Skip to main content

Advertisement

SpringerLink
Log in

The Route to Palatable Fecal Microbiota Transplantation

  • Review Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

The community of symbiotic microorganisms that reside in our gastrointestinal tract is integral to human health. Fecal microbiota transplantation (FMT) has been shown to be highly effective in treating recurrent Clostridioides difficile infection (rCDI) and is now recommended by medical societies for patients suffering from rCDI who have failed to respond to conventional therapy. The main challenges with FMT are its accessibility, acceptability, lack of standardization, and regulatory complexity, which will be discussed in this review. Access to FMT is being addressed through the development of frozen and lyophilized FMT preparations that can be prepared at stool banks and shipped to the point of care. Both access and patient acceptance would be enhanced by oral FMT capsules, and there is potential to reduce capsule burden by utilizing colonic release capsules, targeting the site of disease. This review compares the efficacy of different FMT routes of administration: capsules, nasal feeding tubes, enemas, and colonoscopic infusions. FMT is considered investigational by the Food and Drug Administration. In effort to improve access to FMT, physicians may perform FMT outside of an investigational new drug application for treating CDI infections not responsive to standard therapies. The majority of FMT studies report only minor adverse effects; however, there is risk of transmission of infections.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. den Besten G, van Eunen K, Groen AK, Venema K, Reijngoud DJ, Bakker BM. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J Lipid Res. 2013;54:2325–40.

    Google Scholar 

  2. Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell. 2005;122:107–18.

    CAS  PubMed  Google Scholar 

  3. Baumler AJ, Sperandio V. Interactions between the microbiota and pathogenic bacteria in the gut. Nature. 2016;535:85–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Spanogiannopoulos P, Bess EN, Carmody RN, Turnbaugh PJ. The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism. Nat Rev Microbiol. 2016;14:273–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Quigley EM. Basic definitions and concepts: organization of the gut microbiome. Gastroenterol Clin N Am. 2017;46:1–8.

    Google Scholar 

  6. Backhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. Host-bacterial mutualism in the human intestine. Science. 2005;307:1915–20.

    PubMed  Google Scholar 

  7. Kurokawa K, Itoh T, Kuwahara T, Oshima K, Toh H, Toyoda A, et al. Comparative metagenomics revealed commonly enriched gene sets in human gut microbiomes. DNA Res. 2007;14:169–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Consortium, The Human Microbiome Project. Structure, function and diversity of the healthy human microbiome. Nature. 2012;486:207.

    Google Scholar 

  9. Goldszmid RS. Trinchieri, Giorgio. The price of immunity. Nat Immunol. 2012;13:932.

    CAS  PubMed  Google Scholar 

  10. Barbara G, Cremon C, Azpiroz F. Probiotics in irritable bowel syndrome: where are we? Neurogastroenterol Motil. 2018;30:e13513.

    PubMed  Google Scholar 

  11. Osadchiy V, Martin CR, Mayer EA. The gut-brain axis and the microbiome: mechanisms and clinical implications. Clin Gastroenterol Hepatol. 2019;17:322–32.

    CAS  PubMed  Google Scholar 

  12. Quigley EMM. Microbiota-brain-gut axis and neurodegenerative diseases. Curr Neurol Neurosci Rep. 2017;17:94.

    PubMed  Google Scholar 

  13. Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, et al. Human gut microbiome viewed across age and geography. Nature. 2012;486:222–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Costea PI, Hildebrand F, Arumugam M, Backhed F, Blaser MJ, et al. Enterotypes in the landscape of gut microbial community composition. Nat Microbiol. 2018;3:8–16.

    CAS  PubMed  Google Scholar 

  15. Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. Diversity, stability and resilience of the human gut microbiota. Nature. 2012;489:220–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464:59–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Bergman EN. Energy contributions of volatile fatty acids from the gastrointestinal tract in various species. Physiol Rev. 1990;70:567–90.

    CAS  PubMed  Google Scholar 

  18. Wong JM, de Souza R, Kendall CW, Emam A, Jenkins DJ. Colonic health: fermentation and short chain fatty acids. J Clin Gastroenterol. 2006;40:235–43.

    CAS  PubMed  Google Scholar 

  19. Sonnenburg JL, Backhed F. Diet-microbiota interactions as moderators of human metabolism. Nature. 2016;535:56–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505:559–63.

