Importance of intestinal microbiota in critically ill patients and possibilities of its influence

Česká verzia

Authors: I. Cibulková ¹; V. Řehořová ²; F. Duška ²
Authors place of work: Interní klinika 3. lékařské fakulty Univerzity Karlovy a Fakultní nemocnice Královské Vinohrady, Praha ¹; Klinika anesteziologie a resuscitace 3. lékařské fakulty Univerzity Karlovy a Fakultní nemocnice Královské Vinohrady, Praha ²
Published in the journal: Anest. intenziv. Med., 33, 2022, č. 1, s. 32-38
Category: Review Article

Summary

Human gut microbiota consists of bacteria, archaea, fungi and viruses, and its composition, specific to each individual, is shaped by many factors. Pathological imbalance in the composition and/or diversity of microorganisms (dysbiosis), is associated with a wide range of diseases. The intestinal microbiome is the result of a complicated interplay between the host and the intestinal microflora. Critically ill patients have a reduced number of symbiotic bacteria ( particularly Firmicutes and Bacteroidetes) and, conversely, a relative increase in pathogenic intestinal bacteria (particularly Proteobacteria), and the rate of dysbiosis is directly proportional to the severity of their condition. On the other hand, the intestinal microbiota affects the permeability of the intestinal barrier, immune regulation, systemic inflammation, and, in turn, influences the clinical condition of critically ill patients. Altering the composition of intestinal bacteria by probiotics, prebiotics or antibiotics has long been used in intensive care. Ultimate intervention to affect the intestinal microbiota is fecal microbial transplantation (FMT) from healthy donors. In critically ill patients, FMT is described in case reports and case series as effective and safe method in the treatment of dysmicrobia in severe and fulminant C. difficile colitis, antibiotic-associated diarrhea, severe forms of inflammatory bowel disease or as a rescue therapy of sepsis. Despite the undisputable biological plausibility and positive effect observed in individual patients, FMT cannot be recommended as a routine procedure in this high-risk population, as high-quality prospective controlled clinical studies are completely absent. The article summarizes directions of future research and the method of implementation of FMT in critically ill patients.

Keywords:

Microbiome – intestinal microbiota – critically ill – fecal microbial transplantation – postantibiotic diarrhea

Zdroje

1. Khanna S. Microbiota Replacement Therapies: Innovation in Gastrointestinal Care. Clin Pharmacol Ther. 2018 Jan;103(1):102-111. doi: 10.1002/cpt.923. Epub 2017 Nov 14. PMID: 29071710.

2. Wen L, Duffy A. Factors Influencing the Gut Microbiota, Inflammation, and Type 2 Diabetes. J Nutr. 2017 Jul;147(7):1468S-1475S. doi: 10.3945/jn.116.240754. Epub 2017 Jun 14. PMID: 28615382; PMCID: PMC5483960.

3. Al-Rashidi HE. Gut microbiota and immunity relevance in eubiosis and dysbiosis. Saudi Journal of Biological Sciences, 2021, ISSN 1319-562X, https://doi.org/10.1016/ j.sjbs.2021.10.068.

4. Rastelli M, Knauf C, Cani PD. Gut Microbes and Health: A Focus on the Mechanisms Linking Microbes, Obesity, and Related Disorders. Obesity (Silver Spring). 2018 May;26(5): 792-800. doi: 10.1002/oby.22175. PMID: 29687645; PMCID: PMC5947576.

5. Liu W, Cheng M, Li J, Zhang P, Fan H, Hu Q, et al. Classification of the Gut Microbiota of Patients in Intensive Care Units During Development of Sepsis and Septic Shock. Genomics Proteomics Bioinformatics. 2020 Dec;18(6):696-707. doi: 10.1016/j.gpb.2020.06.011. Epub 2021 Feb 17. PMID: 33607294; PMCID: PMC8377022.

6. Kverka M, Tlaskalova-Hogenova H. Two faces of microbiota in inflammatory and autoimmune diseases: triggers and drugs. APMIS. 2013 May;121(5):403-421. doi: 10.1111/apm.12007. Epub 2012 Oct 24. PMID: 23094605.

