1932

Abstract

Fecal microbiota transplantation (FMT) is a well-established treatment for recurrent infection. FMT has become a more readily available and useful new treatment option as a result of stool banks. The current state of knowledge indicates that dysbiosis of the gut microbiota is implicated in several disorders in addition to infection. Randomized controlled studies have shown FMT to be somewhat effective in treating ulcerative colitis, irritable bowel syndrome, and hepatic encephalopathy. In addition, FMT has been beneficial in treating several other conditions, such as the eradication of multidrug-resistant organisms and graft-versus-host disease. We expect that FMT will soon be implemented as a treatment strategy for several new indications, although further studies are needed.

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2019-01-27
2024-03-28
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Literature Cited

  1. 1.  Debast SB, Bauer MP, Kuijper EJ, Eur. Soc. Clin. Microbiol. Infect. Dis. 2014. European Society of Clinical Microbiology and Infectious Diseases: update of the treatment guidance document for Clostridium difficile infection. Clin. Microbiol. Infect. 20:Suppl. 21–26
    [Google Scholar]
  2. 2.  McDonald LC, Gerding DN, Johnson S et al. 2018. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin. Infect. Dis. 66:987–94
    [Google Scholar]
  3. 3.  Quraishi MN, Widlak M, Bhala N et al. 2017. Systematic review with meta-analysis: the efficacy of faecal microbiota transplantation for the treatment of recurrent and refractory Clostridium difficile infection. Aliment. Pharmacol. Ther. 46:479–93
    [Google Scholar]
  4. 4.  Smits WK, Lyras D, Lacy DB et al. 2016. Clostridium difficile infection. Nat. Rev. Dis. Primers 2:16020
    [Google Scholar]
  5. 5.  Sender R, Fuchs S, Milo R 2016. Revised estimates for the number of human and bacteria cells in the body. PLOS Biol 14:e1002533
    [Google Scholar]
  6. 6.  Lozupone CA, Stombaugh JI, Gordon JI et al. 2012. Diversity, stability and resilience of the human gut microbiota. Nature 489:220–30
    [Google Scholar]
  7. 7.  Rothschild D, Weissbrod O, Barkan E et al. 2018. Environment dominates over host genetics in shaping human gut microbiota. Nature 555:210–15
    [Google Scholar]
  8. 8. Hum. Microbiome Proj. Consort. 2012. Structure, function and diversity of the healthy human microbiome. Nature 486:207–14
    [Google Scholar]
  9. 9.  Kim S, Covington A, Pamer EG 2017. The intestinal microbiota: antibiotics, colonization resistance, and enteric pathogens. Immunol. Rev. 279:90–105
    [Google Scholar]
  10. 10.  Cotter PD, Ross RP, Hill C 2013. Bacteriocins—a viable alternative to antibiotics?. Nat. Rev. Microbiol. 11:95–105
    [Google Scholar]
  11. 11.  Hecht AL, Casterline BW, Earley ZM et al. 2016. Strain competition restricts colonization of an enteric pathogen and prevents colitis. EMBO Rep 17:1281–91
    [Google Scholar]
  12. 12.  Ofir G, Sorek R 2018. Contemporary phage biology: from classic models to new insights. Cell 172:1260–70
    [Google Scholar]
  13. 13.  Khoruts A, Sadowsky MJ 2016. Understanding the mechanisms of faecal microbiota transplantation. Nat. Rev. Gastroenterol. Hepatol. 13:508–16
    [Google Scholar]
  14. 14.  Hooper LV, Macpherson AJ 2010. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat. Rev. Immunol. 10:159–69
    [Google Scholar]
  15. 15.  Morrison DJ, Preston T 2016. Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut Microbes 7:189–200
    [Google Scholar]
  16. 16.  den Besten G, van Eunen K, Groen AK et al. 2013. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J. Lipid Res. 54:2325–40
    [Google Scholar]
  17. 17.  Park J, Kim M, Kang SG et al. 2015. Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR-S6K pathway. Mucosal Immunol 8:80–93
    [Google Scholar]
  18. 18.  Rooks MG, Garrett WS 2016. Gut microbiota, metabolites and host immunity. Nat. Rev. Immunol. 16:341–52
    [Google Scholar]
  19. 19.  Corrêa-Oliveira R, Fachi JL, Vieira A et al. 2016. Regulation of immune cell function by short-chain fatty acids. Clin. Transl. Immunol. 5:e73
