Fecal microbiota transplantation in the treatment of recurrent Clostridium difficile infection
- Thomas J Borody, MD, PhD, FRACP, FACG, FACP, AGAF
Thomas J Borody, MD, PhD, FRACP, FACG, FACP, AGAF
- Center for Digestive Diseases, Australia
- Sharyn Leis, RN
Sharyn Leis, RN
- Clinical Coordinator
- Centre for Digestive Diseases, Australia
- Gerald Pang, PhD
Gerald Pang, PhD
- Center for Digestive Diseases, Australia
- Antony R Wettstein, MBBS (Hons), FRACP
Antony R Wettstein, MBBS (Hons), FRACP
- Center for Digestive Diseases, Australia
Relapse of Clostridium difficile occurs in 10 to 25 percent of patients treated with metronidazole or vancomycin. Furthermore, multiple relapses in the same patient are common, and up to 10 or more bouts of relapsing colitis have occurred in some patients. Cumulative experience from case series and reports shows that fecal bacteriotherapy has been used to treat relapsing C. difficile infection  and, more recently, for inflammatory bowel disease [2-4]. The term fecal microbiota transplantation (FMT) is preferable to fecal bacteriotherapy as it is unknown whether its efficacy is due to one or more bacteria or other gut microorganisms or agents acting alone or in combination.
This topic will review the use of FMT for the treatment of patients with recurrent C. difficile infection. Other issues related to C. difficile infection are discussed separately. (See "Clostridium difficile in adults: Epidemiology, microbiology, and pathophysiology" and "Clostridium difficile infection in adults: Clinical manifestations and diagnosis" and "Clostridium difficile in adults: Treatment".)
RATIONALE FOR FECAL MICROBIOTA TRANSPLANTATION
The gastrointestinal tract harbors a stable, highly complex community of microorganisms which exists in symbiosis with the host. The human gut microbiota is estimated to consist of as many as 1000 to 1200 bacterial species and at least 1014 bacteria, most of which are in the colon . The beneficial roles mediated by the microbiota for the host include the synthesis of vitamins, the fermentation of dietary carbohydrates, the metabolism of bile and host hormones and competitive exclusion ("colonization resistance") of pathogens taking residence in the gut community . The microbiota also influences the development and maturation of the immune system through interactions with the gut epithelium [7,8].
The composition of the microbiota is significantly affected by the extensive use of antibiotics which could lead to a selective removal of a group of bacteria species that serve as a barrier to colonization and/or persistence of pathogens [9,10]. Antibiotic-mediated changes in the composition of the gut microbiota may also lead to homeostatic imbalance through alterations in the gut barrier functions and result in mucosal immune defects, which would predispose the host to enteric infections such as C. difficile by allowing environmentally acquired spores to germinate and successfully colonize the gut .
Although specific antimicrobial therapy is effective against C. difficile infection, recurrence of C. difficile infection is an increasing problem following therapy. Recurrent C. difficile is associated with a decrease in fecal microbial diversity deficient in Bacteroides and Firmicutes, both of which generally dominate within the gut microbiota [12,13]. Transplantation of stool from healthy individuals to patients with recurrent C. difficile restores these strains and breaks the cycle of recurrence [14-17].
- Bakken JS. Fecal bacteriotherapy for recurrent Clostridium difficile infection. Anaerobe 2009; 15:285.
- Borody TJ, Warren EF, Leis S, et al. Treatment of ulcerative colitis using fecal bacteriotherapy. J Clin Gastroenterol 2003; 37:42.
- Anderson JL, Edney RJ, Whelan K. Systematic review: faecal microbiota transplantation in the management of inflammatory bowel disease. Aliment Pharmacol Ther 2012; 36:503.
- Kump PK, Gröchenig HP, Lackner S, et al. Alteration of intestinal dysbiosis by fecal microbiota transplantation does not induce remission in patients with chronic active ulcerative colitis. Inflamm Bowel Dis 2013; 19:2155.
- Qin J, Li R, Raes J, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010; 464:59.
- Robinson CJ, Bohannan BJ, Young VB. From structure to function: the ecology of host-associated microbial communities. Microbiol Mol Biol Rev 2010; 74:453.
- Lee YK, Mazmanian SK. Has the microbiota played a critical role in the evolution of the adaptive immune system? Science 2010; 330:1768.
- Sharma R, Young C, Neu J. Molecular modulation of intestinal epithelial barrier: contribution of microbiota. J Biomed Biotechnol 2010; 2010:305879.
- Jernberg C, Löfmark S, Edlund C, Jansson JK. Long-term ecological impacts of antibiotic administration on the human intestinal microbiota. ISME J 2007; 1:56.
- Dethlefsen L, Relman DA. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci U S A 2011; 108 Suppl 1:4554.
