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Экспериментальная и клиническая гастроэнтерология

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Фекальная трансплантация: клинические реалии и перспективы в терапии метаболического синдрома

https://doi.org/10.31146/1682-8658-ecg-183-11-102-112

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Аннотация

В обзоре приведен анализ имеющихся данных по клинической эффективности фекальной трансплантации при различных заболеваниях. Определены перспективные направления данного вида терапии, а также нерешенные вопросы, касающиеся как собственно методики, так и оценки эффективности.

Об авторах

Е. И. Сас
ФГБВОУ ВО «Военно-медицинская академия имени С. М. Кирова» МО РФ
Россия

Сас Евгений Иванович, д. м. н., профессор 2 кафедры (терапии усовершенствования врачей)

194044, Санкт-Петербург, улица Академика Лебедева, д. 6



В. Б. Гриневич
ФГБВОУ ВО «Военно-медицинская академия имени С. М. Кирова» МО РФ
Россия

Гриневич Владимир Борисович, заведующий 2 кафедрой (терапии усовершенствования врачей), д. м. н., профессор

194044, Санкт-Петербург, улица Академика Лебедева, д. 6



В. А. Барнакова
ФГБВОУ ВО «Военно-медицинская академия имени С. М. Кирова» МО РФ
Россия

Барнакова Васалина Анатольевна, к. м. н., доцент 2 кафедры (терапии усовершенствования врачей)

194044, Санкт-Петербург, улица Академика Лебедева, д. 6



Список литературы

1. Whitman WB, Coleman DC, Wiebe WJ. Prokaryotes: the unseen majority. Proc Nat Acad Sci USA, 1998, Vol. 95, N12, pp. 6578–6583.

2. Ley RE, Peterson DA, Gordon JI. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell, 2006, Vol. 124, N4, pp. 837–848.

3. Eckburg PB, Bik EM, Bernstein CN, et al. Diversity of the human intestinal microbial flora. Science, 2005, Vol. 308, No. 5728, pp. 1635–1638.

4. Xu J Honor, Gordon JI. The symbionts. Proc Natl Acad Sci USA, 2003. Vol. 100, no. 18, pp. 10452–10459.

5. Frank DN, St Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci USA, 2007, Vol. 104, No. 34, pp. 13780–13785.

6. Brandt LJ American Journal of Gastroenterology Lecture: Intestinal microbiota and the role of fecal microbiota transplant (FMT) in treatment of C difficile infection. Am J Gastroenterol, 2013. Vol. 108, No. 2, pp. 177–185.

7. Swidsinski A, Loening-Baucke V, Lochs H, Hale LP.Spatial. Organization of bacterial flora in normal and inflamed intestine: a fluorescence in situ hybridization study in mice. World J Gastroenterol. 2005, Vol. 11, No.8, pp. 1131–1140.

8. Stappenbeck TS, Hooper LV, Gordon JI. Developmental regulation of intestinal angiogenesis by indigenous microbes via Paneth cells. Proc Natl Acad Sci USA, 2002, Vol. 99, No. 24, pp. 15451–15455.

9. Hooper LV, Wong MH, Thelin A, Hansson L, Falk PG, Gordon JI. Molecular analysis of commensal host-microbial relationships in the intestine. Science, 2001, Vol. 291, No.5505, pp. 881–884.

10. Hooper LV, Gordon JI. Commensal host-bacterial relationships in the gut. Science, 2001, Vol. 292, No.5519, pp. 1115–1118.

11. Wostmann B, Bruckner-Kardoss E. Development of cecal distention in germ-free baby rats. Am J Physiol. 1959, Vol. 197, pp. 1345–1346.

12. O’Hara AM, Shanahan F. The gut flora as a forgotten organ. EMBO Rep, 2006, Vol.7, No.7, pp. 688–693.

13. Banasaz M., Norin E, Holma R, Midtvedt T. Increased enterocyte production in gnotobiotic rats mono-associated with Lactobacillus rhamnosus GG. Appl Environ Microbiol, 2002, Vol. 68, No.6, pp. 3031–3034.

14. Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell, 2005, Vol.122, No.1, pp.107–118.

15. Hooper LV Do symbiotic bacteria subvert host immunity? Nat Rev Microbiol, 2009, Vol.7, No. 5, pp.367–374.

16. Salzman NH, Underwood MA, Bevins CL. Paneth cells, defensins, and the commensal microbiota: a hypothesis on intimate interplay at the intestinal mucosa. Semin Immunol, 2007, Vol. 19, No.2, pp. 70–83.

17. Zhang F, Luo W, Shi Y, Fan Z, Ji G. Should we standardize the 1,700-year-old fecal microbiota transplantation? Am J Gastroenterol, 2012, Vol. 107, No.11, 1755 P.

18. Eiseman B, Silen W, Bascom GS, Kauvar AJ. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery, 1958, Vol. 44, No.5, pp. 854–859.

19. Schwan A, Sjolin S, Tottestam U, Aronsson B. Relapsing clostridium difficile enterocolitis cured by rectal infusion of homologous faeces. Lancet. 1983. Vol. 2, No.8354, 845 P.

20. Bakken JS, Borody T, Brandt LJ, et al. Fecal Microbiota Transplantation Workgroup. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol, 2011, Vol. 9, No.12, pp. 1044–1049.

21. Brandt LJ An overview of fecal microbiota transplantation: techniques, indications, and outcomes. Gastrointest Endosc, 2013, Vol.78, No.2, pp. 240–249.

22. Kelly CR, de Leon L, Jasutkar N, et al. Fecal microbiota transplantation for relapsing Clostridium difficile infection in 26 patients: methodology and results. J Clin Gastroenterol, 2012, Vol.46, No.2, pp.145–149.

23. Polak P, Freibergerova M, Jurankova J, et al. First experiences with faecal bacte-riotherapy in treatment of relapsing pseudomembranous colitis due to Clostridium difficile. Klin MikrobiolInfekc Lek, 2011, Vol.17, No.6, pp.214–217. [in Czech].

24. Mellows MH, Kanatzar A. Colonoscopic fecal bacteriotherapy in the treatment of recurrent Clostridium difficile infection– results and follow-up. J Okla State Med Assoc, 2011, Vol.104, No.3, pp. 89–91.

25. Garborg K, Waagsbø B, Stallemo A, Matre J, Sundøy A. Results of faecal donor instillation therapy for recurrent Clostridium difficile-associated diarrhea. Scand J Infect Dis, 2010, Vol.42, No.11–12, pp. 857–861.

26. Rohlke F, Surawicz CM, Stollman N. Fecal flora reconstitution for recurrent Clostridium difficile infection: results and methodology. J Clin Gastroenterol, 2010, Vol.44, No.8, pp. 567–570.

27. Yoon SS, Brandt LJ. Treatment of refractory/recurrent C. difficile-associated disease by donated stool transplanted via colonoscopy: a case series of 12 patients. J Clin Gastroenterol, 2010. Vol. 44, No.8, pp.562–566.

28. MacConnachie AA, Fox R, Kennedy DR, Seaton RA. Faecal transplant for recurrent Clostridium difficile-associated diarrhoea: a UK case series. QJM, 2009, Vol. 102, No.11, pp.781–784.

29. Kassam Z, Hundal R, Marshall JK, Lee CH. Fecal transplant via retention enema for refractory or recurrent Clostridium difficile infection. Arch Intern Med, 2012. Vol.172, No.2, pp. 191–193.

30. Lund-Tønnesen S, Berstad A, Schreiner A, Midtvedt T. Clostridium difficileassociated diarrhea treated with homologous feces. Tidsskr Nor Laegeforen, 1998, Vol.118, No.7, pp.1027–1030. [in Norwegian]

31. Aas J, Gessert CE, Bakken JS. Recurrent Clostridium difficile colitis: case series of 18 patients treated with donor stool administered via a nasogastric tube. Clin Infect Dis, 2003. Vol. 36, No.5, pp. 580–585.

