Key points

Introduction

The intestinal microbiota has been shown to play an important role in several gastrointestinal (GI) disorders, including inflammatory bowel disease (IBD). Evidence supporting the role of bacterial flora in IBD includes the use of antibiotics targeting enteric flora in prevention of postoperative recurrence of Crohn’s disease (CD). As our understanding of what constitutes imbalances of the intestinal microbiota expands, we are able to treat to target for a more “harmonious” balance. One unique example of this manipulation is the use of fecal microbial transplantation (FMT) for treatment of recurrent Clostridium difficile colitis (RCDI). FMT has been used since the fourth century in China, and was first reported in the medical literature when Eiseman and colleagues used fecal enemas in 4 patients for treatment of pseudomembranous colitis. The past decade has seen a steep rise in the incidence of RCDI, bringing FMT to the forefront of both scientific communities and the lay public. Success of FMT in RCDI has been shown by retrospective reviews and more recently by randomized controlled trials. RCDI is prevalent in patients with IBD and also is a risk factor for negative outcomes. FMT use in the IBD population for RCDI has been shown to be both safe and efficacious. The use of FMT to directly treat IBD, however, has shown mixed results. Given our ability to target the dysbiotic state with FMT, its use as targeted therapy has tremendous potential. Studies have involved a multidisciplinary approach, including gastroenterologists, infectious disease specialists, microbiologists, and patient volunteers. This overview discusses the practical considerations of FMT therapy with respect to our current understanding of safety and efficacy in IBD, screening for donors and recipients, specimen handling and storage, methods of delivery, and regulatory considerations.

Introduction

The intestinal microbiota has been shown to play an important role in several gastrointestinal (GI) disorders, including inflammatory bowel disease (IBD). Evidence supporting the role of bacterial flora in IBD includes the use of antibiotics targeting enteric flora in prevention of postoperative recurrence of Crohn’s disease (CD). As our understanding of what constitutes imbalances of the intestinal microbiota expands, we are able to treat to target for a more “harmonious” balance. One unique example of this manipulation is the use of fecal microbial transplantation (FMT) for treatment of recurrent Clostridium difficile colitis (RCDI). FMT has been used since the fourth century in China, and was first reported in the medical literature when Eiseman and colleagues used fecal enemas in 4 patients for treatment of pseudomembranous colitis. The past decade has seen a steep rise in the incidence of RCDI, bringing FMT to the forefront of both scientific communities and the lay public. Success of FMT in RCDI has been shown by retrospective reviews and more recently by randomized controlled trials. RCDI is prevalent in patients with IBD and also is a risk factor for negative outcomes. FMT use in the IBD population for RCDI has been shown to be both safe and efficacious. The use of FMT to directly treat IBD, however, has shown mixed results. Given our ability to target the dysbiotic state with FMT, its use as targeted therapy has tremendous potential. Studies have involved a multidisciplinary approach, including gastroenterologists, infectious disease specialists, microbiologists, and patient volunteers. This overview discusses the practical considerations of FMT therapy with respect to our current understanding of safety and efficacy in IBD, screening for donors and recipients, specimen handling and storage, methods of delivery, and regulatory considerations.

Regulatory guidelines

Therapeutic use of FMT has not followed a traditional path toward investigation and approval. Practitioners in infectious disease and gastroenterology have used it in various forms for many years without formal regulatory guidelines, unprecedented for a biological product. Medical therapy centers presented early options for patients to undergo a therapeutic FMT procedure for indications such as obesity, irritable bowel syndrome, or IBD without regulatory oversight. These practices were primarily based on positive case series, although efficacy and safety were not entirely known. This changed in 2013 when the US Food and Drug Administration (FDA) announced that any practitioner who wished to perform FMT obtain approval through application for an Investigational New Drug (IND). This was subsequently amended to state that an FMT is allowable without an IND for the indication of RCDI only. All other indications would require an IND. It is important for practitioners to recognize that FMT has yet to fully be studied beyond the phase 1 and early phase 2 portions of drug approval. At the time of this publication, FMT is not allowable for therapeutic use in IBD unless an IND has been obtained. The most recent FDA draft guidance was issued in March of 2016. This states that practitioners can use FMT for CDI not responding to standard therapies as long as full informed consent is obtained including the knowledge that FMT is an investigational therapy along with discussion of its reasonable foreseeable risks. The guidance mentions use of stool banks to obtain donor specimens and the regulatory oversight required when banks are used. It should be noted that the FDA is not changing its policy on enforcement discretion that allows for use of FMT without IND as long as

• 1.
  