7. Carvalho BM, Saad MJ. Influence of gut microbiota on subclinical inflammation and insulin resistance. Mediators Inflamm. 2013;2013:986734. doi: 10.1155/2013/986734. Epub 2013 Jun 12. PMID: 23840101; PMCID: PMC3694527.

8. McLean MH, Dieguez D Jr, Miller LM, Young HA. Does the microbiota play a role in the pathogenesis of autoimmune diseases? Gut. 2015 Feb;64(2):332-41. doi: 10.1136/gutjnl-2014-308514. Epub 2014 Nov 21. PMID: 25416067; PMCID: PMC6288812.

9. Mu Q, Kirby J, Reilly CM, Luo XM. Leaky Gut As a Danger Signal for Autoimmune Diseases. Front Immunol. 2017 May 23;8:598. doi: 10.3389/fimmu.2017.00598. PMID: 28588585; PMCID: PMC5440529.

10. McClave SA, Patel J, Bhutiani N. Should fecal microbial transplantation be used in the ICU? Curr Opin Crit Care. 2018 Apr;24(2):105-111. doi: 10.1097/MCC.0000000000000489. PMID: 29432297.

11. Nakov R, Segal JP, Settanni CR, Bibbò S, Gasbarrini A, Cammarota G, et al. Microbiome: what intensivists should know. Minerva Anestesiol. 2020 Jul;86(7):777-785. doi: 10.23736/S0375-9393.20.14278-0. Epub 2020 May 5. PMID: 32368882.

12. Johanson WG, Pierce AK, Sanford JP. Changing pharyngeal bacterial flora of hospitalized patients. Emergence of gram-negative bacilli. N Engl J Med. 1969 Nov 20;281(21): 1137-1140. doi: 10.1056/NEJM196911202812101. PMID: 4899868.

13. Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, et al. EPIC II Group of Investigators. International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009 Dec 2;302(21):2323-9. doi: 10.1001/jama.2009.1754. PMID: 19952319.

14. McClave SA, Lowen CC, Martindale RG. The 2016 ESPEN Arvid Wretlind lecture: The gut in stress. Clin Nutr. 2018 Feb;37(1):19-36. doi: 10.1016/j.clnu.2017.07.015. Epub 2017 Jul 29. PMID: 28818344.

15. Li S, Lv J, Li J, Zhao Z, Guo H, Zhang Y, et al. Intestinal microbiota impact sepsis associated encephalopathy via the vagus nerve. Neurosci Lett. 2018 Jan 1;662:98-104. doi: 10.1016/j.neulet.2017.10.008. Epub 2017 Oct 6. PMID: 28993208.

16. Prescott HC, Dickson RP, Rogers MA, Langa KM, Iwashyna TJ. Hospitalization Type and Subsequent Severe Sepsis. Am J Respir Crit Care Med. 2015 Sep 1;192(5):581-588. doi: 10.1164/rccm.201503-0483OC. PMID: 26016947; PMCID: PMC4595694.

17. Batra P, Soni KD, Mathur P. Efficacy of probiotics in the prevention of VAP in critically ill ICU patients: an updated systematic review and meta-analysis of randomized control trials. J Intensive Care. 2020 Oct 15;8:81. doi: 10.1186/s40560-020-00487-8. PMID: 33082958; PMCID: PMC7561245.

18. Shimizu K, Hirose T, Ogura H. Efficacy of probiotics in the prevention of diarrhea in ventilated critically ill ICU patients: meta-analysis of randomized control trials. J Intensive Care. 2021 Oct 15;9:62. doi: 10.1186/s40560-021-00567-3. PMID: 34667617; PMCID: PMC8517300.

19. Manzanares W, Lemieux M, Langlois PL, Wischmeyer PE. Probiotic and synbiotic therapy in critical illness: a systematic review and meta-analysis. Crit Care. 2016 Aug 19;19:262. doi: 10.1186/s13054-016-1434-y. Erratum in: Crit Care. 2017 Feb 27;21(1):42. PMID: 27538711; PMCID: PMC4991010.

20. Hempel S, Newberry SJ, Maher AR, Wang Z, Miles JN, Shanman R, et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis. JAMA. 2012 May 9;307(18):1959-1569. doi: 10.1001/jama.2012.3507. PMID: 22570464.