32. Mattila E, Uusitalo-Seppala R, Wuorela M, et al. Fecal transplantation, through colonoscopy, is effective therapy for recurrent Clostridium difficile infection. Gastroenterology, 2012, Vol. 142, No.3, pp. 490–496.

33. Loo VG, Poirier L, Miller MA, et al. A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med, 2005, Vol. 353, No.23, pp. 2442–2449.

34. Hamilton MJ, Weingarden AR, Sadowsky MJ, et al. Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection. Gastroenterology, 2010, Vol. 142, pp. 490–496.

35. Kassam Z, Lee CH, Yuan Y, Hunt RH. Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis. Am J Gastroenterol, 2013. Vol. 108, No. 4, pp. 500–508.

36. Silverman MS, Davis I, Pillai DR. Success of self-administered home fecal transplantation for chronic Clostridium difficile infection. Clin Gastroenterol Hepatol. 2010, Vol.8, No.5, pp. 471–473.

37. Bowden TA, Jr, Mansberger AR, Jr, Lykins LE. Pseudomembraneous enteroco-litis: mechanism for restoring floral homeostasis. Am Surg, 1981, Vol.47, No.4, pp. 178–183.

38. Gustafsson A, Lund-Tønnesen S, Berstad A, Midtvedt T, Norin E. Faecal short-chain fatty acids in patients with antibiotic-associated diarrhoea, before and after faecal enema treatment. Scand J Gastroenterol, 1998, Vol. 33, No.7, pp. 721–727.

39. Zipursky J. S. Patient attitudes toward the use of fecal microbiota transplantation in the treatment of recurrent Clostridium difficile infection. Clin Infect Dis, 2012. Vol.55, No.12, pp. 1652–1658.

40. Brandt LJ, Aroniadis OC, Mellow M, et al. Brandt LJ Long-term follow-up of colono-scopic fecal microbiota transplant for recurrent Clostridium difficile infection. Am J Gastroenterol, 2012, Vol. 107, No.7, pp. 1079–1087.

41. Brandt LJ, Borody TJ, Campbell J. Endoscopic fecal microbiota transplantation: “first-line” treatment for severe clostridium difficile infection? J Clin Gastroenterol, 2011, Vol. 45, No.8, pp. 655–657.

42. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med, 2013. Vol. 368, No.5, pp. 407–415.

43. Gough E, Shaikh H, Manges AR. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin Infect Dis, 2011. Vol. 53, No.10, pp. 994–1002.

44. Postigo R., Kim JH. Colonoscopic versus nasogastric fecal transplantation for the treatment of Clostridium difficile infection: a review and pooled analysis. Infection, 2012, Vol.40, No. 6, pp. 643–648.

45. Wu GD Analysis of the human gut microbiome and association with disease. Clin Gastroenterol Hepatol. 2013, Vol.11, No.7, pp. 774–777.

46. Sartor RB Microbial influences in infl ammatory bowel diseases. Gastroenterology, 2008, Vol.134, No.2, pp. 577–594.

47. Peterson DA, Frank DN, Pace NR, Gordon JI. Metagenomic approaches for defining the pathogenesis of inflammatory bowel diseases. Cell Host Microbe, 2008, Vol.3, No.6, pp. 417–427.

48. Willing BP, Dicksved J, Halfvarson J, et al. A pyrosequencing study in twins shows that gastrointestinal microbial profi les vary with inflammatory bowel disease phenotypes. Gastroenterology, 2010, Vol.139, No.6, pp. 1844–1854.

49. Anderson JL, Edney RJ, Whelan K. Systematic review: faecal microbiota transplantation in the management of inflammatory bowel disease. Aliment Pharmacol Ther, 2012. Vol.36, No.6, pp. 503–516.

