Journal of Digestive Diseases 2014; 15; 405–408

doi: 10.1111/1751-2980.12160

Leading article

Fecal microbiota transplantation in treating Clostridium difficile infection William R BROWN Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA

Clostridium difficile infection (CDI) is an increasingly common and severe international health problem. Customary treatment of this infection, usually with antibiotics, is often ineffective and its recurrence is common. In recent years the treatment of recurrent or refractory CDI by the transfer of stool from an uninfected person, so called fecal “microbiota transplantation” has become recognized as effective and KEY WORDS: Clostridium difficile, pseudomembranous enterocolitis.


INTRODUCTION Clostridium difficile (C. difficile) is the pathogenic bacterium responsible for most antibiotic-associated diarrhea and is the pathogen of pseudomembranous colitis (PMC).1 C. difficile infection (CDI) is believed to result from gastrointestinal (GI) dysbiosis, the disrupted intestinal microbiota that is often caused by antibiotics, which enables C. difficile to establish the infection. CDI has been a global concern over the past decade. In 2010 there were 500 000 CDI cases in the USA and the estimated mortality is approximately 20 000 per year.2 The emergence of new virulent strains of C. difficile has accentuated the problem of CDI.3 Correspondence to: William R BROWN, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, 12631 East 17th Avenue, MS B158 AO1 Bldg., Room 7614, Aurora, CO 80045, USA. Email: [email protected] Conflict of interest: None. © 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd

generally safe. The effectiveness of this novel treatment is incompletely defined but is likely to be due to its correction of the intestinal dysbiosis that characterizes the disease. Practical methods for the administration of the transplantation have been described. This review summarizes the current reported experiences with fecal microbiota transplantation in the treatment for CDI. fecal





Customary treatment of CDI consists of the use of antibiotics such as metronidazole, vancomycin or fidaxomicin. However, the recurrence rate of CDI after an initial treatment with these medications is around 20% and up to 40–65% after the patients have been treated for a second episode.4 This high failure rate has prompted the quest for more effective treatments. A most promising approach, which has attracted widespread interest in both the medical and lay communities, is that of fecal microbiota transplantation (FMT), which is referred to also as a fecal enema, fecal bacteriotherapy or fecal bacterial transplantation. FMT aims at restoring a normal, functional intestinal microbiota in patients with CDI by transferring fecal content from a healthy person. FMT was first documented in the 4th century in China5 and in 1958 in the USA6. The report from the USA described four patients who had PMC, with Micrococcus pyogenes (hemolytic coagulase-positive Staphylococcus aureus) cultured from their stool specimens (C. difficile had not then been identified as the causative organism for PMC). The patients all had a



WR Brown

prompt resolution of their symptoms. The first reported case using FMT for the treatment of confirmed recurrent CDI (RCDI) appeared in 1983.7 In the early experience with FMT, retention enema was the most common method of administration, but administration by colonoscopy as well as into the upper small intestine has also been used.8 The overall success rate of FMT in RCDI has been astonishingly and gratifyingly high and is reported to be 92% in a systematic review of 317 patients in 27 case series.9 Experience at this author’s institution has been similarly impressive, as 51 of the 53 FMT-treated patients had prompt resolution of their symptoms, and CDI has recurred only in two patients who had been re-treated with antibiotics for non-gastrointestinal infection (unreported).

Journal of Digestive Diseases 2014; 15; 405–408 Ruminococcaceae families. They also observed that microbiota diversity was increased in patients as soon as one week after FMT, but the overall microbiota composition changes lasted for at least 16 weeks after FMT, suggesting that full microbiota recovery from RCDI might take a much longer time than expected based on the prompt resolution of diarrheal symptoms after FMT. Findings consistent with this report have also been described by others,12 who found that FMT increased fecal microbial diversity, increased the proportions of Lachnospiraceae (phylum Firmicutes) and decreased the proportions of Enterobacteriaceae. PRACTICAL ASPECTS OF FMT ADMINISTRATION

The exact mechanism responsible for the therapeutic effectiveness of FMT in treating CDI remains unknown but some clues have emerged from studies in animals and human individuals. The basic mechanism appears to be that the reintroduction of normal flora via donor feces corrects the intestinal dysbiosis, with the restoration of phylogenetic diversity and resistance. In experiments with mice Lawley et al.10 demonstrated that treatment with clindamycin followed by infection with C. difficile from hospitalized patients resulted in a chronic, contagious disease characterized by reduced phylotypic diversity, opportunistic pathogens, upregulated pro-inflammatory genes and a reduction in the amounts of butyrate and acetate, which are the main nutrients for the colon. Administration of vancomycin suppressed the excretion of C. difficile but, as often occurs in human disease, relapse occurred with the cessation of treatment. FMT with homogenized feces from a healthy mouse, which was given by oral gavage, suppressed C. difficile shedding, and treatment with six phylogenetically diverse species of obligate and facultative anaerobes resolved the CDI.