    CAS  PubMed  Google Scholar 

  21. Wu GD, Chen J, Hoffmann C, Bittinger K, Chen YY, Keilbaugh SA, et al. Linking long-term dietary patterns with gut microbial enterotypes. Science. 2011;334:105–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Kovatcheva-Datchary P, Nilsson A, Akrami R, Lee YS, De Vadder F, et al. Dietary fiber-induced improvement in glucose metabolism is associated with increased abundance of prevotella. Cell Metab. 2015;22:971–82.

    CAS  PubMed  Google Scholar 

  23. Le Bastard Q, Al-Ghalith GA, Gregoire M, Chapelet G, Javaudin F, et al. Systematic review: human gut dysbiosis induced by non-antibiotic prescription medications. Aliment Pharmacol Ther. 2018;47:332–45.

    PubMed  Google Scholar 

  24. Jackson MA, Verdi S, Maxan ME, Shin CM, Zierer J, et al. Gut microbiota associations with common diseases and prescription medications in a population-based cohort. Nat Commun. 2018;9:2655.

    PubMed  PubMed Central  Google Scholar 

  25. Montassier E, Gastinne T, Vangay P, Al-Ghalith GA, Bruley des Varannes S, et al. Chemotherapy-driven dysbiosis in the intestinal microbiome. Aliment Pharmacol Ther. 2015;42:515–28.

    CAS  PubMed  Google Scholar 

  26. Freedberg DE, Lebwohl B, Abrams JA. The impact of proton pump inhibitors on the human gastrointestinal microbiome. Clin Lab Med. 2014;34:771–85.

    PubMed  PubMed Central  Google Scholar 

  27. Wu H, Esteve E, Tremaroli V, Khan MT, Caesar R, Mannerås-Holm L, et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med. 2017;23:850–8.

    CAS  PubMed  Google Scholar 

  28. Jakobsson HE, Jernberg C, Andersson AF, Sjolund-Karlsson M, Jansson JK, Engstrand L. Short-term antibiotic treatment has differing long-term impacts on the human throat and gut microbiome. PLoS One. 2010;5:e9836.

    PubMed  PubMed Central  Google Scholar 

  29. Francino MP. Antibiotics and the human gut microbiome: Dysbioses and accumulation of resistances. Front Microbiol. 2015;6:1543.

    CAS  PubMed  Google Scholar 

  30. Leffler DA, Lamont JT. Clostridium difficile infection. N Engl J Med. 2015;372:1539–48.

    CAS  PubMed  Google Scholar 

  31. Lofgren ET, Cole SR, Weber DJ, Anderson DJ, Moehring RW. Hospital-acquired clostridium difficile infections: estimating all-cause mortality and length of stay. Epidemiology. 2014;25:570–5.

    PubMed  PubMed Central  Google Scholar 

  32. Lessa FC, Mu Y, Bamberg WM, Beldavs ZG, Dumyati GK, Dunn JR, et al. Burden of clostridium difficile infection in the United States. N Engl J Med. 2015;372:825–34.

    CAS  PubMed  Google Scholar 

  33. Barbut F, Cornley O, Fitzpatrick F, Kuijper E, Nagy E, Rupnik M, et al. Clostridium difficile infection in europe: European Hospital and Healthcare Federation (HOPE); 2013. http://www.multivu.com/assets/60637/documents/60637-CDI-HCP-Report-original.pdf. Accessed 01/08/2019

  34. Curcio D, Cane A, Fernandez FA, Correa J. Clostridium difficile-associated diarrhea in developing countries: a systematic review and meta-analysis. Infect Dis Ther. 2019;8:87–103.

    PubMed  PubMed Central  Google Scholar 

  35. Chitnis AS, Holzbauer SM, Belflower RM, Winston LG, Bamberg WM, Lyons C, et al. Epidemiology of community-associated clostridium difficile infection, 2009 through 2011. JAMA Intern Med. 2013;173:1359–67.

    PubMed  Google Scholar 

  36. Vardakas KZ, Polyzos KA, Patouni K, Rafailidis PI, Samonis G, Falagas ME. Treatment failure and recurrence of Clostridium difficile infection following treatment with vancomycin or metronidazole: a systematic review of the evidence. Int J Antimicrob Agents. 2012;40:1–8.

    CAS  PubMed  Google Scholar 

  37. McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol. 2002;97:1769–75.

    CAS  PubMed  Google Scholar 

  38. Debast SB, Bauer MP, Kuijper EJ. European society of clinical microbiology and infectious diseases: update of the treatment guidance document for clostridium difficile infection. Clin Microbiol Infect. 2014;20(Suppl 2):1–26.