- Reid G, Younes JA, Van der Mei HC, et al. Microbiota restoration: natural and supplemented recovery of human microbial communities. Nat Rev Microbiol 2011; 9:27.
- Tvede M, Rask-Madsen J. Bacteriotherapy for chronic relapsing Clostridium difficile diarrhoea in six patients. Lancet 1989; 1:1156.
- Chang JY, Antonopoulos DA, Kalra A, et al. Decreased diversity of the fecal Microbiome in recurrent Clostridium difficile-associated diarrhea. J Infect Dis 2008; 197:435.
- Khoruts A, Dicksved J, Jansson JK, Sadowsky MJ. Changes in the composition of the human fecal microbiome after bacteriotherapy for recurrent Clostridium difficile-associated diarrhea. J Clin Gastroenterol 2010; 44:354.
- Grehan MJ, Borody TJ, Leis SM, et al. Durable alteration of the colonic microbiota by the administration of donor fecal flora. J Clin Gastroenterol 2010; 44:551.
- Floch MH. Fecal bacteriotherapy, fecal transplant, and the microbiome. J Clin Gastroenterol 2010; 44:529.
- Rohlke F, Surawicz CM, Stollman N. Fecal flora reconstitution for recurrent Clostridium difficile infection: results and methodology. J Clin Gastroenterol 2010; 44:567.
- Schwan A, Sjölin S, Trottestam U, Aronsson B. Relapsing Clostridium difficile enterocolitis cured by rectal infusion of normal faeces. Scand J Infect Dis 1984; 16:211.
- Persky SE, Brandt LJ. Treatment of recurrent Clostridium difficile-associated diarrhea by administration of donated stool directly through a colonoscope. Am J Gastroenterol 2000; 95:3283.
- You DM, Franzos MA, Holman RP. Successful treatment of fulminant Clostridium difficile infection with fecal bacteriotherapy. Ann Intern Med 2008; 148:632.
- 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; 44:562.
- Silverman MS, Davis I, Pillai DR. Success of self-administered home fecal transplantation for chronic Clostridium difficile infection. Clin Gastroenterol Hepatol 2010; 8:471.
- MacConnachie AA, Fox R, Kennedy DR, Seaton RA. Faecal transplant for recurrent Clostridium difficile-associated diarrhoea: a UK case series. QJM 2009; 102:781.
- Nieuwdorp M, van Nood E, Speelman P, et al. [Treatment of recurrent Clostridium difficile-associated diarrhoea with a suspension of donor faeces]. Ned Tijdschr Geneeskd 2008; 152:1927.
- Russell G, Kaplan J, Ferraro M, Michelow IC. Fecal bacteriotherapy for relapsing Clostridium difficile infection in a child: a proposed treatment protocol. Pediatrics 2010; 126:e239.
- Aas J, Gessert CE, Bakken JS. Recurrent Clostridium difficile colitis: case series involving 18 patients treated with donor stool administered via a nasogastric tube. Clin Infect Dis 2003; 36:580.
- Faust G, Langelier D, Haddad H, et al. Treatment of recurrent pseudomembranous colitis with stool transplantation: Report of six cases. Can J Gasteroenterol 2002; 16:A43.
- Landy J, Al-Hassi HO, McLaughlin SD, et al. Review article: faecal transplantation therapy for gastrointestinal disease. Aliment Pharmacol Ther 2011; 34:409.
- Kassam Z, Hundal R, Marshall JK, Lee CH. Fecal transplant via retention enema for refractory or recurrent Clostridium difficile infection. Arch Intern Med 2012; 172:191.
- Brandt LJ, Aroniadis OC, Mellow M, et al. Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection. Am J Gastroenterol 2012; 107:1079.
- van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013; 368:407.
- Trubiano JA, Gardiner B, Kwong JC, et al. Faecal microbiota transplantation for severe Clostridium difficile infection in the intensive care unit. Eur J Gastroenterol Hepatol 2013; 25:255.
- Kassam Z, Lee CH, Yuan Y, Hunt RH. Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis. Am J Gastroenterol 2013; 108:500.
- Brandt LJ, Borody TJ, Campbell J. Endoscopic fecal microbiota transplantation: "first-line" treatment for severe clostridium difficile infection? J Clin Gastroenterol 2011; 45:655.
- Gallegos-Orozco JF, Paskvan-Gawryletz CD, Gurudu SR, Orenstein R. Successful colonoscopic fecal transplant for severe acute Clostridium difficile pseudomembranous colitis. Rev Gastroenterol Mex 2012; 77:40.
- Gough E, Shaikh H, Manges AR. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin Infect Dis 2011; 53:994.
- Bowden TA Jr, Mansberger AR Jr, Lykins LE. Pseudomembraneous enterocolitis: mechanism for restoring floral homeostasis. Am Surg 1981; 47:178.
