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Fecal Microbiota Transplant: We Know Its History, but Can We Predict Its Future?

      Fecal microbiota transplant (FMT), sometimes referred to as simply fecal transplant, is a process of transferring feces from one person to another to alter the fecal microbiome of the recipient for the purposes of treating certain diseases. The idea of fecal transplantation dates back to the 4th century CE, but consideration of its use for the treatment of Clostridium difficile infection (CDI) only began in the early 1980s.

      Brandt LJ, Aroniadis OC. An overview of fecal microbiota transplantation: techniques, indications, and outcomes [published online ahead of print May 2, 2013]. Gastrointest Endosc. http://dx.doi.org/10.1016/j.gie.2013.03.1329.

      C difficile infection is one of the most common hospital-acquired infections and represents a major health problem in the United States.
      • Khanna S.
      • Pardi D.S.
      Clostridium difficile infection: new insights into management.
      Patients with recurrent CDI (RCDI) have an alteration in gut flora (dysbiosis). This alteration likely accounts for rates of RCDI of 10% to 20% after initial antibiotic treatment and recurrence rates as great as 40% to 65% in patients who have previously been treated for an RCDI episode.
      • Brandt L.J.
      American Journal of Gastroenterology Lecture: Intestinal microbiota and the role of fecal microbiota transplant (FMT) in treatment of C. difficile infection.
      Probiotic therapy, particularly using the yeast Saccharomyces boulardii in combination with high-dose antibiotic therapy, has been used for RCDI, although with limited success.
      • Surawicz C.M.
      • Brandt L.J.
      • Binion D.G.
      • et al.
      Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections.
      However, reintroduction of normal flora via donor feces is believed to correct the imbalance in gut microbiotic flora. On the other hand, antimicrobial therapy for CDI does not restore this imbalance and continues to alter the intestinal microbiome.
      Over the past several years, FMT has been reported to be highly effective in treating patients with RCDI.

      Brandt LJ, Aroniadis OC. An overview of fecal microbiota transplantation: techniques, indications, and outcomes [published online ahead of print May 2, 2013]. Gastrointest Endosc. http://dx.doi.org/10.1016/j.gie.2013.03.1329.

      The enormous potential for the use of FMT as a treatment for a myriad of other diseases includes inflammatory bowel disease
      • Damman C.J.
      • Miller S.I.
      • Surawicz C.M.
      • Zisman T.L.
      The microbiome and inflammatory bowel disease: is there a therapeutic role for fecal microbiota transplantation?.
      and insulin resistance/metabolic syndrome,

      Brandt LJ, Aroniadis OC. An overview of fecal microbiota transplantation: techniques, indications, and outcomes [published online ahead of print May 2, 2013]. Gastrointest Endosc. http://dx.doi.org/10.1016/j.gie.2013.03.1329.

      to name only two. A study in monozygotic and dizygotic twins suggested a genetic basis for an individual's gut microbiome, and obesity is associated with a significant decrease in the level of microbiome diversity.
      • Turnbaugh P.J.
      • Hamady M.
      • Yatsunenko T.
      • et al.
      A core gut microbiome in obese and lean twins.
      An individual's gut microbiota influences the body's ability to extract dietary calories and how these calories are used and stored. Studies in mice colonized with human fecal microbiota have documented that diet can affect gastrointestinal transit through microbiota-dependent or microbiota-independent pathways, depending on the dietary change.
      • Kashyap P.C.
      • Marcobal A.
      • Ursell L.K.
      • et al.
      Complex interactions among diet, gastrointestinal transit, and gut microbiota in humanized mice.
      The microbiota effect was found to depend mainly on the amount and type of dietary polysaccharides. This suggests that a relationship may exist between disorders such as irritable bowel syndrome or inflammatory bowel disease and gut microbiota.
      • Kashyap P.C.
      • Marcobal A.
      • Ursell L.K.
      • et al.
      Complex interactions among diet, gastrointestinal transit, and gut microbiota in humanized mice.
      In this issue of Mayo Clinic Proceedings, Patel et al
      • Patel N.C.
      • Griesbach C.L.
      • DiBaise J.K.
      • Orenstein R.
      Fecal microbiota transplant for recurrent Clostridium difficile infection: Mayo Clinic in Arizona Experience.
      present their results on the use of FMT to treat RCDI using a standardized evaluation process and protocol. All patients had 2 or more documented episodes of RCDI (mean, 4; range, 2-7) and ongoing diarrhea in the absence of antimicrobial therapy. Eligible donors met defined screening criteria. The FMT preparation was administered via outpatient colonoscopy. Over a 2-year period, 31 patients were treated. Three patients required more than one transplant procedure; in 2 of these patients, the second FMT was delivered through a nasojejunal feeding tube. Improvement or resolution of diarrhea occurred in 97% of the patients. The onset of improvement was rapid, with 26 of 30 patients (87%) experiencing improvement or resolution by 1 week. The response was durable in most patients, and 6 who had follow-up at 1 year reported maintained improvement. Adverse events occurred in one patient who experienced a self-limited colonic perforation during the colonoscopy.
      The results of this study are consistent with those in published reports of the use of FMT for RCDI.
      • Kassam Z.
      • Lee C.H.
      • Yuan Y.
      • Hunt R.H.
      Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis.
      When FMT is used as a treatment for RCDI, donors must be carefully screened. This screening process involves obtaining an extensive clinical history and the testing of donor serology and stool composition.