    CAS  PubMed  Google Scholar 

  39. Perera AD, Akbari RP, Cowher MS, Read TE, McCormick JT, et al. Colectomy for fulminant clostridium difficile colitis: predictors of mortality. Am Surg. 2010;76:418–21.

    PubMed  Google Scholar 

  40. Surawicz CM, Brandt LJ, Binion DG, Ananthakrishnan AN, Curry SR, et al. Guidelines for diagnosis, treatment, and prevention of clostridium difficile infections. Am J Gastroenterol. 2013;108:478–98

  41. 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;46:479–93.

    CAS  PubMed  Google Scholar 

  42. Cammarota G, Ianiro G, Tilg H, Rajilic-Stojanovic M, Kump P, et al. European consensus conference on faecal microbiota transplantation in clinical practice. Gut. 2017;66:569–80.

    PubMed  PubMed Central  Google Scholar 

  43. Ianiro G, Maida M, Burisch J, Simonelli C, Hold G, Ventimiglia M, et al. Efficacy of different faecal microbiota transplantation protocols for clostridium difficile infection: a systematic review and meta-analysis. United European Gastroenterol J. 2018;6:1232–44.

    PubMed  PubMed Central  Google Scholar 

  44. McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC, et al. 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. 2018;66:987–94.

    CAS  PubMed  Google Scholar 

  45. Mullish BH, Quraishi MN, Segal JP, Williams HRT, Goldenberg SD. Introduction to the joint British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS) faecal microbiota transplant guidelines. J Hosp Infect. 2018;100:130–2.

    CAS  PubMed  Google Scholar 

  46. Terveer EM, van Beurden YH, Goorhuis A, Seegers J, Bauer MP, et al. How to: establish and run a stool bank. Clin Microbiol Infect. 2017;23:924–30.

    CAS  PubMed  Google Scholar 

  47. van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, et al. Duodenal infusion of donor feces for recurrent clostridium difficile. N Engl J Med. 2013;368:407–15.

    PubMed  Google Scholar 

  48. Cammarota G, Masucci L, Ianiro G, Bibbo S, Dinoi G, et al. Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther. 2015;41:835–43.

    CAS  PubMed  Google Scholar 

  49. Hvas CL, Dahl Jorgensen SM, Jorgensen SP, Storgaard M, Lemming L, et al. Fecal microbiota transplantation is superior to fidaxomicin for treatment of recurrent clostridium difficile infection. Gastroenterology. 2019;156:1324–32 e1323.

    PubMed  Google Scholar 

  50. Hota SS, Sales V, Tomlinson G, Salpeter MJ, McGeer A, Coburn B, et al. Oral vancomycin followed by fecal transplantation versus tapering oral vancomycin treatment for recurrent clostridium difficile infection: an open-label, randomized controlled trial. Clin Infect Dis. 2017;64:265–71.

    PubMed  Google Scholar 

  51. Galperine T, Sokol H, Guery B. Fecal microbiota transplantation: do we need harmonization? Clin Infect Dis. 2017;64:1292.

    PubMed  Google Scholar 

  52. Jansen JW. Fecal microbiota transplant vs oral vancomycin taper: important undiscussed limitations. Clin Infect Dis. 2017;64:1292–3.

    PubMed  Google Scholar 

  53. Kelly CR, Khoruts A, Staley C, Sadowsky MJ, Abd M, Alani M, et al. Effect of fecal microbiota transplantation on recurrence in multiply recurrent clostridium difficile infection: a randomized trial. Ann Intern Med. 2016;165:609–16.

    PubMed  PubMed Central  Google Scholar 

  54. Dubberke ER, Lee CH, Orenstein R, Khanna S, Hecht G, Gerding DN. Results from a randomized, placebo-controlled clinical trial of a rbx2660-a microbiota-based drug for the prevention of recurrent Clostridium difficile infection. Clin Infect Dis. 2018;67:1198–204.

    CAS  PubMed  Google Scholar 

  55. Ianiro G, Masucci L, Quaranta G, Simonelli C, Lopetuso LR, Sanguinetti M, et al. Randomised clinical trial: Faecal microbiota transplantation by colonoscopy plus vancomycin for the treatment of severe refractory clostridium difficile infection-single versus multiple infusions. Aliment Pharmacol Ther. 2018;48:152–9.

    CAS  PubMed  Google Scholar 

  56. Lee CH, Steiner T, Petrof EO, Smieja M, Roscoe D, Nematallah A, et al. Frozen vs fresh fecal microbiota transplantation and clinical resolution of diarrhea in patients with recurrent clostridium difficile infection: a randomized clinical trial. JAMA. 2016;315:142–9.

    CAS  PubMed  Google Scholar 

  57. Jiang ZD, Ajami NJ, Petrosino JF, Jun G, Hanis CL, Shah M, et al. Randomised clinical trial: Faecal microbiota transplantation for recurrent clostridum difficile infection - fresh, or frozen, or lyophilised microbiota from a small pool of healthy donors delivered by colonoscopy. Aliment Pharmacol Ther. 2017;45:899–908.

    CAS  PubMed  Google Scholar 

  58. Jiang ZD, Jenq RR, Ajami NJ, Petrosino JF, Alexander AA, et al. Safety and preliminary efficacy of orally administered lyophilized fecal microbiota product compared with frozen product given by enema for recurrent clostridium difficile infection: a randomized clinical trial. PLoS One. 2018;13:e0205064.

    PubMed  PubMed Central  Google Scholar 

  59. Youngster I, Sauk J, Pindar C, Wilson RG, Kaplan JL, Smith MB, et al. Fecal microbiota transplant for relapsing clostridium difficile infection using a frozen inoculum from unrelated donors: a randomized, open-label, controlled pilot study. Clin Infect Dis. 2014;58:1515–22.

    PubMed  PubMed Central  Google Scholar 

  60. Kao D, Roach B, Silva M, Beck P, Rioux K, Kaplan GG, et al. Effect of oral capsule- vs colonoscopy-delivered fecal microbiota transplantation on recurrent clostridium difficile infection: a randomized clinical trial. JAMA. 2017;318:1985–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Allegretti A, Fischer M, Papa E, Elliott RJ, Klank J, et al. Fecal microbiota transplantation delivered via oral capsules achieves microbial engraftment similar to traditional delivery modalities: Safety, efficacy and engraftment results from a multi-center cluster randomized dose-finding study. Am J Gastroenterol. 2017:540.

  62. Allegretti JR, Fischer M, Sagi SV, Bohm ME, Fadda HM, Ranmal SR, et al. Fecal microbiota transplantation capsules with targeted colonic versus gastric delivery in recurrent clostridium difficile infection: a comparative cohort analysis of high and lose dose. Dig Dis Sci. 2019;64:1672–8.

    CAS  PubMed  Google Scholar 

  63. Ibekwe VC, Khela MK, Evans DF, Basit AW. A new concept in colonic drug targeting: A combined ph-responsive and bacterially-triggered drug delivery technology. Aliment Pharmacol Ther. 2008;28:911–6.

    CAS  PubMed  Google Scholar 

  64. D'Haens GR, Sandborn WJ, Zou G, Stitt LW, Rutgeerts PJ, et al. Randomised non-inferiority trial: 1600 mg versus 400 mg tablets of mesalazine for the treatment of mild-to-moderate ulcerative colitis. Aliment Pharmacol Ther. 2017;46:292–302.

    CAS  PubMed  Google Scholar 

  65. Smith M, Kassam Z, Burgess J, Perrotta AR, Burns LJ, et al. The international public stool bank: A scalable model for standardized screening and processing of donor stool for fecal microbiota transplantation. Am J Gastroenterol. 2015:Sa1064.

  66. Staley C, Hamilton MJ, Vaughn BP, Graiziger CT, Newman KM, Kabage AJ, et al. Successful resolution of recurrent clostridium difficile infection using freeze-dried, encapsulated fecal microbiota; pragmatic cohort study. Am J Gastroenterol. 2017;112:940–7.

    PubMed  PubMed Central  Google Scholar 

  67. Youngster I, Gerding DN. Editorial: Making fecal microbiota transplantation easier to swallow: Freeze-dried preparation for recurrent Clostridium difficile infections. Am J Gastroenterol. 2017;112:948–50.

    PubMed  Google Scholar 

  68. Hirsch BE, Saraiya N, Poeth K, Schwartz RM, Epstein ME, Honig G. Effectiveness of fecal-derived microbiota transfer using orally administered capsules for recurrent clostridium difficile infection. BMC Infect Dis. 2015;15:191.

    PubMed  PubMed Central  Google Scholar 

  69. Krajicek E, Fischer M, Allegretti JR, Kelly CR. Nuts and bolts of fecal microbiota transplantation. Clin Gastroenterol Hepatol. 2019;17:345–52.

    PubMed  Google Scholar 

  70. Allegretti JR, Kao D, Sitko J, Fischer M, Kassam Z. Early antibiotic use after fecal microbiota transplantation increases risk of treatment failure. Clin Infect Dis. 2018;66:134–5.

