Fecal Microbiota Transplantation: An Update

Mark Davis, ND

Fecal microbiota transplantation (FMT) is the process of introducing fecal flora from a healthy donor to the gastrointestinal (GI) tract of another person – typically an individual with imbalanced flora and symptoms – for the purpose of improving the recipient’s health. Mechanisms may include the restoration of a healthy microbial ecosystem in the recipient and the delivery of immune-modulating factors within the donor stool.

History

FMT has been used to treat severe diarrhea since the 4th century CE,1 and for a variety of other indications since the 16th century1 and 17th century2 CE. The first published use of FMT to treat severe diarrhea in the United Sates was in 1958,3 and naturopathic doctors have used it since at least the 1970s.4

Legal Status

Clinicians in the United States were at liberty to use FMT at their discretion until a series of FDA guidelines in April5 and June6 of 2013 defined stool as a drug and biological agent, which limited clinicians to only using FMT for people with Clostridium difficile (C diff) infections that are not responding to standard therapies. FMT may be used for other indications within the context of an FDA-approved clinical trial. The FDA does not regulate individuals’ personal use of FMT, and many people with refractory C diff infections (rCDI), inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), multiple sclerosis (MS), and other conditions have done FMT at home and reported a variety of results. Home FMT has been observed to be safely and quickly curative for rCDI7 and, in my experience, has been safe and apparently beneficial for people with ulcerative colitis, Crohn’s colitis, IBS, MS, and other conditions.

Instructions for In-office and Home FMT

Donors

Most offices that prepare and administer FMT ask patients to identify their own donors. Donor-screening criteria have been covered extensively elsewhere.8,9 Often, a patient’s first-identified donor passes all recommended lab tests, but occasionally I’ve needed to screen 3 or more donors to find one who passes the lab testing; I’ve screened asymptomatic potential donors who tested positive for helminths, protozoans, and C diff, and potential donors in other practices have tested positive for pathogenic bacteria and blood-borne diseases. Testing a donor typically costs the patient $350-$1200, depending on lab contracts and insurance benefits. The American Gastroenterological Association has offered up coding guidelines for FMT donor-screening.10

In 2012, ambitious students from MIT and Harvard, who were concerned about lives lost due to lack of FMT donor availability, founded the non-profit Open Biome, which now distributes pre-screened frozen fecal slurry aliquots for use in FMT to clinicians in the United States and some other countries at a cost of $250 per aliquot.11 Clinicians using the Open Biome product must agree to use it only for patients who fit the FDA criteria.

Some conventional and naturopathic offices prepare fresh and frozen fecal slurries from their own donor banks. My clinic has maintained an FMT donor bank since 2011, and in that time we’ve provided FMT retention enemas to many grateful patients who have simply not had a healthy person in their lives whom they could ask to bring in his or her stool every day.

Preparation

At its simplest, FMT preparation consists of blending the pre-screened donor stool with enough diluent to make it pourable, filtering out the larger particles, pouring the resultant fecal slurry into an enema bottle or bag, and administering it per rectum right away. The specifics of how to prepare FMT at home and in-office have been covered in detail elsewhere.7,9

Delivery Method

Retention enemas are a simple and safe delivery method, which can be administered by clinicians in the office or by patients at home.7 FMT has been delivered via modified colon hydrotherapy units, but the safety and efficacy of this has not been reported.12 Both upper and lower endoscopy FMT delivery carry inherent risks of perforation and anesthesia; lower endoscopy shares the ~90% cure rate for rCDI that retention enema does, while upper-GI delivery methods have a ~80% cure rate for rCDI.13 Capsulized FMT is more appealing to patients than rectal administration, and appears to be very low risk. Capsules have been associated with 95-100% cure rate when prepared from 100 grams of stool taken once,14,15 or 50 grams of stool taken twice.16 Capsules are prepared by centrifuging the fecal slurry to extract a bacterial pellet, then triple-encapsulating the pellet. We have prepared and used FMT capsules at Bright Medicine Clinic since February of 2011, with excellent outcomes for patients with uncomplicated rCDI, although we have seen some relapses after cure.

Evidence Base

FMT has been examined for rCDI more than for any other condition, via 1 randomized controlled trial (RCT),17 2 meta-analyses,13,18 hundreds of published case reports, and thousands of clinical uses, all generally agreeing on an approximate 92% cure rate.

There is also a meta-analysis19 examining the use of FMT for IBD, which reviews 9 cohort studies, 8 case studies, and one RCT.20 This evidence is more sparse and conflicted, with different methodologies, age groups, and types of IBD; however, the conclusion of the meta-analysis roughly agrees with what I have seen in my own practice: about 25% of my UC patients, and more than half of my Crohn’s colitis patients, experience remission following FMT.

There are case studies reporting apparent benefit for patients with IBS, MS, metabolic syndrome, idiopathic thrombocytopenic purpura,21 chronic fatigue,22 Parkinson’s disease,23 and other conditions.