    [Google Scholar]
  20. 20.  Wahlström A, Sayin SI, Marschall HU, Bäckhed F 2016. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab 24:41–50
    [Google Scholar]
  21. 21.  Ridlon JM, Kang DJ, Hylemon PB 2006. Bile salt biotransformations by human intestinal bacteria. J. Lipid Res. 47:241–59
    [Google Scholar]
  22. 22.  Inagaki T, Moschetta A, Lee YK et al. 2006. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. PNAS 103:3920–25
    [Google Scholar]
  23. 23.  Cipriani S, Mencarelli A, Chini MG et al. 2011. The bile acid receptor GPBAR-1 (TGR5) modulates integrity of intestinal barrier and immune response to experimental colitis. PLOS ONE 6:e25637
    [Google Scholar]
  24. 24.  Högenauer K, Arista L, Schmiedeberg N et al. 2014. G-protein-coupled bile acid receptor 1 (GPBAR1, TGR5) agonists reduce the production of proinflammatory cytokines and stabilize the alternative macrophage phenotype. J. Med. Chem. 57:10343–54
    [Google Scholar]
  25. 25.  Vavassori P, Mencarelli A, Renga B et al. 2009. The bile acid receptor FXR is a modulator of intestinal innate immunity. J. Immunol. 183:6251–61
    [Google Scholar]
  26. 26.  Thanissery R, Winston JA, Theriot CM 2017. Inhibition of spore germination, growth, and toxin activity of clinically relevant C. difficile strains by gut microbiota derived secondary bile acids. Anaerobe 45:86–100
    [Google Scholar]
  27. 27.  Chang JY, Antonopoulos DA, Kalra A et al. 2008. Decreased diversity of the fecal microbiome in recurrent Clostridium difficile-associated diarrhea. J. Infect. Dis. 197:435–38
    [Google Scholar]
  28. 28.  Deshpande A, Pasupuleti V, Thota P et al. 2015. Risk factors for recurrent Clostridium difficile infection: a systematic review and meta-analysis. Infect. Control Hosp. Epidemiol. 36:452–60
    [Google Scholar]
  29. 29.  Adamu BO, Lawley TD 2013. Bacteriotherapy for the treatment of intestinal dysbiosis caused by Clostridium difficile infection. Curr. Opin. Microbiol. 16:596–601
    [Google Scholar]
  30. 30.  Cammarota G, Masucci L, Ianiro G et al. 2015. Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment. Pharmacol. Ther. 41:835–43
    [Google Scholar]
  31. 31.  Kao D, Roach B, Silva M et al. 2017. Effect of oral capsule- versus colonoscopy-delivered fecal microbiota transplantation on recurrent Clostridium difficile infection: a randomized clinical trial. JAMA 318:1985–93
    [Google Scholar]
  32. 32.  van Nood E, Vrieze A, Nieuwdorp M et al. 2013. Duodenal infusion of donor feces for recurrent Clostridium difficile. N. Engl. J. . Med 368:407–15
    [Google Scholar]
  33. 33.  Lee CH, Steiner T, Petrof EO et al. 2016. Frozen versus fresh fecal microbiota transplantation and clinical resolution of diarrhea in patients with recurrent Clostridium difficile infection: a randomized clinical trial. JAMA 315:142–49
    [Google Scholar]
  34. 34.  Hocquart M, Lagier JC, Cassir N et al. 2018. Early fecal microbiota transplantation improves survival in severe Clostridium difficile infections. Clin. Infect. Dis. 66:645–50
    [Google Scholar]
  35. 35.  Orenstein R, Dubberke E, Hardi R et al. 2016. Safety and durability of RBX2660 (microbiota suspension) for recurrent Clostridium difficile infection: results of the PUNCH CD study. Clin. Infect. Dis. 62:596–602
    [Google Scholar]
  36. 36.  Baur D, Gladstone BP, Burkert F et al. 2017. Effect of antibiotic stewardship on the incidence of infection and colonisation with antibiotic-resistant bacteria and Clostridium difficile infection: a systematic review and meta-analysis. Lancet Infect. Dis. 17:990–1001
    [Google Scholar]
  37. 37.  Youngster I, Mahabamunuge J, Systrom HK et al. 2016. Oral, frozen fecal microbiota transplant (FMT) capsules for recurrent Clostridium difficile infection. BMC Med 14:134
    [Google Scholar]
  38. 38.  Maier L, Pruteanu M, Kuhn M et al. 2018. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature 555:623–28
    [Google Scholar]
  39. 39.  Angelberger S, Reinisch W, Makristathis A et al. 2013. Temporal bacterial community dynamics vary among ulcerative colitis patients after fecal microbiota transplantation. Am. J. Gastroenterol. 108:1620–30