    PubMed  Google Scholar 

  71. Vermeire S, Joossens M, Verbeke K, Wang J, Machiels K, Sabino J, et al. Donor species richness determines faecal microbiota transplantation success in inflammatory bowel disease. J Crohns Colitis. 2016;10:387–94.

    PubMed  Google Scholar 

  72. Kump P, Wurm P, Grochenig HP, Wenzl H, Petritsch W, 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;47:67–77.

    CAS  PubMed  Google Scholar 

  73. Browne HP, Forster SC, Anonye BO, Kumar N, Neville BA, Stares MD, et al. Culturing of ‘unculturable’ human microbiota reveals novel taxa and extensive sporulation. Nature. 2016;533:543–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Hirotaka S, Katsuhiro A, Ichiro T, Takuya T, Takashi A, et al. Anaerobic stool preparation method for fecal microbiota transplantation is not superior to conventional aerobic method in preserving anaerobic bacteria. Am J Gastroenterol. 2017:125.

  75. Chu ND, Smith MB, Perrotta AR, Kassam Z, Alm EJ. Profiling living bacteria informs preparation of fecal microbiota transplantations. PLoS One. 2017;12:e0170922.

    PubMed  PubMed Central  Google Scholar 

  76. Papanicolas LE, Choo JM, Wang Y, Leong LEX, Costello SP, Gordon DL, et al. Bacterial viability in faecal transplants: which bacteria survive? EBioMedicine. 2019;41:509–16.

    PubMed  PubMed Central  Google Scholar 

  77. Costello SP, Hughes PA, Waters O, Bryant RV, Vincent AD, Blatchford P, et al. Effect of fecal microbiota transplantation on 8-week remission in patients with ulcerative colitis: a randomized clinical trial. JAMA. 2019;321:156–64.

    PubMed  PubMed Central  Google Scholar 

  78. Costello SP, Conlon MA, Vuaran MS, Roberts-Thomson IC, Andrews JM. Faecal microbiota transplant for recurrent Clostridium difficile infection using long-term frozen stool is effective: clinical efficacy and bacterial viability data. Aliment Pharmacol Ther. 2015;42:1011–8.

    CAS  PubMed  Google Scholar 

  79. Muyldermans G, de Smet F, Pierard D, Steenssens L, Stevens D, Bougatef A, et al. Neonatal infections with Pseudomonas aeruginosa associated with a water-bath used to thaw fresh frozen plasma. J Hosp Infect. 1998;39:309–14.

    CAS  PubMed  Google Scholar 

  80. Sleight SC, Wigginton NS, Lenski RE. Increased susceptibility to repeated freeze-thaw cycles in escherichia coli following long-term evolution in a benign environment. BMC Evol Biol. 2006;6:104.

    PubMed  PubMed Central  Google Scholar 

  81. Food and Drug Administration, Center for Biologics Evaluation and Research, Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium Difficile Infection Not Responsive to Standard Therapies; 2016 http://www.fda.gov/regulatory-information/search-fda-guidance-documents/enforcement-policy-regarding-investigational-new-drug-requirements-use-fecal-microbiota-0, Accessed July 2019.

  82. Food and Drug Administration, Center for Biologics Evaluation and Research, Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium Difficile Infection Not Responsive to Standard Therapies; 2013 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/enforcement-policy-regarding-investigational-new-drug-requirements-use-fecal-microbiota, Accessed July 2019.

  83. Infectious Diseases Society of America, Response to FDA Enforcement Policy Regarding Investigational New Drug Drug Requirements for Uses of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies; 2016, https://www.idsociety.org/globalassets/idsa/topics-of-interest/emerging-clinical-issues/idsa_fmt_comment_may_2016_final.pdf, Accessed July 2019.

  84. Khoruts A, Sadowsky MJ. Understanding the mechanisms of faecal microbiota transplantation. Nat Rev Gastroenterol Hepatol. 2016;13:508–16.

    PubMed  PubMed Central  Google Scholar 

  85. Brown JR, Flemer B, Joyce SA, Zulquernain A, Sheehan D, Shanahan F, et al. Changes in microbiota composition, bile and fatty acid metabolism, in successful faecal microbiota transplantation for clostridioides difficile infection. BMC Gastroenterol. 2018;18:131.