      Brandt LJ, Aroniadis OC. An overview of fecal microbiota transplantation: techniques, indications, and outcomes [published online ahead of print May 2, 2013]. Gastrointest Endosc. http://dx.doi.org/10.1016/j.gie.2013.03.1329.

      • Brandt L.J.
      American Journal of Gastroenterology Lecture: Intestinal microbiota and the role of fecal microbiota transplant (FMT) in treatment of C. difficile infection.
      At the present time, insurance coverage for donor screening is not uniform. Fecal microbiota transplant is performed most commonly via colonoscopy, but the transplant also can be delivered via enemas or into the stomach or small bowel via nasogastric or nasoduodenal tubes.
      • Brandt L.J.
      American Journal of Gastroenterology Lecture: Intestinal microbiota and the role of fecal microbiota transplant (FMT) in treatment of C. difficile infection.
      Efficacy does not appear to be different whether FMT is performed colonoscopically or nasogastrically.
      • Postigo R.
      • Kim J.H.
      Colonoscopic versus nasogastric fecal transplantation for the treatment of Clostridium difficile infection: a review and pooled analysis.
      The established Current Procedural Terminology (CPT) code for FMT is 44705, “Preparation of fecal microbiota for instillation, including assessment of donor specimen.” There are additional CPT codes for the method of instillation (eg, upper endoscopy, colonoscopy).
      Despite much progress in understanding the underlying biology of this technology, the briefly burgeoning field of FMT has recently experienced a potential setback at most institutions since the US Food and Drug Administration (FDA) convened a public workshop on May 2-3, 2013, that addressed FMT, ie, after acceptance of the article by Patel et al for publication in the Proceedings. A summary of the FDA presentation is available online.

      Slater JE. Fecal microbiota for transplantation. US Food and Drug Administration website. http://www.fda.gov/downloads/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferences/UCM352641.ppt. Accessed June 2, 2013.

      The FDA states: “When used to cure, treat, mitigate or prevent a disease fecal microbiota for transplantation meets the legal definition of a drug and biological product.” Therefore, the use of FMT to cure, treat, mitigate, or prevent a disease or condition is considered an unapproved new drug for which an Investigational New Drug application (IND) is required. For most institutions, obtaining an IND will be too cumbersome and time consuming. Further, the requirement for an IND raises questions of whether the current CPT code for the “preparation of fecal microbiota for instillation” (ie, 44705) is still applicable. Thus, we can expect that although FMT will still be available at many treatment centers, the number of treatment centers will almost certainly decline in the short term. The FDA's decision to place more restrictions on FMT, however, can be justified by unanswered questions that remain about FMT. First and foremost is recipient safety. Although the reported total adverse events (in an estimated treated population of >400 patients worldwide) are small, the potential for transmission of infectious agents remains.
      • Brandt L.J.
      American Journal of Gastroenterology Lecture: Intestinal microbiota and the role of fecal microbiota transplant (FMT) in treatment of C. difficile infection.
      For example, despite rigorous donor testing, 2 of 13 patients who received FMT at the Virginia Mason Medical Center in Seattle, Washington, had development of norovirus gastroenteritis soon after.

      Schwartz M, Gluck M, Koon S. Norovirus gastroenteritis after fecal microbiota transplantation for treatment of Clostridium difficile infection despite asymptomatic donors and lack of sick contacts. Am J Gastroenterol. In Press.

      As stated by the FDA, “the long-term effects of alterations in the gut microbiome are unknown.”

      Slater JE. Fecal microbiota for transplantation. US Food and Drug Administration website. http://www.fda.gov/downloads/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferences/UCM352641.ppt. Accessed June 2, 2013.