    [Google Scholar]
  40. 40.  Quera R, Espinoza R, Estay C, Rivera D 2014. Bacteremia as an adverse event of fecal microbiota transplantation in a patient with Crohn's disease and recurrent Clostridium difficile infection. J. Crohns Colitis 8:252–53
    [Google Scholar]
  41. 41.  Vermeire S, Joossens M, Verbeke K et al. 2012. Pilot study on the safety and efficacy of faecal microbiota transplantation in refractory Crohn's disease. Gastroenterology 142:Suppl. 1S360
    [Google Scholar]
  42. 42.  Terveer EM, van Beurden YH, Goorhuis A et al. 2017. How to: Establish and run a stool bank. Clin. Microbiol. Infect. 23:924–30
    [Google Scholar]
  43. 43.  McIlroy J, Ianiro G, Mukhopadhya I et al. 2018. Review article: the gut microbiome in inflammatory bowel disease—avenues for microbial management. Aliment. Pharm. Ther. 47:26–42
    [Google Scholar]
  44. 44.  Critch J, Day AS, Otley A et al. 2012. Use of enteral nutrition for the control of intestinal inflammation in pediatric Crohn disease. J. Pediatr. Gastroenterol. Nutr. 54:298–305
    [Google Scholar]
  45. 45.  Ledder O, Turner D 2018. Antibiotics in IBD: still a role in the biological era?. Inflamm. Bowel Dis. 24:1676–88
    [Google Scholar]
  46. 46.  De Cruz P, Prideaux L, Wagner J et al. 2012. Characterization of the gastrointestinal microbiota in health and inflammatory bowel disease. Inflamm. Bowel Dis. 18:372–90
    [Google Scholar]
  47. 47.  Costello S, Waters O, Bryant R et al. 2017. Short duration, low intensity pooled faecal microbiota transplantation induces remission in patients with mild-moderately active ulcerative colitis: a randomised controlled trial. J. Crohns Colitis 11:S23
    [Google Scholar]
  48. 48.  Moayyedi P, Surette MG, Kim PT et al. 2015. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology 149:102–9.e6
    [Google Scholar]
  49. 49.  Paramsothy S, Kamm MA, Kaakoush NO et al. 2017. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet 389:1218–28
    [Google Scholar]
  50. 50.  Rossen NG, Fuentes S, van der Spek MJ et al. 2015. Findings from a randomized controlled trial of fecal transplantation for patients with ulcerative colitis. Gastroenterology 149:110–18.e4
    [Google Scholar]
  51. 51.  Costello SP, Soo W, Bryant RV et al. 2017. Systematic review with meta-analysis: faecal microbiota transplantation for the induction of remission for active ulcerative colitis. Aliment. Pharmacol. Ther. 46:213–24
    [Google Scholar]
  52. 52.  Paramsothy S, Paramsothy R, Rubin DT et al. 2017. Faecal microbiota transplantation for inflammatory bowel disease: a systematic review and meta-analysis. J. Crohns Colitis 11:1180–99
    [Google Scholar]
  53. 53.  Cui B, Feng Q, Wang H et al. 2015. Fecal microbiota transplantation through mid-gut for refractory Crohn's disease: safety, feasibility, and efficacy trial results. J. Gastroenterol. Hepatol. 30:51–58
    [Google Scholar]
  54. 54.  Vermeire S, Joossens M, Verbeke K et al. 2016. Donor species richness determines faecal microbiota transplantation success in inflammatory bowel disease. J. Crohns Colitis 10:387–94
    [Google Scholar]
  55. 55.  Chen T, Zhou Q, Zhang D et al. 2018. Effect of faecal microbiota transplantation for treatment of Clostridium difficile infection in patients with inflammatory bowel disease: a systematic review and meta-analysis of cohort studies. J. Crohns Colitis 12:710–17
    [Google Scholar]
  56. 56.  Zhuang X, Xiong L, Li L et al. 2017. Alterations of gut microbiota in patients with irritable bowel syndrome: a systematic review and meta-analysis. J. Gastroenterol. Hepatol. 32:28–38
    [Google Scholar]
  57. 57.  Camilleri M, Madsen K, Spiller R et al. 2012. Intestinal barrier function in health and gastrointestinal disease. Neurogastroenterol. Motil. 24:503–12
    [Google Scholar]
  58. 58.  De Palma G, Lynch MDJ, Lu J et al. 2017. Transplantation of fecal microbiota from patients with irritable bowel syndrome alters gut function and behavior in recipient mice. Sci. Transl. Med. 9:eaaf6397
    [Google Scholar]