At the time of this writing, clinicaltrials.gov lists 20 FMT trials comparing fresh vs frozen stool, capsulated vs colonoscopic delivery, and other aspects of FMT for adult and pediatric rCDI. In addition, there are trials currently studying FMT for adults and children with ulcerative colitis, Crohn’s disease, UC-associated pouchitis, IBS, hepatic encephalopathy, HIV, metabolic syndrome, and diabetes. One trial is also looking at autologous prophylactic FMT for individuals undergoing hematopoietic stem-cell transplantation,24 and another trial is using FMT to treat GI problems in children with autism.25

The Future

Mark Smith, PhD, and Eric Alm, PhD, of Open Biome, as well as influential FMT researcher and clinician Colleen Kelly, MD (who was first introduced to the idea of FMT by a naturopathic medical student with rCDI), argued recently that the FDA should reclassify FMT from a drug to a tissue.26 It is more like blood and bone marrow, they argue, than like a vaccine or pharmaceutical whose composition can be precisely replicated from batch to batch. This author had the opportunity to ask Wellington Sun, MD (the head of the FDA’s division of Vaccines, Blood & Biologics, which oversees regulation of FMT), whether the FDA would consider that reclassification. Dr Sun responded that tissues are defined as consisting of or derived from human cells, and the fecal flora which comprise FMT do not and could never meet that definition.27

It seems that FMT regulation is stuck between the “rock” of being defined as a drug, and the “hard place” of being an organic material that varies from batch to batch, which means it could never meet the consistency and reproducibility standards that the FDA sets for drugs and biologics.

There have been attempts to develop products that remove the unpredictability factor in human donor feces. For example, researchers in Toronto have designed a “robo-gut” – a synthetic colon that is pH-controlled, anaerobic, and has a nutrient slurry running through it like a real colon would – and they culture a few dozen microbes originally derived from the stool of healthy donor. They call their work the “rePOOPulate project” and report successfully curing 2 cases of human rCDI that did not relapse despite subsequent oral antibiotic use.28 Dr Elaine Petrof, the lead researcher behind the project, has a message for companies such as Rebiotix and Seres Health, which are trying to commercialize a “synthetic stool” product: “Honestly, good luck to you.”29 The Rebiotix product RBX2660 has done well in initial small unpublished trials, showing an 87% cure rate of human rCDI in a small trial.30

The Present

FMT is in an awkward place at present. It’s clearly providing benefit for some, but current FDA regulations are limiting clinicians from providing it. As a result, home-FMT how-to videos are being viewed tens of thousands of times. People are doing FMT at home, sometimes with unscreened donors, or with their own stool, or their pet’s stool, or in milkshakes. People want this therapy and they don’t need a clinician to get it, but they are likely to experience less harm, and potentially reap more benefit, if they do FMT with the knowledge and guidance of an informed clinician. Clinicians supporting their patients through home-FMT might invoke the harm-reduction models of needle-exchange programs and safe-sex programs championed by public health advocates and clinicians. Even in a world of emerging microbial medicines seeking to be licensed as drugs, I believe that being knowledgeable about the safety, efficacy and best practice of FMT will serve clinicians of this generation for their whole careers.

*****

Davis_Headshot_2014Mark Davis, ND, specializes in naturopathic gastroenterology at the Bright Medicine Clinic in Portland, Oregon. Dr Davis is one of a handful of physicians in the North America with clinical expertise in fecal microbiota transplantation (FMT), which he offers via retention enema and capsule. Dr Davis sits on the board of directors of the Fecal Transplant Foundation, and he is the chairperson of the Fecal Microbiota Transplantation committee for the C diff Foundation. He received his ND degree with honors in research from the National College of Natural Medicine. His website is brightmedicineclinic.com.

 

 

References:

  1. Zhang F, Luo W, Shi Y, et al. Should we standardize the 1,700-year-old fecal microbiota transplantation? Am J Gastroenterol. 2012;107(11):1755; author reply p.1755-1756.
  2. Lehrer S. Duodenal infusion of feces for recurrent Clostridium difficile. N Engl J Med. 2013;368(22):2144.
  3. Eiseman B, Silen W, Bascom GS, Kauvar AJ. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery. 1958;44(5):854-859.
  4. Pamela Snider, ND; personal communication; September 13, 2014.
  5. Midthun K. Letter to the American Gastroenterological Association. April 25, 2013. Available at: http://highroadsolution.com/file_upload_2/files/fda+response+letter+to+fmt+inquiry.pdf. Accessed November 11, 2014.
  6. US Food and Drug Administration. Guidance for Industry: Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to TreatClostridium difficile Infection Not Responsive to Standard Therapies. July, 2013. FDA Web site. http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/UCM361393.pdf. Accessed November 11, 2014.
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  8. Relman D, Vender RJ, Rustgi AK, et al. Current Consensus Guidance on Donor Screening and Stool Testing for FMT. Letter to Wellington Sun, MD. July 15, 2013. Available at: http://www.gastro.org/research/Joint_Society_FMT_Guidance.pdf. Accessed November 11, 2014.
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  19. Colman RJ, Rubin DT. Fecal microbiota transplantation as therapy for inflammatory bowel disease: A systematic review and meta-analysis. J Crohns Colitis. 2014 Sep 12. pii: S1873-9946(14)00243-8.
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  22. BACTERIOTHERAPY IN CHRONIC FATIGUE SYNDROME (CFS): A RETROSPECTIVE REVIEW. Program No. P362. ACG 2012 Annual Scientific Meeting Abstracts. Las Vegas, NV: American College of Gastroenterology.
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  24. gov. [List of studies, using search terms “fecal transplant” OR “fecal microbiota transplantation.”] Available at: http://clinicaltrials.gov/ct2/results?term=%22fecal+transplant%22+OR+%22fecal+microbiota+transplantation%22. Accessed November 11, 2014.
  25. Arizona State University. ASU to lead new FDA approved autism treatment study. August 19, 2014. Available at: http://www.biodesign.asu.edu/news/asu-to-lead-new-fda-approved-autism-treatment-study-. Accessed November 11, 2014.
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