      In one study, 4 of 77 patients treated with FMT had subsequent development of autoimmune diseases,
      • Brandt L.J.
      American Journal of Gastroenterology Lecture: Intestinal microbiota and the role of fecal microbiota transplant (FMT) in treatment of C. difficile infection.
      although a direct cause and effect has not been proven. Most recently, flares of underlying inflammatory bowel disease following FMT have been reported,

      de Leon LM, Watson JB, Kelly CR. Transient flare of ulcerative colitis after fecal microbiota transplantation for recurrent Clostridium difficile infection [published online ahead of print May 10, 2013]. Clin Gastroenterol Hepatol. http://dx.doi.org/10.1016/j.cgh.2013.04.045.

      which is unfortunate given that FMT is a potential therapy for refractory inflammatory bowel disease.
      • Anderson J.L.
      • Edney R.J.
      • Whelan K.
      Systematic review: faecal microbiota transplantation in the management of inflammatory bowel disease.
      Only one randomized, controlled trial using FMT for CDI has been published.
      • van Nood E.
      • Vrieze A.
      • Nieuwdorp M.
      • et al.
      Duodenal infusion of donor feces for recurrent Clostridium difficile.
      This study, performed in the Netherlands, randomized patients with RCDI to receive 1 of 3 treatments: (1) vancomycin, 500 mg orally 4 times per day for 4 days, followed by bowel lavage and FMT delivered via a nasoduodenal tube; (2) a standard vancomycin regimen of 500 mg orally 4 times per day for 14 days; or (3) a standard vancomycin regimen with bowel lavage. The study was stopped after an interim analysis showed superior efficacy in the FMT group. Resolution of diarrhea without relapse using FMT was significantly more effective for the treatment of RCDI than the use of vancomycin. After 10 weeks, resolution was seen in 13 of 16 patients (81%) after the first FMT, and an additional 2 patients had successful resolution after a second FMT from a different donor. Resolution occurred in only 4 of 13 patients (31%) who received vancomycin therapy alone and 3 of 13 patients (23%) who received vancomycin with bowel lavage. Interestingly, after FMT, recipient patients acquired increased fecal bacterial diversity similar to that in healthy donors.
      In a retrospective, multicenter trial that included patients with RCDI unresponsive to standard therapy who had undergone FMT 3 or more months previously at 5 US medical centers, 77 patients were evaluated for long-term follow-up.
      • Brandt L.J.
      • Aroniadis O.C.
      • Mellow M.
      • et al.
      Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection.
      Primary cure was defined as resolution of diarrhea without recurrence within 90 days of FMT; secondary cure was defined as resolution of C difficile–associated diarrhea after one additional course of vancomycin with or without repeated FMT. The primary and secondary cure rates were 91% and 98%, respectively, at a mean follow-up of 17 months. More than 50% of patients expressed a preference for an additional FMT should RCDI occur.
      Although the data on FMT for the treatment of RCDI are compelling, additional studies are needed to determine long-term efficacy and safety.
      • Kassam Z.
      • Lee C.H.
      • Yuan Y.
      • Hunt R.H.
      Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis.
      To address the question in the title of this editorial—ie, can we predict the future of FMT?—the answer is, as of now, unclear. There are unanswered questions (Table), but it appears that the study of the gut microbiome has opened a new world in medicine. In addition, we believe synthetic and commercially marketed multimicrobial stool substitutes are an inevitable development in this field.
      TableNonstandardized and Unknown Aspects of Fecal Microbiome Transplant for the Treatment of Recurrent Clostridium difficile Infection
      Who should donate?
      How should we screen donors?
      Who should pay for screening and delivery?
      When should we initiate fecal microbiota transplant?
       • Two, 3, or 4 failures of antibiotic therapy?
       • Failure after trial of combination probiotics (eg, Saccharomyces boulardii) and antibiotic therapy?
      What location of delivery (upper gastrointestinal tract vs colon) is best?
      What method of delivery is best (nasogastric vs nasoduodenal; colonoscopy vs retention enema)?
      What is/are the best parameters to determine clinical success?
       • Diarrhea
       • Abdominal pain
       • Stool assays (C difficile toxin enzyme immunoassays, glutamate dehydrogenase concentrations)
      Long-term consequences

      Addendum

      On June 17, 2013, the FDA responded to concerns that FMT is not appropriate for study under IND and would make FMT unavailable to many patients.

      U.S. Food and Drug Administration. Important information about IND requirements for use of fecal microbiota to treat Clostridium difficile infection not responsive to standard therapies. Published June 17, 2013. Available at: http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferences/ucm357258.htm?source=govdelivery. Accessed July 2, 2013.

      The FDA now intends to “exercise enforcement discretion” regarding IND requirements for the use of FMT to treat C difficile infection unresponsive to standard therapies provided treating physicians obtain adequate informed patient consent or consent from a legally authorized representative. According to the FDA, “this informed consent 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.” The FDA is still in the developmental phase of policies for the study and use of FMT products under an IND and intends to issue guidance reflecting the agency's intention to exercise enforcement discretion. Notably, the FDA emphasized that during this time, compliance to IND regulations is strongly encouraged. Finally, the FDA encourages collaboration with sponsors to conduct clinical trials.
      Based on this, the use of FMT certainly appears to be in flux. In the meantime, we encourage the cautious use of FMT specifically for patients with recurrent C difficile infection not responsive to traditional antimicrobial therapy.

      References

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