50. Barnich N, Darfeuille-Michaud A. Adherent-invasive Escherichia coli and Crohn’s disease. Curr Opin Gastroenterol, 2007, Vol.23, No.1, pp. 16–20.

51. Packey CD Commensal bacteria, traditional and opportunistic pathogens, dysbiosis and bacterial killing in inflammatory bowel diseases. Curr Opin Infect Dis, 2009, Vol.22, No.3, pp. 292–301.

52. Allegretti JR, Hamilton MJ. Restoring the gut microbiome for the treatment of inflammatory bowel diseases. World J Gastroenterol, 2014, Vol.20, No.13, pp. 3468–3474.

53. Borody TJ, Campbell J. Fecal microbiota transplantation: techniques, applications, and issues. Gastroenterol Clin North Am, 2012, Vol.41, No.4, pp. 781–803.

54. Kunde S, Pham A, Bonczyk S, et al. Safety, tolerability, and clinical response after fecal transplantation in children and young adults with ulcerative colitis. J Pediatr Gastroenterol Nutr, 2013, Vol.56, No.6, pp. 597–601.

55. Angelberger S, Reinisch W, Makristathis A, et al. Temporal bacterial community dynamics vary among ulcerative colitis patients after fecal microbiota transplantation. Am J Gastroenterol, 2013, Vol.108, No.10, pp. 1620–1630.

56. Ford AC., Talley NJ. Irritable bowel syndrome. BMJ, 2012, Vol.345. e5836 P.

57. Gralnek IM, Hays RD, Kilbourne A, Naliboff B, Mayer EA. The impact of irritable bowel syndrome on health-related quality of life Gastroenterology, 2000, Vol.119, No.3, pp. 654–660.

58. Mayer EA, Savidge T, Shulman RJ. Brain-gut microbiome interactions and functional bowel disorders. Gastroenterology. 2014. Vol.146, No.6, pp. 1500–1512.

59. Kassinen A, Krogius-Kurikka L, Mäkivuokko H, et al. The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects. Gastroenterology, 2007, Vol.133, No.1, pp. 24–33.

60. Carroll I. M., Ringel-Kulka T., Siddle J. P., Ringel Y. Alterations in composition and diversity of the intestinal microbiota in diarrhea-predominant irritable bowel syndrome. Neurogastroenterol Motil, 2012. Vol. 24, No.6, pp. 521–530.

61. Codling C, O’Mahony L, Shanahan F, Quigley EM, Marchesi JR. molecular analysis of fecal and mucosal bacterial communities in irritable bowel syndrome. Dig Dis Sci, 2010, Vol.55, No.2, pp. 392–397.

62. Jalanka-Tuovinen J, Salojärvi J, Salonen A, et al. Faecal microbiota composition and host-microbe cross-talk following gastroenteritis and post-infectious irritable bowel syndrome. Gut, 2014, Vol.63, No.11, pp. 1737–1745.

63. Rajilić-Stojanović M Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome. Gastroenterology, 2011, Vol. 141, No.5, pp. 1792–1801.

64. Rajilić-Stojanović M, Biagi E, Heilig HG, et al. Functional dysbiosis within the gut microbiota of patients with constipated-irritable bowel syndrome. Aliment Pharmacol Ther, 2012, Vol.35, No.7, pp. 828–838.

65. Durbán A, Abellán JJ, Jiménez-Hernández N, et al. Structural alterations of faecal and mucosa-associated bacterial communities in irritable bowel syndrome. Environ Microbiol Rep, 2012, Vol. 4, No.2, pp. 242–247.

66. Ng SC, Lam EF, Lam TT, et al. Effect of probiotic bacteria on the intestinal micro-biota in irritable bowel syndrome. J Gastroenterol Hepatol, 2013, Vol.28, No.10, pp. 1624–1631.