    PubMed  PubMed Central  Google Scholar 

  86. Jalanka J, Mattila E, Jouhten H, Hartman J, de Vos WM, Arkkila P, et al. Long-term effects on luminal and mucosal microbiota and commonly acquired taxa in faecal microbiota transplantation for recurrent clostridium difficile infection. BMC Med. 2016;14:155.

    PubMed  PubMed Central  Google Scholar 

  87. Moss EL, Falconer SB, Tkachenko E, Wang M, Systrom H, et al. Long-term taxonomic and functional divergence from donor bacterial strains following fecal microbiota transplantation in immunocompromised patients. PLoS One. 2017;12:e0182585.

    PubMed  PubMed Central  Google Scholar 

  88. Weingarden A, Gonzalez A, Vazquez-Baeza Y, Weiss S, Humphry G, et al. Dynamic changes in short- and long-term bacterial composition following fecal microbiota transplantation for recurrent clostridium difficile infection. Microbiome. 2015;3:10.

    PubMed  PubMed Central  Google Scholar 

  89. Chiang JY. Bile acids: Regulation of synthesis. J Lipid Res. 2009;50:1955–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Baktash A, Terveer EM, Zwittink RD, Hornung BVH, Corver J, Kuijper EJ, et al. Mechanistic insights in the success of fecal microbiota transplants for the treatment of clostridium difficile infections. Front Microbiol. 2018;9:1242.

    PubMed  PubMed Central  Google Scholar 

  91. Ridlon JM, Kang DJ, Hylemon PB. Bile salt biotransformations by human intestinal bacteria. J Lipid Res. 2006;47:241–59.

    CAS  PubMed  Google Scholar 

  92. Hashimoto S, Igimi H, Uchida K, Satoh T, Benno Y, Takeuchi N. Effects of beta-lactam antibiotics on intestinal microflora and bile acid metabolism in rats. Lipids. 1996;31:601–9.

    CAS  PubMed  Google Scholar 

  93. Antunes LC, Han J, Ferreira RB, Lolic P, Borchers CH, Finlay BB. Effect of antibiotic treatment on the intestinal metabolome. Antimicrob Agents Chemother. 55(2011):1494–503.

  94. Francis MB, Allen CA, Shrestha R, Sorg JA. Bile acid recognition by the clostridium difficile germinant receptor, cspc, is important for establishing infection. PLoS Pathog. 2013;9:e1003356.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Thanissery R, Winston JA, Theriot CM. Inhibition of spore germination, growth, and toxin activity of clinically relevant C. difficile strains by gut microbiota derived secondary bile acids. Anaerobe. 2017;45:86–100.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Buffie CG, Bucci V, Stein RR, McKenney PT, Ling L, et al. Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile. Nature. 2014;517:205.

    PubMed  PubMed Central  Google Scholar 

  97. Weingarden AR, Chen C, Bobr A, Yao D, Lu Y, et al. Microbiota transplantation restores normal fecal bile acid composition in recurrent clostridium difficile infection. Am J Physiol Gastrointest Liver Physiol. 2014;306:G310–9.

    CAS  PubMed  Google Scholar 

  98. Weingarden AR, Dosa PI, DeWinter E, Steer CJ, Shaughnessy MK, et al. Changes in colonic bile acid composition following fecal microbiota transplantation are sufficient to control clostridium difficile germination and growth. PLoS One. 2016;11:e0147210.

    PubMed  PubMed Central  Google Scholar 

  99. Mullish BH, McDonald JAK, Pechlivanis A, Allegretti JR, Kao D, et al. Microbial bile salt hydrolases mediate the efficacy of faecal microbiota transplant in the treatment of recurrent clostridioides difficile infection. Gut. 2019;68:1791–800.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Allegretti JR, Kearney S, Li N, Bogart E, Bullock K, Gerber GK, et al. Recurrent clostridium difficile infection associates with distinct bile acid and microbiome profiles. Aliment Pharmacol Ther. 2016;43:1142–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Theriot CM, Koenigsknecht MJ, Carlson PE Jr, Hatton GE, Nelson AM, et al. Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to clostridium difficile infection. Nat Commun. 2014;5:3114.

    PubMed  PubMed Central  Google Scholar 

  102. Ott SJ, Waetzig GH, Rehman A, Moltzau-Anderson J, Bharti R, et al. Efficacy of sterile fecal filtrate transfer for treating patients with clostridium difficile infection. Gastroenterology. 2017;152:799–811 e797.

    PubMed  Google Scholar 

  103. Goldenberg SD, Batra R, Beales I, Digby-Bell JL, Irving PM, et al. Comparison of different strategies for providing fecal microbiota transplantation to treat patients with recurrent clostridium difficile infection in two english hospitals: a review. Infect Dis Ther. 2018;7:71–86.