  Full informed consent is obtained from the recipient that includes knowledge that FMT is an experimental treatment.

  
  
• 2.
  

  The stool is not obtained from a stool bank.

  
  
• 3.
  

  A licensed health care provider tests the donor’s blood and stool for the purposes of FMT.

At of the time of this draft, the regulation is up for public discussion on the FDA Web site. Key issues are defining what constitutes a stool bank and how to regulate their distribution of FMT product, particularly across state lines.

Donor and recipient considerations

Excitement within the scientific community over the therapeutic potential of FMT has translated to the lay public. Despite the apparent “ick factor” of the procedure, patients with IBD have demonstrated a willingness to undergo FMT, especially among those with more severe disease. Despite this willingness to undergo the procedure, many patients still find it difficult to seek out a suitable donor. There is also tremendous expense involved with the process of FMT, as many insurance carriers will not pay for the screening tests needed on both stool and serum for a healthy donor. The time involved to process the screening tests for the donor can lead to delays and further morbidity with the anticipated recipient.

An FMT donor for the purpose of IBD should be relatively healthy and free of diseases associated with intestinal microbiota ( Box 1 ). Food allergies of the recipient should be taken into consideration when assessing the appropriate donor to prevent allergic complications following transplantation. Initially in RCDI, the FDA wanted recipients to know their donors, but this came with many practical barriers. There are theoretic advantages and disadvantages for the recipient to have a familiar relationship to the donor. A first-degree relative may share genetic likeness that could confer a higher probability of successful engraftment. Alternatively, this shared genetic profile in IBD may prove an unhealthy match for treating a genetically based inflammatory disorder in the host. One possible disadvantage of using an intimate contact from the same household is the possible shared microbial environment that led to an inflammatory state in the first place. We may find that unrelated donors allow for implantation of a richer diversity in intestinal flora when compared with related donors. Ethical questions also present themselves when relatives serve as donors in the event that an adverse event may occur. A central stool bank that uses anonymous donations would avert awkward encounters during those instances.

For the purpose of informed consent, a donor must be at least 18 years of age. If younger than 18, both child and parental consent must be obtained. Donor selection should include the same screening process that is required for blood donation. A joint society letter from the Infectious Disease Society of America (IDSA), American Society for Gastrointestinal Endoscopy (ASGE), American College of Gastroenterology (ACG), the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHN), and the American Gastroenterological Association (AGA) written to the FDA provides a consensus guidance on donor selection and stool testing for the purposes of FMT for RCDI. This document includes a reference to the AABB Donor Questionnaire Documents on the FDA biologics Web site. These requirements are for minimum safety purposes and should be followed for IBD. Beyond these minimum safety precautions, we do not know what donor considerations should be used. The following are the exclusion criteria that are recommended by the consensus guidance statement:

Published efficacy data of fecal microbiota transplantation in inflammatory bowel disease

Therapeutic challenges in IBD persist despite the advent of newer molecular targets in biological therapy. With our current toolkit, clinicians still face the unenviable task of informing patients with IBD that the overall response rate to current therapeutic modalities reaches only 50%. In the past 5 years, FMT has emerged as a window into the science of manipulation of dysbiosis. As such, the number of studies investigating the utility of FMT as a viable treatment option for a dysbiotic state has risen exponentially. Our understanding of what constitutes a healthy microbiota is evolving. From a bird’s-eye perspective, reduced diversity of flora is seen in patients with IBD when compared with healthy controls. There are also differences in both the type and function of flora that are present in patients with IBD. Dysbiosis is characterized by decreased firmacutes and bacteroides and an increase in proteobacteria and actinobacteria . Antibiotics have been shown to ameliorate both small intestinal bacterial overgrowth (SIBO) and pouchitis, and smaller studies have shown their ability to induce remission in a small trial in C difficile (CD). FMT offers the theoretic advantage over antibiotics of restoring diversity of flora to potentially cure a dysbiotic state.