- Gustafsson A, Lund-Tønnesen S, Berstad A, et al. Faecal short-chain fatty acids in patients with antibiotic-associated diarrhoea, before and after faecal enema treatment. Scand J Gastroenterol 1998; 33:721.
- Garborg K, Waagsbø B, Stallemo A, et al. Results of faecal donor instillation therapy for recurrent Clostridium difficile-associated diarrhoea. Scand J Infect Dis 2010; 42:857.
- McCrea M, Guskiewicz K, Randolph C, et al. Incidence, clinical course, and predictors of prolonged recovery time following sport-related concussion in high school and college athletes. J Int Neuropsychol Soc 2013; 19:22.
- Bouhnik Y, Pochart P, Marteau P, et al. Fecal recovery in humans of viable Bifidobacterium sp ingested in fermented milk. Gastroenterology 1992; 102:875.
- Kullen MJ, Amann MM, O'Shaughnessy MJ, et al. Differentiation of ingested and endogenous bifidobacteria by DNA fingerprinting demonstrates the survival of an unmodified strain in the gastrointestinal tract of humans. J Nutr 1997; 127:89.
- McNulty NP, Yatsunenko T, Hsiao A, et al. The impact of a consortium of fermented milk strains on the gut microbiome of gnotobiotic mice and monozygotic twins. Sci Transl Med 2011; 3:106ra106.
- Petrof EO, Gloor GB, Vanner SJ, et al. Stool substitute transplant therapy for the eradication of Clostridium difficile infection: 'RePOOPulating' the gut. Microbiome 2013; 1:3.
- Postigo R, Kim JH. Colonoscopic versus nasogastric fecal transplantation for the treatment of Clostridium difficile infection: a review and pooled analysis. Infection 2012; 40:643.
- EISEMAN B, SILEN W, BASCOM GS, KAUVAR AJ. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery 1958; 44:854.
- Kelly CR, de Leon L, Jasutkar N. Fecal microbiota transplantation for relapsing Clostridium difficile infection in 26 patients: methodology and results. J Clin Gastroenterol 2012; 46:145.
- Mattila E, Uusitalo-Seppälä R, Wuorela M, et al. Fecal transplantation, through colonoscopy, is effective therapy for recurrent Clostridium difficile infection. Gastroenterology 2012; 142:490.
- Youngster I, Sauk J, Pindar C, 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.
- Ilan Youngster, George H. Russell, Christina Pindar, et al. Oral, Capsulized, Frozen Fecal Microbiota Transplantation for Relapsing Clostridium difficile Infection. JAMA 2014.
- Miao CL, Mowery AD, Khara HS, et al. Difficile small bowel enteritis after total proctocolectomy successfully treated with fecal transplant. Am J Gastroenterol 2014; 109:S442.
- 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.
- Borody TJ, Wettstein AR, Hills L, et al. Clostrodium difficile infection complicating inflammatory bowel disease: pre-treatment and post-treatment findings. Abstract accepted for DDW, San Diego, CA, 17-22 May 2008.
- Duplessis CA, You D, Johnson M, Speziale A. Efficacious outcome employing fecal bacteriotherapy in severe Crohn's colitis complicated by refractory Clostridium difficile infection. Infection 2012; 40:469.
- Hamilton MJ, Weingarden AR, Sadowsky MJ, Khoruts A. Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection. Am J Gastroenterol 2012; 107:761.
- 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; 56:597.
- Borody TJ, Wettstein A, Nowak A, et al. Fecal microbiota transplantation (FMT) eradicates Clostridium difficile infection (CDI) in inflammatory bowel disease (IBD). 21st United European Gastroenterology Week 2013, Session: Beneficial and detrimental effects of bacteria in the GI tract, October 15, 2013.
- Borody TJ, Warren EF, Leis SM, et al. Bacteriotherapy using fecal flora: toying with human motions. J Clin Gastroenterol 2004; 38:475.
- Khoruts A, Sadowsky MJ, Hamilton MJ. Development of Fecal Microbiota Transplantation Suitable for Mainstream Medicine. Clin Gastroenterol Hepatol 2014.
- Important information about IND requirements for use of fecal microbiota to treat Clostridium difficile infection not responsive to standard therapies. US Food and Drug Administration. Available at: http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferences/ucm357258.htm (Accessed on June 25, 2013).
- RATIONALE FOR FECAL MICROBIOTA TRANSPLANTATION
- PATIENT SELECTION
- Efficacy based on route of administration
- - Enema
- - Colonoscope
- - Nasogastric/jejunal tube
- - Oral
- Patients who have undergone subtotal/total colectomy
- Patients with underlying inflammatory bowel disease
- SUGGESTED PROTOCOL
- Administration via the lower GI tract
- Administration via the upper GI tract
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS