM, Elisei W. Mesalazine and/or Lactobacillus casei in preventing recurrence of symptomatic uncomplicated diverticular disease of the colon: A prospective, randomized, open-label study. J Clin Gastroenterol. 2006;40(4):312-6. DOI:10.1097/01.mcg.0000210092.77296.6d
43. Tursi A, Brandimarte G, Elisei W, et al. Randomised clinical trial: Mesalazine and/or probiotics in maintaining remission of symptomatic uncomplicated diverticular disease – A double-blind, randomised, placebo-controlled study. Aliment Pharmacol Ther. 2013;38(7):741-51. DOI:10.1111/apt.12463
44. Casula E, Pisano MB, Serreli G, et al. Probiotic lactobacilli attenuate oxysterols-induced alteration of intestinal epithelial cell monolayer permeability: Focus on tight junction modulation. Food Chem Toxicol. 2023;172:113558. DOI:10.1016/j.fct.2022.113558
45. Топчий Т.Б., Ардатская М.Д., Буторова Л.И., и др. Особенности состояния кишечника на фоне новой коронавирусной инфекции. Терапевтический архив. 2022;92(7):920-6 [Topchiy TВ, Ardatskaya MD, Butorova LI, et al. Features of the intestine conditions at patients with a new coronavirus infection. Terapevticheskii Arkhiv (Ter. Arkh.). 2022;94(7):920-6 (in Russian)]. DOI:10.26442/00403660.2022.07.201768
46. Ахмедов В.А. Коррекция нарушений микробного состава кишечника как потенциальное звено в комплексной терапии пациентов с COVID-19. Терапевтический архив. 2022;94(2):277-82 [Akhmedov VA. Correction of intestinal microbial composition disturbances as a potential link in complex therapy of patients with COVID-19. Terapevticheskii Arkhiv (Ter. Arkh.). 2022;94(2):277-82 (in Russian)]. DOI:10.26442/00403660.2022.02.201388
47. Паценко М.Б., Ардатская М.Д., Анучкин А.А., и др. Отдаленные последствия COVID-19 у пациентов с функциональными расстройствами кишечника, реабилитационные возможности микробиоценоз-ориентированной терапии. Терапевтический архив. 2023;95(12):1119-27 [Patsenko MB, Ardatskaya MD, Anuchkin AA, et al. Long-term consequences of COVID-19 in patients with functional bowel disorders, rehabilitation prospective of microbiocenosis-oriented therapy. Terapevticheskii Arkhiv (Ter. Arkh.). 2023;95(12):1119-27 (in Russian)]. DOI:10.26442/00403660.2023.12.202523
48. Salaris C, Scarpa M, Elli M, et al. Lacticaseibacillus paracasei DG enhances the lactoferrin anti-SARS-CoV-2 response in Caco-2 cells. Gut Microbes. 2021;13(1):1961970. DOI:10.1080/19490976.2021.1961970
49. Castagliuolo I, Scarpa M, Brun P, et al. Co-administration of vitamin D3 and Lacticaseibacillus paracasei DG increase 25-hydroxyvitamin D serum levels in mice. Ann Microbiol. 2021;71(1):42. DOI:10.1186/s13213-021-01655-3
50. Карахалис Л.Ю., Жигаленко А.Р., Доценко С.В., Воронкова В.В. Подготовка пациенток с хроническим эндометритом к процедуре вспомогательных репродуктивных технологий. Акушерство и гинекология. 2023;12:152-7 [Karakhalis LYu, Zhigalenko AR, Dotsenko SV, Voronkova VV. Preparation of patients with chronic endometritis for the procedure of assisted reproductive technologies. Akusherstvo i Ginekologiya = Obstetrics and Gynecology. 2023;12:152-7 (in Russian)]. DOI:10.18565/aig.2023.291
51. Cai T, Gallelli L, Cione E, et al. The use of Lactobacillus casei DG® prevents symptomatic episodes and reduces the antibiotic use in patients affected by chronic bacterial prostatitis: Results from a phase IV study. World J Urol. 2021;39(9):3433-40. DOI:10.1007/s00345-020-03580-7
________________________________________________
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14. Gasaly N, de Vos P, Hermoso MA. Impact of bacterial metabolites on gut barrier function and host immunity: A focus on bacterial metabolism and its relevance for intestinal inflammation. Front Immunol. 2021;12:658354. DOI:10.3389/fimmu.2021.658354
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16. Masterson D. "Total microbiome company" is bringing microbiome innovation to the masses. 2022. Available at: https://www.nutraingredients-usa.com/Article/2022/09/08/total-microbiome-company-is-bringing-microbi.... Accessed: 16.12.2023.