A major concern in the use of FMT is the potential for transmitting infectious agents; therefore, rigorous screening tests of donor samples are necessary. At a minimum, the stools should be tested for enteric pathogens, parasites and ova, as well as C. difficile toxin. In controlled trials, the U.S. National Institutes of Health has also required that donor blood be screened for hepatitis A, B and C, human immunodeficiency virus types 1 and 2 and syphilis.8 Some donor exclusions that have been advocated are the receipt of antibiotics within 3 months (because the perturbing effects of antibiotics can persist for at least that long), tattoos or body piercing in the previous 3 months and a previous history of diarrhea, and so on.8 Some nuts and bolts of FMT by colonoscopic administration have been listed by an experienced advocate of FMT:8 diluted stool in water, saline or milk should be filtered to remove particulate matter that could clog the channel of the colonoscope, and recipients should take a large-volume colonic lavage before the procedure. If possible, recipients should stop vancomycin and other antibiotics 3 days before the procedure, and take loperamide about an hour before the procedure in order to help them to hold the administered stool. The colonoscope passes to the cecum, and the stool suspension is delivered through the instrument by syringe.

In recent research on human beings Song et al.11 analyzed the fecal microbiota of healthy donors and patients with RCDI who had been successfully treated with FMT by 16S rRNA gene amplicon pyrosequencing, showing that in comparison with healthy donor samples and the stools of patients after FMT, pretreatment stool samples had increased members of the Streptococcaceae, Enterococcaceae or Enterobacteriaceae and lower populations of putative butyrate producers such as Lachnospiraceae and

The administration of fecal material by means other than by colonoscopy or those in combination with colonoscopy include retention enema,13 nasogastric tube14 and combined enteroscopy and colonoscopy.12 No clear-cut superiority of any of these methods has been established, although slightly higher success rates have been recorded with colonoscopic administration. A review of 182 patients in 12 published studies found no difference in treatment efficacy or the recurrence of CDI between patients who received FMT


© 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd

Journal of Digestive Diseases 2014; 15; 405–408 colonoscopically and those who received it by nasogastric tube.14 In another review15 the overall success rate of FMT was 80–98%, regardless of administration method. PATIENTS’ ACCEPTANCE, SAFETY ISSUES AND LONG-TERM OUTCOMES OF FMT FOR CDI The long-term outcomes of FMT have not been fully understood yet, but the available data are encouraging. In a study16 involving five medical centers with 77 patients who were followed up for more than 3 months, the primary cure rate (symptom relief in the absence of recurrence within 90 days of FMT) was 91% and the secondary cure rate (symptom relief after one further course of vancomycin with or without a repeated FMT) was 98%. Nearly all patients stated that they would have another FMT if they had RCDI, and over half of the patients preferred FMT to antibiotics. Some gastrointestinal complaints, such as abdominal cramping, gaseousness and an absence of bowel movement were transiently present after FMT. The authors also reported that 4 of the 77 patients developed autoimmune diseases such as rheumatoid arthritis, Sjögren’s syndrome, idiopathic thrombocytopenia and peripheral neuropathy after FMT, but a causal relationship between the disease and FMT had not been established. In a study of patients who had received multiple FMT,13 no adverse events were recorded and no patients who were cured with FMT had further episodes during a follow-up duration of 6–24 months. Safety of FMT in immunocompromised patients has always been a consideration but may not be a concern, based on the experiences of Brandt8 and with two solid organ transplant patients.17 Several studies2,3,18–21 have commented on the safety or absence of severe FMT-associated side effects. Nonetheless, the longterm safety of FMT must be evaluated further through controlled studies in large populations among various countries. In the USA, the Food and Drug Administration (FDA), concerned about the unregulated and rapidly increased use of FMT, announced the guidelines in 2013 that defined FMT as a biological therapy that required physicians to obtain an investigational new drug application.22,23 However, in response to the widespread feeling among healthcare providers that the requirement would make FMT unavailable to most patients, FDA rescinded the guidelines and now requires only that the treating physician obtain