  59. 59.  Johnsen PH, Hilpüsch F, Cavanagh JP et al. 2018. Faecal microbiota transplantation versus placebo for moderate-to-severe irritable bowel syndrome: a double-blind, randomised, placebo-controlled, parallel-group, single-centre trial. Lancet Gastroenterol. Hepatol. 3:17–24
    [Google Scholar]
  60. 60.  Halkjær SI, Boolsen AW, Günther S et al. 2017. Can fecal microbiota transplantation cure irritable bowel syndrome?. World J. Gastroenterol. 23:4112–20
    [Google Scholar]
  61. 61.  Bajaj JS, Heuman DM, Hylemon PB et al. 2014. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J. Hepatol. 60:940–47
    [Google Scholar]
  62. 62.  Zhang Z, Zhai H, Geng J et al. 2013. Large-scale survey of gut microbiota associated with MHE via 16S rRNA-based pyrosequencing. Am. J. Gastroenterol. 108:1601–11
    [Google Scholar]
  63. 63.  Shawcross DL, Davies NA, Williams R, Jalan R 2004. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J. Hepatol. 40:247–54
    [Google Scholar]
  64. 64.  Ahluwalia V, Betrapally NS, Hylemon PB et al. 2016. Impaired gut-liver-brain axis in patients with cirrhosis. Sci. Rep. 6:26800
    [Google Scholar]
  65. 65.  Bajaj JS, Kassam Z, Fagan A et al. 2017. Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: a randomized clinical trial. Hepatology 66:1727–38
    [Google Scholar]
  66. 66.  MacMillan ML, DeFor TE, Weisdorf DJ 2012. What predicts high risk acute graft-versus-host disease (GVHD) at onset?: identification of those at highest risk by a novel acute GVHD risk score. Br. J. Haematol. 157:732–41
    [Google Scholar]
  67. 67.  Mathewson ND, Jenq R, Mathew AV et al. 2016. Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease. Nat. Immunol. 17:505–13
    [Google Scholar]
  68. 68.  Kakihana K, Fujioka Y, Suda W et al. 2016. Fecal microbiota transplantation for patients with steroid-resistant acute graft-versus-host disease of the gut. Blood 128:2083–88
    [Google Scholar]
  69. 69.  Spindelboeck W, Schulz E, Uhl B et al. 2017. Repeated fecal microbiota transplantations attenuate diarrhea and lead to sustained changes in the fecal microbiota in acute, refractory gastrointestinal graft-versus-host-disease. Haematologica 102:e210–13
    [Google Scholar]
  70. 70.  Millan B, Park H, Hotte N et al. 2016. Fecal microbial transplants reduce antibiotic-resistant genes in patients with recurrent Clostridium difficile infection. Clin. Infect. Dis. 62:1479–86
    [Google Scholar]
  71. 71.  Liu B, Pop M 2009. ARDB–antibiotic resistance genes database. Nucleic Acids Res 37:D443–47
    [Google Scholar]
  72. 72.  Bilinski J, Grzesiowski P, Sorensen N et al. 2017. Fecal microbiota transplantation in patients with blood disorders inhibits gut colonization with antibiotic-resistant bacteria: results of a prospective, single-center study. Clin. Infect. Dis. 65:364–70
    [Google Scholar]
  73. 73.  Davido B, Batista R, Michelon H et al. 2017. Is faecal microbiota transplantation an option to eradicate highly drug-resistant enteric bacteria carriage?. J. Hosp. Infect. 95:433–37
    [Google Scholar]
  74. 74.  Dinh A, Fessi H, Duran C et al. 2018. Clearance of carbapenem-resistant Enterobacteriaceae versus vancomycin-resistant enterococci carriage after fecal microbiota transplant: a prospective comparative study. J. Hosp. Infect. 99:481–86
    [Google Scholar]
  75. 75.  Singh R, de Groot PF, Geerlings SE et al. 2018. Fecal microbiota transplantation against intestinal colonization by extended spectrum beta-lactamase producing Enterobacteriaceae: a proof of principle study. BMC Res. Notes 11:190
    [Google Scholar]
  76. 76.  Kommineni S, Bretl DJ, Lam V et al. 2015. Bacteriocin production augments niche competition by enterococci in the mammalian gastrointestinal tract. Nature 526:719–22
    [Google Scholar]
  77. 77.  de Groot PF, Frissen MN, de Clercq NC, Nieuwdorp M 2017. Fecal microbiota transplantation in metabolic syndrome: history, present and future. Gut Microbes 8:253–67
    [Google Scholar]
  78. 78.  Kootte RS, Levin E, Salojärvi J et al. 2017. Improvement of insulin sensitivity after lean donor feces in metabolic syndrome is driven by baseline intestinal microbiota composition. Cell Metab 26:611–19.e6