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19. Rinninella E, Raoul P, Cintoni M, et al. What is the healthy gut microbiota composition? A changing ecosystem across age, environment, diet, and diseases. Microorganisms. 2019;7(1):14. DOI:10.3390/microorganisms7010014
20. Flint HJ, Bayer EA, Rincon MT, et al. Polysaccharide utilization by gut bacteria: Potential for new insights from genomic analysis. Nat Rev Microbiol. 2008;6(2):121-31. DOI:10.1038/nrmicro1817
21. Moya A, Ferrer M. Functional redundancy-induced stability of gut microbiota subjected to disturbance. Trends Microbiol. 2016;24(5):402-13. DOI:10.1016/j.tim.2016.02.002
22. Qin J, Li R, Raes J, Arumugam M, et al.; MetaHIT Consortium; Bork P, Ehrlich SD, Wang J. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464(7285):59-65. DOI:10.1038/nature08821
23. Forster SC, Kumar N, Anonye BO, et al. A human gut bacterial genome and culture collection for improved metagenomic analyses. Nat Biotechnol. 2019;37(2):186-92. DOI:10.1038/s41587-018-0009-7
24. Zelezniak A, Andrejev S, Ponomarova O, et al. Metabolic dependencies drive species co-occurrence in diverse microbial communities. Proc Natl Acad Sci USA. 2015;112(20):6449-54. DOI:10.1073/pnas.1421834112
25. Hall CV, Lord A, Betzel R, et al. Co-existence of network architectures supporting the human gut microbiome. iScience. 2019;22:380-91. DOI:10.1016/j.isci.2019.11.032
26. Haffner JJ, Katemauswa M, Kagone TS, et al. The core human fecal metabolome. bioRxiv. 2021.05.08.442269. DOI:10.1101/2021.05.08.442269
27. Human Microbiome Market Size & Share, by Product (Probiotics, Prebiotics, Diagnostic Tests, Drugs); Disease Type (Infectious Disease, Obesity, Diabetes, Gastrointestinal Diseases, Cancer, Cardiovascular Diseases); Organism Type (Aerobic Organisms, Obligate & Facultative Anaerobes, Genetically Engineered Strains, BSL-2 & Spore-Forming Species); Application (Therapeutics, Diagnostics) – Global Supply & Demand Analysis, Growth Forecasts, Statistics Report 2023–2035. Available at: https://www.researchnester.com/reports/human-microbiome-market/4062. Accessed: 16.12.2023.
28. Human Microbiome Market (4th Edition): Focus on Therapeutics, Diagnostics and Fecal Microbiota Therapy: Distribution by Type of Molecule (Small Molecule and Biologic), Type of Product (Probiotic Drugs and Other Drugs), Target Indication. Industry Trends and Global Forecasts, 2022–2035. Available at: https://www.giiresearch.com/report/root1071905-human-microbiome-market-4th-edition-focus-on.html. Accessed: 16.12.2023.
29. Balzaretti S, Taverniti V, Guglielmetti S, et al. A novel rhamnose-rich hetero-exopolysaccharide isolated from Lactobacillus paracasei DG activates THP-1 human monocytic cells. Appl Environ Microbiol. 2017;83(3):e02702-16. DOI:10.1128/AEM.02702-16
30. Radicioni M, Koirala R, Fiore W, et al. Survival of L. casei DG® (Lactobacillus paracasei CNCMI1572) in the gastrointestinal tract of a healthy paediatric population. Eur J Nutr. 2019;58(8):3161-70. DOI:10.1007/s00394-018-1860-5
31. Arioli S, Koirala R, Taverniti V, et al. Quantitative recovery of viable Lactobacillus paracasei CNCM I-1572 (L. casei DG®) after gastrointestinal passage in healthy adults. Front Microbiol. 2018;9:1720. DOI:10.3389/fmicb.2018.01720
32. Altaha BM, Wadi J, Shehabi AA. Detection probiotic's DNA of Lactobacillus paracasei in healthy human faeces. J Pharm Res Int. 2018;23:44636. DOI:10.9734/JPRI/2018/44636
33. Drago L, De Vecchi E, Valli M, Gismondo MR. Colonizzazione intestinale di Lactobacillus casei subsp. casei I-1572 CNCM (L. casei DG) in volontari sani e in topi germ-free. Farmaci e Terapia. 2002;19(1/2):72-6.