21. Wischmeyer PE, McDonald D, Knight R. Role of the microbiome, probiotics, and 'dysbiosis therapy' in critical illness. Curr Opin Crit Care. 2016 Aug;22(4):347-353. doi: 10.1097/MCC.0000000000000321. PMID: 27327243; PMCID: PMC5065053.22.

22.Muñoz P, Bouza E, Cuenca-Estrella M, Eiros JM, Pérez MJ, Sánchez-Somolinos M, et al. Saccharomyces cerevisiae fungemia: an emerging infectious disease. Clin Infect Dis. 2005 Jun 1;40(11):1625-1634. doi: 10.1086/429916. Epub 2005 Apr 25. PMID: 15889360.

23. Bongaerts GP, Severijnen RS. A reassessment of the PROPATRIA study and its implications for probiotic therapy. Nat Biotechnol. 2016 Jan;34(1):55-63. doi: 10.1038/nbt.3436. PMID: 26744983.

24. Ott SJ, Waetzig GH, Rehman A, Moltzau-Anderson J, Bharti R, Grasis JA, et al. Efficacy of Sterile Fecal Filtrate Transfer for Treating Patients With Clostridium difficile Infection. Gastroenterology. 2017 Mar;152(4):799-811.e7. doi: 10.1053/j.gastro.2016.11.010. Epub 2016 Nov 17. PMID: 27866880.

25. Kelly CR, Ihunnah C, Fischer M, Khoruts A, Surawicz C, Afzali A, et al. Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am J Gastroenterol. 2014 Jul;109(7):1065-1071. doi: 10.1038/ajg.2014.133. Epub 2014 Jun 3. PMID: 24890442; PMCID: PMC5537742.

26. DeFilipp Z, Bloom PP, Torres Soto M, Mansour MK, Sater MRA, Huntley MH, et al. Drug-Resistant E. coli Bacteremia Transmitted by Fecal Microbiota Transplant. N Engl J Med. 2019 Nov 21;381(21):2043-2050. doi: 10.1056/NEJMoa1910437. Epub 2019 Oct 30. PMID: 31665575.

27. Kelly CR, Fischer M, Allegretti JR, LaPlante K, Stewart DB, Limketkai BN, et al. ACG Clinical Guidelines: Prevention, Diagnosis, and Treatment of Clostridioides difficile Infections. Am J Gastroenterol. 2021 Jun 1;116(6):1124-1147. doi: 10.14309/ajg.0000000000001278. PMID: 34003176.

28. Kump P, Wurm P, Gröchenig HP, Wenzl H, Petritsch W, Halwachs B, et al. The taxonomic composition of the donor intestinal microbiota is a major factor influencing the efficacy of faecal microbiota transplantation in therapy refractory ulcerative colitis. Aliment Pharmacol Ther. 2018 Jan;47(1):67-77. doi: 10.1111/apt.14387. Epub 2017 Oct 20. PMID: 29052237; PMCID: PMC5765501.

29. Quraishi MN, Widlak M, Bhala N, Moore D, Price M, Sharma N, et al. Systematic review with meta-analysis: the efficacy of faecal microbiota transplantation for the treatment of recurrent and refractory Clostridium difficile infection. Aliment Pharmacol Ther. 2017 Sep;46(5):479-493. doi: 10.1111/apt.14201. Epub 2017 Jul 14. PMID: 28707337.

30. De Roo AC, Regenbogen SE. Clostridium difficile Infection: An Epidemiology Update. Clin Colon Rectal Surg. 2020 Mar;33(2):49-57. doi: 10.1055/s-0040-1701229. Epub 2020 Feb 25. PMID: 32104156; PMCID: PMC7042002.

31. Kelly CR, Fischer M, Allegretti JR, LaPlante K, Stewart DB, Limketkai BN, et al. ACG Clinical Guidelines: Prevention, Diagnosis, and Treatment of Clostridioides difficile Infections. Am J Gastroenterol. 2021 Jun 1;116(6):1124-1147. doi: 10.14309/ajg.0000000000001278. PMID: 34003176.