FMT in treating C. difficile infection


‘adequate informed consent from the patient’. The informed statement ‘should include, at a minimum, a statement that the use of FMT products to treat C. difficile is investigational and a discussion of its potential risks’. POSSIBLE USES OF FMT BESIDES THE TREATMENT FOR RCDI The established effectiveness and apparent safety of FMT in treating RCDI has prompted much interest in its possible use in the initial treatment of CDI,24 the prevention of CDI in high-risk patients25 and in the treatment of diseases that may be linked to an abnormal gut microbiota.8,26,27 Diseases that have been suspected of being microbiota-linked and may be the candidates for FMT include inflammatory bowel disease, irritable bowel disease, obesity, allergic diseases, autoimmune diseases and neuropsychiatric illness. However, under none of these conditions has FMT been studied rigorously, and validation of its use in them will require carefully conducted controlled clinical trials. FUTURE DIRECTIONS FOR FECAL BACTERIOTHERAPY Despite the evident success and safety of FMT, concerns on the risk of donor–recipient transmission of disease, patients’ acceptance, and the complex and unpredictable effects on the recipient’s immune system have prompted the search for stool substitutes for FMT.28–31 A preparation of purified intestinal bacterial cultures derived from a single healthy donor was administered colonoscopically to two patients with repeatedly RCDI caused by a hypervirulent strain;29 the patients recovered within 2 to 3 days. 16S rRNA gene sequencing analysis of pretreatment and posttreatment stool samples revealed that rRNA sequences present in the stool substitute in the pretreatment samples were not common but constituted more than 25% of the sequences up to 6 months post-treatment. Pamer28 has predicted that the discovery of commensal microbes and studies of their impact on the host will result in developing new probiotic agents and microbial consortia that will eventually replace FMT. In conclusion, FMT is an effective, seemingly safe and relatively inexpensive treatment for RCDI, with a cure rate approaching more than 90%. The mechanism of FMT is incompletely defined but is likely to be due to the correction of intestinal dysbiosis that characterizes

© 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd


WR Brown

this sometimes serious, even lethal, infection, which can be resistant to conventional therapies. Despite its success and increasing popularity, FMT deserves more critical evaluation through well-designed and wellexecuted clinical trials and a development of standard protocols. The future of fecal bacteriotherapy will probably involve the refinement of current methods with the use of stool substitutes.

Journal of Digestive Diseases 2014; 15; 405–408

15 16


REFERENCES 18 1 Bartlett JG. Clinical practice. Antibiotic-associated diarrhea. N Engl J Med 2002; 346: 334–9. 2 Pathak R, Enuh HA, Patel A, Wickremesinghe P. Treatment of relapsing Clostridium difficile infection using fecal microbiota transplantation. Clin Exp Gastroenterol 2013; 7: 1–6. 3 Mattila E, Uusitalo-Seppälä R, Wuorela M et al. Fecal transplantation, through colonoscopy, is effective therapy for recurrent Clostridium difficile infection. Gastroenterology 2012; 142: 490–6. 4 McFarland LV, Surawicz CM, Rubin M, Fekety R, Elmer GW, Greenberg RN. Recurrent Clostridium difficile disease: epidemiology and clinical characteristics. Infect Control Hosp Epidemiol 1999; 20: 43–50. 5 Zhang F, Luo W, Shi Y, Fan Z, Ji G. Should we standardize the 1,700-year-old fecal microbiota transplantation? Am J Gastroenterol 2012; 107: 1755; author reply 1755–6. 6 Eiseman B, Silen W, Bascon GS, Kauvar AJ. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery 1958; 44: 854–9. 7 Schwan A, Sjölin S, Trottestam U, Aronsson B. Relapsing Clostridium difficile enterocolitis cured by rectal infusion of homologous faeces. Lancet 1983; 2: 845. 8 Brandt LJ. American Journal of Gastroenterology Lecture: Intestinal microbiota and the role of fecal microbiota transplant (FMT) in treatment of C. difficile infection. Am J Gastroenterol 2013; 108: 177–85. 9 Gough E, Shaikh H, Manges AR. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin Infect Dis 2011; 53: 994–1002. 10 Lawley TD, Clare S, Walker AW et al. Targeted restoration of the intestinal microbiota with a simple, defined bacteriotherapy resolves relapsing Clostridium difficile disease in mice. Plos Pathog 2012; 8: e1002995. 11 Song Y, Garg S, Girotra M et al. Microbiota dynamics in patients treated with fecal microbiota transplantation for recurrent Clostridium difficile infection. PLoS ONE 2013; 8: e81330. 12 Dutta SK, Girotra M, Garg S et al. Efficacy of combined jejunal and colonic fecal microbiota transplantation for recurrent Clostridium difficile infection. Clin Gastroenterol Hepatol 2014; pii: S1542-3565(14)00048-2 [Epub ahead of print]. 13 Lee CH, Belanger JE, Kassam Z et al. The outcome and longterm follow-up of 94 patients with recurrent and refractory Clostridium difficile infection using single to multiple fecal microbiota transplantation via retention enema. Eur J Clin Microbiol Infect Dis 2014; 33: 1425–8. 14 Postigo R, Kim JH. Colonoscopic versus nasogastric fecal transplantation for the treatment of Clostridium difficile



21 22 23



26 27 28 29

30 31

infection: a review and pooled analysis. Infection 2012; 40: 643–8. Dodin M, Katz DE. Faecal microbiota transplantation for Clostridium difficile infection. Int J Clin Pract 2014; 68: 363–8. 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: 1079–87. Friedman-Moraco RJ, Mehta AK, Lyon GM, Kraft CS. Fecal microbiota transplantation for refractory Clostridium difficile colitis in solid organ transplant recipients. Am J Transplant 2014; 14: 477–80. Austin M, Mellow M, Tierney WM. Fecal microbiota transplantation in the treatment of Clostridium difficile infections. Am J Med 2014; 127: 479–83. Broecker F, Kube M, Klumpp J et al. Analysis of the intestinal microbiome of a recovered Clostridium difficile patient after fecal transplantation. Digestion 2013; 88: 243–51. Cammarota G, Ianiro G, Gasbarrini A. Fecal microbiota transplantation for the treatment of Clostridium difficile infection: a systematic review. J Clin Gastroenterol 2014; [Epub ahead of print]. Di Bella S, Drapeau C, García-Almodóvar E, Petrosillo N. Fecal microbiota transplantation: the state of the art. Infect Dis Rep 2013; 5: e13. Moore T, Rodriguez A, Bakken JS. Fecal microbiota transplantation: a practical update for the infectious disease specialist. Clin Infect Dis 2014; 58: 541–5. FDA. Guidance for industry: 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 July 18. Cited 20 May 2014. Available from URL: http://www.fda. gov/biologicsbloodvaccines/guidancecomplianceregulatory information/guidances/vaccines/ucm361379.htm. Borody TJ, Peattie D, Kapur A. Could fecal microbiota transplantation cure all Clostridium difficile infections? Future Microbiol 2014; 9: 1–3. Lofgren ET, Moehring RW, Anderson DJ, Weber DJ, Fefferman NH. A mathematical model to evaluate the routine use of fecal microbiota transplantation to prevent incident and recurrent Clostridium difficile infection. Infect Control Hosp Epidemiol 2014; 35: 18–27. Borody TJ, Khoruts A. Fecal microbiota transplantation and emerging applications. Nat Rev Gastroenterol Hepatol 2011; 9: 88–96. Khanna S, Tosh PK. A clinician’s primer on the role of the microbiome in human health and disease. Mayo Clin Proc 2014; 89: 107–14. Pamer EG. Fecal microbiota transplantation: effectiveness, complexities, and lingering concerns. Mucosal Immunol 2014; 7: 210–4. 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. Petrof EO, Khoruts A. From stool transplants to next-generation microbiota therapeutics. Gastroenterology 2014; 146: 1573–82. Rineh A, Kelso MJ, Vatansever F, Tegos GP, Hamblin MR. Clostridium difficile infection: molecular pathogenesis and novel therapeutics. Expert Rev Anti Infect Ther 2014; 12: 131–50.

© 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd

Fecal microbiota transplantation in treating Clostridium difficile infection.

Clostridium difficile infection (CDI) is an increasingly common and severe international health problem. Customary treatment of this infection, usuall...
126KB Sizes 1 Downloads 6 Views