    PubMed  PubMed Central  Google Scholar 

  104. Kelly CR, Kahn S, Kashyap P, Laine L, Rubin D, Atreja A, et al. Update on fecal microbiota transplantation 2015: indications, methodologies, mechanisms, and outlook. Gastroenterology. 2015;149:223–37.

    PubMed  PubMed Central  Google Scholar 

  105. Woodworth MH, Neish EM, Miller NS, Dhere T, Burd EM, Carpentieri C, et al. Laboratory testing of donors and stool samples for fecal microbiota transplantation for recurrent clostridium difficile infection. J Clin Microbiol. 2017;55:1002–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Dubois N, Ling K, Osman M, Burns L, Mendolia G, Blackler D, et al. Prospective assessment of donor eligibility for fecal microbiota transplantation at a public stool bank: results from the evaluation of 1387 candidate donors. Open Forum Infect Dis. 2 (2015), Suppl 1, 962

  107. Food and Drug Administration, Important safety alert regarding use of fecal microbiota for transplantation and risk of serious adverse reactions due to transmission of multi-drug resistant organisms, 2019. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/important-safety-alert-regarding-use-fecal-microbiota-transplantation-and-risk-serious-adverse. Accessed June 2019.

  108. Panchal P, Budree S, Scheeler A, Medina G, Seng M, et al. Scaling safe access to fecal microbiota transplantation: past, present, and future. Curr Gastroenterol Rep. 2018;20:14.

    PubMed  Google Scholar 

  109. World Health Organization, Blood Transfusion Safety; 1975 https://www.who.int/bloodsafety/voluntary_donation/en/. Accessed June 2019

  110. Wang S, Xu M, Wang W, Cao X, Piao M, et al. Systematic review: Adverse events of fecal microbiota transplantation. PLoS One. 2016;11:e0161174.

    PubMed  PubMed Central  Google Scholar 

  111. Baxter M, Ahmad T, Colville A, Sheridan R. Fatal aspiration pneumonia as a complication of fecal microbiota transplant. Clin Infect Dis. 2015;61:136–7.

    PubMed  Google Scholar 

  112. van Beurden YH, de Groot PF, van Nood E, Nieuwdorp M, Keller JJ, Goorhuis A. Complications, effectiveness, and long term follow-up of fecal microbiota transfer by nasoduodenal tube for treatment of recurrent Clostridium difficile infection. United European Gastroenterol J. 2017;5:868–79.

    PubMed  Google Scholar 

  113. Youngster I, Mahabamunuge J, Systrom HK, Sauk J, Khalili H, et al. Oral, frozen fecal microbiota transplant (fmt) capsules for recurrent clostridium difficile infection. BMC Med. 2016;14:134.

    PubMed  PubMed Central  Google Scholar 

  114. De Leon LM, Watson JB, Kelly CR. Transient flare of ulcerative colitis after fecal microbiota transplantation for recurrent Clostridium difficile infection. Clin Gastroenterol Hepatol. 2013;11:1036–8.

    PubMed  Google Scholar 

  115. Mandalia A, Kraft CS, Dhere T. Diverticulitis after fecal microbiota transplant for C. difficile infection. Am J Gastroenterol. 2014;109:1956–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Jalanka J, Hillamaa A, Satokari R, Mattila E, Anttila VJ, Arkkila P. The long-term effects of faecal microbiota transplantation for gastrointestinal symptoms and general health in patients with recurrent Clostridium difficile infection. Aliment Pharmacol Ther. 2018;47:371–9.

    CAS  PubMed  Google Scholar 

  117. 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;50:403–7.

    PubMed  Google Scholar 

  118. Juul FE, Garborg K, Bretthauer M, Skudal H, Oines MN, et al. Fecal microbiota transplantation for primary clostridium difficile infection. N Engl J Med. 2018;378:2535–6.

    PubMed  Google Scholar 

  119. Norin E. Experience with cultivated microbiota transplant: ongoing treatment of clostridium difficile patients in Sweden. Microb Ecol Health Dis. 2015;26:27638.

    PubMed  Google Scholar 

  120. Gustafsson A, Lund-Tonnesen 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;33:721–7.

    CAS  PubMed  Google Scholar 

  121. Camacho-Ortiz A, Gutierrez-Delgado EM, Garcia-Mazcorro JF, Mendoza-Olazaran S, Martinez-Melendez A, et al. Randomized clinical trial to evaluate the effect of fecal microbiota transplant for initial clostridium difficile infection in intestinal microbiome. PLoS One. 2017;12:e0189768.