32. van Prehn J, Reigadas E, Vogelzang EH, Bouza E, Hristea A, Guery B, Krutova M, Norén T, Allerberger F, Coia JE, Goorhuis A, van Rossen TM, Ooijevaar RE, Burns K, Scharvik Olesen BR, Tschudin-Sutter S, Wilcox MH, Vehreschild MJGT, Fitzpatrick F, Kuijper Eet al. Guideline Committee of the European Study Group on Clostridioides difficile. European Society of Clinical Microbiology and Infectious Diseases: 2021 update on the treatment guidance document for Clostridioides difficile infection in adults. Clin Microbiol Infect. 2021 Dec;27 Suppl 2:S1-S21. doi: 10.1016/j.cmi.2021.09.038. Epub 2021 Oct 20. PMID: 34678515.

33. Thabit AK, Alsolami MH, Baghlaf NA, Alsharekh RM, Almazmumi HA, Alselami AS, et al. Comparison of three current Clostridioides difficile infection guidelines: IDSA/SHEA, ESCMID, and ACG guidelines. Infection. 2019 Dec;47(6):899-909. doi: 10.1007/s15010-019-01348-9. Epub 2019 Aug 19. PMID: 31428991.

34. Tariq R, Pardi DS, Bartlett MG, Khanna S. Low Cure Rates in Controlled Trials of Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection: A Systematic Review and Meta-analysis. Clin Infect Dis. 2019 Apr 8;68(8):1351-1358. doi: 10.1093/cid/ciy721. PMID: 30957161.

35. Lee MSL, Ramakrishna B, Moss AC, Gold HS, Branch-Elliman W. Successful treatment of fulminant Clostridioides difficile infection with emergent fecal microbiota transplantation in a patient with acute myeloid leukemia and prolonged, severe neutropenia. Transpl Infect Dis. 2020 Feb;22(1):e13216. doi: 10.1111/tid.13216. Epub 2019 Dec 17. PMID: 31769569.

36. Gorbach SL, Bartlett JG. Pseudomembranous enterocolitis: a review of its diverse forms. J Infect Dis. 1977 Mar;135 Suppl:S89-94. doi: 10.1093/infdis/135.supplement.s89. PMID: 321711.

37. Maseda D, Zackular JP, Trindade B, Kirk L, Roxas JL, Rogers LM, et al. Nonsteroidal Anti-inflammatory Drugs Alter the Microbiota and Exacerbate Clostridium difficile Colitis while Dysregulating the Inflammatory Response. mBio. 2019 Jan 8;10(1):e02282-18. doi: 10.1128/mBio.02282-18. PMID: 30622186; PMCID: PMC6325247.

38. Antonelli M, Martin-Loeches I, Dimopoulos G, Gasbarrini A, Vallecoccia MS. Clostridioides difficile (formerly Clostridium difficile) infection in the critically ill: an expert statement. Intensive Care Med. 2020 Feb;46(2):215-224. doi: 10.1007/s00134-019-05873-x. Epub 2020 Jan 14. PMID: 31938827.

39. Luo Y, Tixier EN, Grinspan AM. Fecal Microbiota Transplantation for Clostridioides difficile in High-Risk Older Adults Is Associated with Early Recurrence. Dig Dis Sci. 2020 Dec;65(12):3647-3651. doi: 10.1007/s10620-020-06147-z. Epub 2020 Feb 20. PMID: 32078714.

40. Cao F, Chen CX, Wang M, Liao HR, Wang MX, Hua SZ, et al. Updated meta-analysis of controlled observational studies: proton-pump inhibitors and risk of Clostridium difficile infection. J Hosp Infect. 2018 Jan;98(1):4-13. doi: 10.1016/j.jhin.2017.08.017. Epub 2017 Aug 24. PMID: 28842261.

41. Alhazzani W, Alenezi F, Jaeschke RZ, Moayyedi P, Cook DJ. Proton pump inhibitors versus histamine 2 receptor antagonists for stress ulcer prophylaxis in critically ill patients: a systematic review and meta-analysis. Crit Care Med. 2013 Mar;41(3):693-705. doi: 10.1097/CCM.0b013e3182758734. PMID: 23318494.