67. Parkes GC, Rayment NB, Hudspith BN, et al. Distinct microbial populations exist in the mucosa-associated microbiota of sub-groups of irritable bowel syndrome. Neurogastroenterol Motil, 2012, Vol.24, No.1, pp. 31–39.

68. Carroll IM, Ringel-Kulka T, Keku TO, et al. Molecular analysis of the luminal- and mucosal-associated intestinal microbiota in diarrhea-predominant irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol, 2011, Vol.301, No.5, pp. G799–G807.

69. Dupont HL Review article: evidence for the role of gut microbiota in irritable bowel syndrome and its potential influence on therapeutic targets. Aliment Pharmacol Ther, 2014, Vol.39, No.10, pp. 1033–1042.

70. Halvorson HA, Schlett CD, Riddle MS. Postinfectious irritable bowel syndrome- a meta- analysis. Am J Gastroenterol, 2006, Vol.101, No.8, pp. 1894–1899.

71. Th abane M, Kottachchi DT, Marshall JK. Systematic review and meta-analysis: the incidence and prognosis of post-infectious irritable bowel syndrome. Aliment Pharmacol Ther, 2007, Vol. 26, No.4, pp. 535–544.

72. Törnblom H, Holmvall P, Svenungsson B, Lindberg G. Gastrointestinal symptoms after infectious diarrhea: a five-year follow-up in a Swedish cohort of adults. Clin Gastroenterol Hepatol, 2007, Vol. 5, No.4, pp. 461–464.

73. Maxwell PR, Rink E, Kumar D, Mendall MA. Antibiotics increase functional abdominal symptoms. Am J Gastroenterol, 2002, Vol. 97, No.1, pp. 104–108.

74. Smits LP, Bouter KE, de Vos WM, Borody TJ, Nieuwdorp M. Therapeutic potential of fecal microbiota transplantation. Gastroenterology, 2013, Vol. 145, No.5, pp. 946–953.

75. Grehan MJ, Borody TJ, Leis SM, Campbell J, Mitchell H, Wettstein A. Durable alteration of the colonic microbiota by the administration of donor fecal flora. J Clin Gastroenterol, 2010, Vol.44, No.8, pp. 551–561.

76. Andrews P, Borody T, Shortis NP, Thompson S. Bacteriotherapy for chronic constipation – a long term follow-up. Gastroenterology. 1995, Vol.108, No.4 suppl 2, pp. A563.

77. Ogden CL, Carroll MD, Kit BK, Flegal FM. Prevalence of obesity among adults: United States, 2011–2012. NCHS Data Brief, 2013, No.131, pp. 1–8.

78. Parek PJ, Arusi E, Vinik AI, Johnson DA. The role and influence of gut micro-biota in pathogenesis and management of obesity and metabolic syndrome. Front Endocrinol, 2014, Vol. 47, pp. 1–7.

79. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006, Vol. 444, No.7122, pp. 1027–1031.

80. Bäckhed F, Ding H, Wang T, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA, 2004. Vol.101, No.44, pp. 15718–15723.

81. Vrieze A, Van Nood E, Holleman F, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology, 2012, Vol.143, No.4, pp. 913–917.

82. Janeway CA, Jr, Travers P, Walport M, and Shlomchik MJ. Immunobiology: The Immune System in Health and Disease. 5th ed. New York: Garland Science. 2001.

83. Mazmanian SK, Round JL, Kasper DL. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature, 2008, Vol. 453, No.7195, pp. 620–625.

84. Ochoa-Repáraz J, Mielcarz DW, Ditrio LE, et al. Central nervous system demyelinating disease protection by the human commensal Bacteroides fragilis depends on polysaccharide A expression. J Immunol, 2010, Vol.185, No.7, pp. 4101–4108.

85. Borody TJ, Leis S, Campbell J, et al. Fecal microbiota transplantation (FMT) in multiple sclerosis (MS). Am J Gastroenterol, 2011, Vol. 106, pp. S352.