    PubMed  PubMed Central  Google Scholar 

  122. Ungaro R, Mehandru S, Allen PB, Peyrin-Biroulet L, Colombel JF. Ulcerative colitis. Lancet. 2017;389:1756–70.

    PubMed  Google Scholar 

  123. Kostic AD, Xavier RJ, Gevers D. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology. 2014;146:1489–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Sands BE, Peyrin-Biroulet L, Loftus EV Jr, Danese S, Colombel JF, et al. Vedolizumab versus adalimumab for moderate-to-severe ulcerative colitis. N Engl J Med. 2019;381:1215–26.

    CAS  PubMed  Google Scholar 

  125. Paramsothy S, Kamm MA, Kaakoush NO, Walsh AJ, van den Bogaerde J, Samuel D, et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet. 2017;389:1218–28.

    PubMed  Google Scholar 

  126. Cammarota G, Ianiro G. Fmt for ulcerative colitis: closer to the turning point. Nat Rev Gastroenterol Hepatol. 2019;16:266–8.

    PubMed  Google Scholar 

  127. Thompson WG, Longstreth GF, Drossman DA, Heaton KW, Irvine EJ, Muller-Lissner SA. Functional bowel disorders and functional abdominal pain. Gut. 1999;45(Suppl 2):II43–7.

    PubMed  PubMed Central  Google Scholar 

  128. Lacy BE, Mearin F, Chang L, Chey WD, Lembo AJ, Simren M, et al. Bowel disorders. Gastroenterology. 2016;150:1393–407.

    Google Scholar 

  129. Soares RL. Irritable bowel syndrome: a clinical review. World J Gastroenterol. 2014;20:12144–60.

    PubMed  PubMed Central  Google Scholar 

  130. Pimentel M, Talley NJ, Quigley EM, Hani A, Sharara A, Mahachai V. Report from the multinational irritable bowel syndrome initiative 2012. Gastroenterology. 2013;144:e1–5.

    PubMed  Google Scholar 

  131. Holtmann GJ, Ford AC, Talley NJ. Pathophysiology of irritable bowel syndrome. Lancet Gastroenterol Hepatol. 2016;1:133–46.

    PubMed  Google Scholar 

  132. Johnsen PH, Hilpusch F, Cavanagh JP, Leikanger IS, Kolstad C, Valle PC, et al. 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. 2018;3:17–24.

    PubMed  Google Scholar 

  133. Halkjaer SI, Christensen AH, Lo BZS, Browne PD, Gunther S, Hansen LH, et al. Faecal microbiota transplantation alters gut microbiota in patients with irritable bowel syndrome: results from a randomised, double-blind placebo-controlled study. Gut. 2018;67:2107–15.

    CAS  PubMed  Google Scholar 

  134. Tian H, Ge X, Nie Y, Yang L, Ding C, et al. Fecal microbiota transplantation in patients with slow-transit constipation: a randomized, clinical trial. PLoS One. 2017;12:e0171308.

    PubMed  PubMed Central  Google Scholar 

  135. Vedanta Biosciences, Bacterial Consortia, in, https://www.vedantabio.com/platform/how-our-drugs-work, Accessed May 2019.

  136. Tanoue T, Morita S, Plichta DR, Skelly AN, Suda W, et al. A defined commensal consortium elicits CD8 T cells and anti-cancer immunity. Nature. 2019;565:600–5.

    CAS  PubMed  Google Scholar 

  137. Seres Therapeutics, Product Pipeline, https://www.serestherapeutics.com/pipeline, Accessed May 2019.

  138. Blount KF, Shannon WD, Deych E, Jones C. Restoration of bacterial microbiome composition and diversity among treatment responders in a phase 2 trial of RBX2660: an investigational microbiome restoration therapeutic. Open Forum Infect Dis. 2019;6:ofz095.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

Dr. Michael Camilleri (Mayo Clinic, Rocheter, MN) is thanked for critiquing the review and providing insightful suggestions.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Butler University, 4600 Sunset Ave, Indianapolis, Indiana, 46208, USA

    Hala M. Fadda

Authors
  1. Hala M. Fadda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hala M. Fadda.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fadda, H.M. The Route to Palatable Fecal Microbiota Transplantation. AAPS PharmSciTech 21, 114 (2020). https://doi.org/10.1208/s12249-020-1637-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-020-1637-z

KEY WORDS

Search

Navigation