    [Google Scholar]
  79. 79.  Vrieze A, Van Nood E, Holleman F et al. 2012. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 143:913–16.e7
    [Google Scholar]
  80. 80.  McElhanon BO, McCracken C, Karpen S, Sharp WG 2014. Gastrointestinal symptoms in autism spectrum disorder: a meta-analysis. Pediatrics 133:872–83
    [Google Scholar]
  81. 81.  Niehus R, Lord C 2006. Early medical history of children with autism spectrum disorders. J. Dev. Behav. Pediatr. 27:S120–27
    [Google Scholar]
  82. 82.  Slykerman RF, Thompson J, Waldie KE et al. 2017. Antibiotics in the first year of life and subsequent neurocognitive outcomes. Acta Paediatr 106:87–94
    [Google Scholar]
  83. 83.  Hsiao EY, McBride SW, Hsien S et al. 2013. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155:1451–63
    [Google Scholar]
  84. 84.  Kang D-W, Adams JB, Gregory AC et al. 2017. Microbiota transfer therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome 5:10
    [Google Scholar]
  85. 85.  Borody T, Leis S, Campbell J et al. 2011. Fecal microbiota transplantation (FMT) in multiple sclerosis (MS). Am. J. Gastroenterol. 106:S352
    [Google Scholar]
  86. 86.  Fang S, Kraft CS, Dhere T et al. 2016. Successful treatment of chronic Pouchitis utilizing fecal microbiota transplantation (FMT): a case report. Int. J. Colorectal Dis. 31:1093–94
    [Google Scholar]
  87. 87.  Günaltay S, Rademacher L, Hultgren Hörnquist E et al. 2017. Clinical and immunologic effects of faecal microbiota transplantation in a patient with collagenous colitis. World J. Gastroenterol. 23:1319–24
    [Google Scholar]
  88. 88.  Makkawi S, Camara-Lemarroy C, Metz L 2018. Fecal microbiota transplantation associated with 10 years of disease stability in a patient with SPMS. Neurol. Neuroimmunol. Neuroinflamm. 5:4e459
    [Google Scholar]
  89. 89.  Tian H, Ge X, Nie Y et al. 2017. Fecal microbiota transplantation in patients with slow-transit constipation: a randomized, clinical trial. PLOS ONE 12:e0171308
    [Google Scholar]
  90. 90.  van Beurden YH, van Gils T, van Gils NA et al. 2016. Serendipity in refractory celiac disease: full recovery of duodenal villi and clinical symptoms after fecal microbiota transfer. J. Gastrointestin. Liver Dis. 25:385–88
    [Google Scholar]
  91. 91.  Freedman SN, Shahi SK, Mangalam AK 2018. The “gut feeling”: breaking down the role of gut microbiome in multiple sclerosis. Neurotherapeutics 15:109–25
    [Google Scholar]
  92. 92.  Shahi SK, Freedman SN, Mangalam AK 2017. Gut microbiome in multiple sclerosis: the players involved and the roles they play. Gut Microbes 8:607–15
    [Google Scholar]
  93. 93.  Berer K, Gerdes LA, Cekanaviciute E et al. 2017. Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice. PNAS 114:10719–24
    [Google Scholar]
  94. 94.  Cekanaviciute E, Yoo BB, Runia TF et al. 2017. Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models. PNAS 114:10713–18
    [Google Scholar]
  95. 95.  Sampson TR, Debelius JW, Thron T et al. 2016. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease. Cell 167:1469–80.e12
    [Google Scholar]
  96. 96.  Unger MM, Spiegel J, Dillmann KU et al. 2016. Short chain fatty acids and gut microbiota differ between patients with Parkinson's disease and age-matched controls. Parkinsonism Relat. Disord. 32:66–72
    [Google Scholar]
  97. 97.  Sun MF, Zhu YL, Zhou ZL et al. 2018. Neuroprotective effects of fecal microbiota transplantation on MPTP-induced Parkinson's disease mice: gut microbiota, glial reaction and TLR4/TNF-α signaling pathway. Brain Behav. Immun. 70:48–60
    [Google Scholar]
  98. 98.  Sivan A, Corrales L, Hubert N et al. 2015. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350:1084–89
    [Google Scholar]
  99. 99.  Gopalakrishnan V, Spencer CN, Nezi L et al. 2018. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359:97–103
    [Google Scholar]
  100. 100.  Routy B, Le Chatelier E, Derosa L et al. 2018. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359:91–97
    [Google Scholar]
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