42. Marra AR, Edmond MB, Wenzel RP, Bearman GM. Hospital-acquired Clostridium difficile-associated disease in the intensive care unit setting: epidemiology, clinical course and outcome. BMC Infect Dis. 2007 May 21;7:42. doi: 10.1186/1471-2334-7-42. PMID: 17517130; PMCID: PMC1888698.

43. Schneider KM, Wirtz TH, Kroy D, Albers S, Neumann UP, Strowig T, et al. Successful Fecal Microbiota Transplantation in a Patient with Severe Complicated Clostridium difficile Infection after Liver Transplantation. Case Rep Gastroenterol. 2018 Feb 21;12(1):76-84. doi: 10.1159/000481937. PMID: 29606940; PMCID: PMC5869577.

44. Zhang D, Prabhu VS, Marcella SW. Attributable Healthcare Resource Utilization and Costs for Patients With Primary and Recurrent Clostridium difficile Infection in the United States. Clin Infect Dis. 2018 Apr 17;66(9):1326-1332. doi: 10.1093/cid/cix1021. PMID: 29360950; PMCID: PMC5905590.

45. Karanika S, Paudel S, Zervou FN, Grigoras C, Zacharioudakis IM, Mylonakis E. Prevalence and Clinical Outcomes of Clostridium difficile Infection in the Intensive Care Unit: A Systematic Review and Meta-Analysis. Open Forum Infect Dis. 2015 Dec 1;3(1):ofv186. doi: 10.1093/ofid/ofv186. PMID: 26788544; PMCID: PMC4716350.

46. Allegretti JR, Mullish BH, Kelly C, Fischer M. The evolution of the use of faecal microbiota transplantation and emerging therapeutic indications. Lancet. 2019 Aug 3;394(10196):420-431. doi: 10.1016/S0140-6736(19)31266-8. PMID: 31379333.

47. Fischer M, Sipe BW, Rogers NA, Cook GK, Robb BW, Vuppalanchi R, et al. Faecal microbiota transplantation plus selected use of vancomycin for severe-complicated Clostridium difficile infection: description of a protocol with high success rate. Aliment Pharmacol Ther. 2015 Aug;42(4):470-6. doi: 10.1111/apt.13290. Epub 2015 Jun 19. PMID: 26096320.

48. Pickens CI, Wunderink RG. Principles and Practice of Antibiotic Stewardship in the ICU. Chest. 2019 Jul;156(1):163-171. doi: 10.1016/j.chest.2019.01.013. Epub 2019 Jan 25. PMID: 30689983; PMCID: PMC7118241.

49. Al Momani LA, Abughanimeh O, Boonpheng B, Gabriel JG, Young M. Fidaxomicin vs Vancomycin for the Treatment of a First Episode of Clostridium Difficile Infection: A Meta-analysis and Systematic Review. Cureus. 2018 Jun 11;10(6):e2778. doi: 10.7759/cureus.2778. PMID: 30112254; PMCID: PMC6089486.

50. Penziner S, Dubrovskaya Y, Press R, Safdar A. Fidaxomicin therapy in critically ill patients with Clostridium difficile infection. Antimicrob Agents Chemother. 2015 Mar;59(3): 1776-1781. doi: 10.1128/AAC.04268-14. Epub 2014 Dec 22. PMID: 25534722; PMCID: PMC4325788.

51. Neemann K, Eichele DD, Smith PW, Bociek R, Akhtari M, Freifeld A. Fecal microbiota transplantation for fulminant Clostridium difficile infection in an allogeneic stem cell transplant patient. Transpl Infect Dis. 2012 Dec;14(6):E161-5. doi: 10.1111/tid.12017. Epub 2012 Nov 2. PMID: 23121625.

52. Cheng YW, Fischer M. Fecal Microbiota Transplantation: Redefining Surgical Management of Refractory Clostridium difficile Infection. Clin Colon Rectal Surg. 2020 Mar;33(2): 92-97. doi: 10.1055/s-0040-1701233. Epub 2020 Feb 25. PMID: 32104162; PMCID: PMC7042019.

53. Cammarota G, Ianiro G, Magalini S, Gasbarrini A, Gui D. Decrease in Surgery for Clostridium difficile Infection After Starting a Program to Transplant Fecal Microbiota. Ann Intern Med. 2015 Sep 15;163(6):487-488. doi: 10.7326/L15-5139. PMID: 26370022.