34. Ferrario C, Taverniti V, Milani C, et al. Modulation of fecal Clostridiales bacteria and butyrate by probiotic intervention with Lactobacillus paracasei DG varies among healthy adults. J Nutr. 2014;144(11):1787-96. DOI:10.3945/jn.114.197723
35. Torshin IYu, Gromova OA, Maksimov VA, et al. Analysis of the strain-specific effects of lactobacilli L. casei DG (L. paracasei CNCM I-1572) and the possibility of their use in clinical practice. Experimental and Clinical Gastroenterology. 2019;162(2):151-8 (in Russian). DOI:10.31146/1682-8658-ecg-162-2-151-158
36. Taverniti V, Cesari V, Gargari G, et al. Probiotics modulate mouse gut microbiota and influence intestinal immune and serotonergic gene expression in a site-specific fashion. Front Microbiol. 2021;12:706135. DOI:10.3389/fmicb.2021.706135
37. Zambori C, Morvay AA, Sala C, et al. Antimicrobial effect of probiotics on bacterial species from dental plaque. J Infect Dev Ctries. 2016;10(3):214-21. DOI:10.3855/jidc.6800
38. Cremon C, Guglielmetti S, Gargari G, et al. Effect of Lactobacillus paracasei CNCM I-1572 on symptoms, gut microbiota, short chain fatty acids, and immune activation in patients with irritable bowel syndrome: A pilot randomized clinical trial. United European Gastroenterol J. 2018;6(4):604-13. DOI:10.1177/2050640617736478
39. Khlinov IB, Khlynova RI, Voronova EI, et al. Efficacy and safety of Lactobacillus paracasei CNCM I-1572 and fructo-oligosaccharides in the treatment of patients with irritable bowel syndrome with constipation. Experimental and Clinical Gastroenterology. 2021;1(6):57-62 (in Russian). DOI:10.31146/1682-8658-ecg-190-6-57-62
40. Compare D, Rocco A, Coccoli P, et al. Lactobacillus casei DG and its postbiotic reduce the inflammatory mucosal response: An ex-vivo organ culture model of post-infectious irritable bowel syndrome. BMC Gastroenterol. 2017;17(1):53. DOI:10.1186/s12876-017-0605-x
41. Turco F, Andreozzi P, Palumbo I, et al. Bacterial stimuli activate nitric oxide colonic mucosal production in diverticular disease. Protective effects of L. casei DG® (Lactobacillus paracasei CNCM I-1572). United European Gastroenterol J. 2017;5(5):715-24. DOI:10.1177/2050640616684398
42. Tursi A, Brandimarte G, Giorgetti GM, Elisei W. Mesalazine and/or Lactobacillus casei in preventing recurrence of symptomatic uncomplicated diverticular disease of the colon: A prospective, randomized, open-label study. J Clin Gastroenterol. 2006;40(4):312-6. DOI:10.1097/01.mcg.0000210092.77296.6d
43. Tursi A, Brandimarte G, Elisei W, et al. Randomised clinical trial: Mesalazine and/or probiotics in maintaining remission of symptomatic uncomplicated diverticular disease – A double-blind, randomised, placebo-controlled study. Aliment Pharmacol Ther. 2013;38(7):741-51. DOI:10.1111/apt.12463
44. Casula E, Pisano MB, Serreli G, et al. Probiotic lactobacilli attenuate oxysterols-induced alteration of intestinal epithelial cell monolayer permeability: Focus on tight junction modulation. Food Chem Toxicol. 2023;172:113558. DOI:10.1016/j.fct.2022.113558
45. Topchiy TВ, Ardatskaya MD, Butorova LI, et al. Features of the intestine conditions at patients with a new coronavirus infection. Terapevticheskii Arkhiv (Ter. Arkh.). 2022;94(7):920-6 (in Russian). DOI:10.26442/00403660.2022.07.201768
46. Akhmedov VA. Correction of intestinal microbial composition disturbances as a potential link in complex therapy of patients with COVID-19. Terapevticheskii Arkhiv (Ter. Arkh.). 2022;94(2):277-82 (in Russian). DOI:10.26442/00403660.2022.02.201388
47. Patsenko MB, Ardatskaya MD, Anuchkin AA, et al. Long-term consequences of COVID-19 in patients with functional bowel disorders, rehabilitation prospective of microbiocenosis-oriented therapy. Terapevticheskii Arkhiv (Ter. Arkh.). 2023;95(12):1119-27 (in Russian). DOI:10.26442/00403660.2023.12.202523
48. Salaris C, Scarpa M, Elli M, et al. Lacticaseibacillus paracasei DG enhances the lactoferrin anti-SARS-CoV-2 response in Caco-2 cells. Gut Microbes. 2021;13(1):1961970. DOI:10.1080/19490976.2021.1961970
49. Castagliuolo I, Scarpa M, Brun P, et al. Co-administration of vitamin D3 and Lacticaseibacillus paracasei DG increase 25-hydroxyvitamin D serum levels in mice. Ann Microbiol. 2021;71(1):42. DOI:10.1186/s13213-021-01655-3
50. Karakhalis LYu, Zhigalenko AR, Dotsenko SV, Voronkova VV. Preparation of patients with chronic endometritis for the procedure of assisted reproductive technologies. Akusherstvo i Ginekologiya = Obstetrics and Gynecology. 2023;12:152-7 (in Russian). DOI:10.18565/aig.2023.291
51. Cai T, Gallelli L, Cione E, et al. The use of Lactobacillus casei DG® prevents symptomatic episodes and reduces the antibiotic use in patients affected by chronic bacterial prostatitis: Results from a phase IV study. World J Urol. 2021;39(9):3433-40. DOI:10.1007/s00345-020-03580-7
Авторы
С.М. Захаренко*
ФГБУ «Детский научно-клинический центр по инфекционным болезням» ФМБА России, Санкт-Петербург, Россия
*zaharenko.sm@niidi.ru
ФГБУ «Детский научно-клинический центр по инфекционным болезням» ФМБА России, Санкт-Петербург, Россия
*zaharenko.sm@niidi.ru
________________________________________________
Sergey M. Zakharenko*
Federal State-Financed Institution Pediatric Research and Clinical Center for Infectious Diseases, Saint Petersburg, Russia
*zaharenko.sm@niidi.ru
Цель портала OmniDoctor – предоставление профессиональной информации врачам, провизорам и фармацевтам.