86. Borody TJ, Torres M, Campbell J, et al. Treatment of severe constipation improves Parkinson’s disease (PD) symptoms. Am J Gastroenterol, 2009, Vol. 94(suppl), pp. S999.

87. Derkinderen P, Shannon KM, Brundin P. Gut feelings about smoking and coffee in Parkinson’s disease. Mov Disord, 2014, Vol.29, No.8, pp. 976–979.

88. Sekirov I, Russell SL, Antunes LC, Finlay BB. Gut microbiota in health and disease. Physiol Rev, 2010, Vol.90, No.3, pp. 859–904.

89. Finegold SM, Molitoris D, Song Y, et al. Gastrointestinal microflora studies in late-onset autism. Clin Infect Dis, 2002, Vol.35, pp. 6–16.

90. Bolte E. R. Autism and Clostridium tetani. Med Hypotheses, 1998, Vol. 51, No.2, pp. 133–144.

91. Sandler RH, Finegold SM, Bolte ER, et al. Short-term benefit from oral vanco-mycin treatment of regressive-onset autism. J Child Neurol, 2000, Vol.15, No.7, pp. 429–435.

92. Mayer EA Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci, 2011, Vol. 12, No.8, pp. 453–466.

93. Sudo N, Chida Y, Aiba Y, et al. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol, 2004, Vol. 558, pp. 263–275.

94. O’Mahony S.M., Marchesi J. R., Scully P., et al. Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol Psychiatry, 2009, Vol. 65, No.3, pp. 263–267.

95. Bailey MT Maternal separation disrupts the integrity of the intestinal microflora in infant rhesus monkeys. Dev Psychobiol, 1999, Vol. 35, No.2, pp. 146–155.

96. Mättö J, Maunuksela L, Kajander K, et al. Composition and temporal stability of gastrointestinal microbiota in irritable bowel syndrome- a longitudinal study in IBS and control subjects. FEMS Immunol Med Microbiol, 2005, Vol. 43, No.2, pp. 213–222.

97. Bercik P, Denou E, Collins J, et al. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology, 2011, Vol. 141, No.2, pp. 599–609, 609.e1–609.e3.

98. FDA Safety Alert: Fecal Transplant May Have Caused a Patient’s Death Due to Transmission of a Multi-Drug Resistant Organism 2019 https://linksmedicus.com/news/fda-safety-alert-fecal-transplant-may-caused-patients-death-due-transmission-multi-drug-resistantorganism.

99. Lawley T. D., Clare S., Walker A. W., et al. Targeted restoration of the intestinal microbiota with a simple, defined bacteriotherapy resolves relapsing Clostridium difficile disease in mice. PLoSPathog, 2012, Vol.8, No.10, pp. e1002995.

100. Petrof E. O., Gloor G. B., Vanner S. J., et al. Stool substitute transplant therapy for the eradication of Clostridium difficile infection: ‘rePOOPulating’ the gut. Microbiome, 2013, Vol.1, No.1, pp. 1–12.

101. Liat Gutin, Yvette Piceno, Douglas Fadrosh et al. Fecal microbiota transplant for Crohn disease: A study evaluating safety, efficacy, and microbiome profi le. United European Gastroenterology Journal, 2019, Vol.7, No.6, pp. 807–814


Для цитирования:


Сас Е.И., Гриневич В.Б., Барнакова В.А. Фекальная трансплантация: клинические реалии и перспективы в терапии метаболического синдрома. Экспериментальная и клиническая гастроэнтерология. 2020;183(11):102-112. https://doi.org/10.31146/1682-8658-ecg-183-11-102-112

For citation:


Sas E.I., Grinevich V.B., Barnakova V.A. Fecal transplantation: clinical realities and prospects in the treatment of metabolic syndrome. Experimental and Clinical Gastroenterology. 2020;183(11):102-112. (In Russ.) https://doi.org/10.31146/1682-8658-ecg-183-11-102-112

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