54. Tixier EN, Verheyen E, Ungaro RC, Grinspan AM. Faecal microbiota transplant decreases mortality in severe and fulminant Clostridioides difficile infection in critically ill patients. Aliment Pharmacol Ther. 2019 Nov;50(10):1094-1099. doi: 10.1111/apt.15526. Epub 2019 Oct 14. PMID: 31612528; PMCID: PMC6817391.

55. Cheng YW, Xu, H, Phelps E, Rogers N, Sagi S, Bohm M, et al. Fecal Microbiota Transplant Decreases Mortality in Patients With Refractory Severe and Severe ComplicatedClostridium difficileInfection Not Eligible for Colectomy, Fellows-in-Training Award (Colon Category). Am. J. Gastroenterol.2017;112(p S48,S50).

56. Alukal J, Dutta SK, Surapaneni BK, Le M, Tabbaa O, Phillips L, et al. Safety and efficacy of fecal microbiota transplant in 9 critically ill patients with severe and complicated Clostridium difficile infection with impending colectomy. J Dig Dis. 2019 Jun;20(6):301-307. doi: 10.1111/1751-2980.12750. Epub 2019 May 10. PMID: 30969003.

57. Hocquart M, Lagier JC, Cassir N, Saidani N, Eldin C, Kerbaj J, et al. Early Fecal Microbiota Transplantation Improves Survival in Severe Clostridium difficile Infections. Clin Infect Dis. 2018 Feb 10;66(5):645-650. doi: 10.1093/cid/cix762. PMID: 29020328.

58. Agrawal M, Aroniadis OC, Brandt LJ, Kelly C, Freeman S, Surawicz C, et al. The Long-term Efficacy and Safety of Fecal Microbiota Transplant for Recurrent, Severe, and Complicated Clostridium difficile Infection in 146 Elderly Individuals. J Clin Gastroenterol. 2016 May-Jun;50(5):403-407. doi: 10.1097/MCG.0000000000000410. PMID: 26352106.

59. Oka A, Sartor RB. Microbial-Based and Microbial-Targeted Therapies for Inflammatory Bowel Diseases. Dig Dis Sci. 2020 Mar;65(3):757-788. doi: 10.1007/s10620-020-06090-z. PMID: 32006212; PMCID: PMC7311927.

60. Zuo T, Ng SC. The Gut Microbiota in the Pathogenesis and Therapeutics of Inflammatory Bowel Disease. Front Microbiol. 2018 Sep 25;9:2247. doi: 10.3389/fmicb.2018.02247. PMID: 30319571; PMCID: PMC6167487.

61. Capurso L, Koch M. Infezione da Clostridium difficile e malattie infiammatorie croniche intestinali [Clostridium difficile infection and chronic inflammatory bowel disease.]. Recenti Prog Med. 2021 Jan;112(1):42-55. Italian. doi: 10.1701/3551.35256. PMID: 33576350.

62. Tan P, Li X, Shen J, Feng Q. Fecal Microbiota Transplantation for the Treatment of Inflammatory Bowel Disease: An Update. Front Pharmacol. 2020 Sep 18;11:574533. doi: 10.3389/fphar.2020.574533. PMID: 33041818; PMCID: PMC7530266.

63. Khoruts A, Rank KM, Newman KM, Viskocil K, Vaughn BP, Hamilton MJ, et al. Inflammatory Bowel Disease Affects the Outcome of Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection. Clin Gastroenterol Hepatol. 2016 Oct;14(10):1433-1438. doi: 10.1016/j.cgh.2016.02.018. Epub 2016 Feb 22. PMID: 26905904; PMCID: PMC5552196.

64. Fischer M, Kao D, Mehta SR, Martin T, Dimitry J, Keshteli AH, et al. Predictors of Early Failure After Fecal Microbiota Transplantation for the Therapy of Clostridium Difficile Infection: A Multicenter Study. Am J Gastroenterol. 2016 Jul;111(7):1024-1031. doi: 10.1038/ajg.2016.180. Epub 2016 May 17. PMID: 27185076.

65. Moayyedi P, Surette MG, Kim PT, Libertucci J, Wolfe M, Onischi C, et al. Fecal Microbiota Transplantation Induces Remission in Patients With Active Ulcerative Colitis in a Randomized Controlled Trial. Gastroenterology. 2015 Jul;149(1):102-109.e6. doi: 10.1053/j.gastro.2015.04.001. Epub 2015 Apr 7. PMID: 25857665.

66. Paramsothy S, Paramsothy R, Rubin DT, Kamm MA, Kaakoush NO, Mitchell HM, et al. Faecal Microbiota Transplantation for Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. J Crohns Colitis. 2017 Oct 1;11(10):1180-1199. doi: 10.1093/ecco-jcc/jjx063. PMID: 28486648.

67. Uygun A, Ozturk K, Demirci H, Oger C, Avci IY, Turker T, et al. Fecal microbiota transplantation is a rescue treatment modality for refractory ulcerative colitis. Medicine (Baltimore). 2017 Apr;96(16):e6479. doi: 10.1097/MD.0000000000006479. PMID: 28422836; PMCID: PMC5406052.

68. Cheng YW, Phelps E, Ganapini V, Khan N, Ouyang F, Xu H, et al. Fecal microbiota transplantation for the treatment of recurrent and severe Clostridium difficile infection in solid organ transplant recipients: A multicenter experience. Am J Transplant. 2019 Feb;19(2):501-511. doi: 10.1111/ajt.15058. Epub 2018 Aug 31. PMID: 30085388; PMCID: PMC6349556.

69. Spindelboeck W, Schulz E, Uhl B, Kashofer K, Aigelsreiter A, Zinke-Cerwenka W, et al. Repeated fecal microbiota transplantations attenuate diarrhea and lead to sustained changes in the fecal microbiota in acute, refractory gastrointestinal graft-versus-host-disease. Haematologica. 2017 May;102(5):e210-e213. doi: 10.3324/haematol.2016.154351. Epub 2017 Feb 2. PMID: 28154090; PMCID: PMC5477627.

70. Li Q, Wang C, Tang C, He Q, Zhao X, Li N, et al. Successful treatment of severe sepsis and diarrhea after vagotomy utilizing fecal microbiota transplantation: a case report. Crit Care. 2015 Feb 9;19(1):37. doi: 10.1186/s13054-015-0738-7. PMID: 25881250; PMCID: PMC4346118.

71. Wei Y, Yang J, Wang J, Yang Y, Huang J, Gong H, et al. Successful treatment with fecal microbiota transplantation in patients with multiple organ dysfunction syndrome and diarrhea following severe sepsis. Crit Care. 2016 Oct 18;20(1):332. doi: 10.1186/s13054-016-1491-2. PMID: 27751177; PMCID: PMC5067912.

72. Wurm P, Spindelboeck W, Krause R, Plank J, Fuchs G, Bashir M, et al. Antibiotic-Associated Apoptotic Enterocolitis in the Absence of a Defined Pathogen: The Role of Intestinal Microbiota Depletion. Crit Care Med. 2017 Jun;45(6):e600-e606. doi: 10.1097/CCM.0000000000002310. PMID: 28333760; PMCID: PMC5432091.

73. Wei Y, Li N, Xing H, Guo T, Gong H, Chen D. Effectiveness of fecal microbiota transplantation for severe diarrhea after drug-induced hypersensitivity syndrome. Medicine (Baltimore). 2019 Dec;98(52):e18476. doi: 10.1097/MD.0000000000018476. PMID: 31876732; PMCID: PMC6946448.

74. Dai M, Liu Y, Chen W, Buch H, Shan Y, Chang L, et al. Rescue fecal microbiota transplantation for antibiotic-associated diarrhea in critically ill patients. Crit Care. 2019 Oct 21;23(1):324. doi: 10.1186/s13054-019-2604-5. PMID: 31639033; PMCID: PMC6805332.

75. Cibulková I, Řehořová V, Hajer J, Duška F. Multi-donor Fecal Microbial Transplantation for Critically Ill Patients: Rationale and Standard Operating Procedure. https://www.preprints.org/manuscript/202112.0332/v1.