The efficacy of therapeutic use of FMT for IBD has yet to be determined, as results of both case reports and clinical trials have been mixed. The first case report of FMT in IBD was a physician who used a 1-time FMT via enema to achieve both endoscopic and histologic remission 6 months following the intervention. Thomas Borody has been performing and studying FMT for many years. These have been performed in Australia where regulatory agencies have not provided restrictions on its use. A large series of case reports provided mostly positive results, but they lacked controls and were open-labeled. Additionally, the cases varied with regard to route of administration, preparation of the stool product, and screening protocol. Successful open-labeled trials have been shown in the pediatric population in CD. A recent systematic review and meta-analysis of FMT in IBD included 18 studies with only 1 randomized controlled trial (RCT). This found an overall remission rate of 45%, which decreased to 36% when evaluating cohort studies only. When accounting for FMT done for ulcerative colitis (UC), the remission rate dipped to 22%.

Three RCTs recently published have only somewhat enhanced our understanding, although again with variable outcomes. In the trial by Moayyedi and colleagues, patients were randomized to receive either weekly fecal enemas or water enemas for 6 weeks with the primary outcome measure of remission of UC. Use of immune suppressive therapy, including anti–tumor necrosis factor (anti-TNF), agents was permitted in the study. The data safety monitoring board (DSMB) stopped the trial early after only 4 of the 27 patients were in remission in the FMT arm, and 2 of the 26 patients in the placebo arm, citing low likelihood of achieving their primary outcome measure. After this occurred, patients already screened and enrolled were allowed to continue with the treatments. Notably, these patients received FMT from one specific donor (donor B) and had a high response rate, pushing the results into clinical significance (9/38 [24%] FMT patients achieved remission versus 2/37 [5%] in the placebo group). Despite a small sample size, this was the largest RCT for FMT in UC. Two interesting findings emerged from this study. First, patients who underwent FMT had a statistically significant increase in microbial diversity when compared with the placebo group at week 6. These patients also had a significant effect of similar fecal microbial profile to their donors. Second, the study used 6 donors; with patients treated by one specific donor (donor B) conferring a positive effect for 7 of 11 patients receiving this stool, although without achieving significance versus placebo. Other researchers have posited that the diversity of donor flora can influence the success of FMT for IBD. Although this is an intriguing finding, further research is required before fully understanding what donor or stool profile will be beneficial to which recipient.

In the trial by Rossen and colleagues, patients with UC were randomized to receive FMT via nasogastric tube (NGT) from healthy donors or given autologous fecal material with primary endpoint of clinical remission at week 12. The intervention was performed at the beginning of the trial and again 3 weeks later. Notably, patients who had received anti-TNF or methotrexate within 8 weeks of the trial were excluded. An interim analysis by the DSMB also advised termination of the trial after 48 patients were recruited due to futility. At 12 weeks, 7 (30%) of 23 patients receiving FMT from donors achieved clinical remission versus 8 (32%) of 25 in the autologous FMT group. Stool analysis revealed changes in the responders to donated FMT had a microbial profile similar toward those of their donors. The authors posited route of administration and need for increased number of FMT procedures as a reason for lack of more robust response in the donated FMT group.

Most recently, a multicenter RCT performed in Australia by Paramsothy and colleagues compared participants who underwent a single FMT delivered via colonoscopy, then 5 FMT enemas per week for a total of 8 weeks with those receiving placebo enemas (matched for color and smell). The investigators showed a trend toward significant differences in both steroid-free and endoscopic remission and response rates between the groups. This intensive therapy used pooled donors to negate any potential influence of a single donor and found a large increase in fecal diversity in the successfully treated patients.

The aforementioned RCTs represent a positive step forward toward our understanding of how IBD responds to manipulation of the intestinal microbiota. There are currently more than 35 registered trials on clinicaltrials.gov that involve FMT as therapy for IBD. Progress in our ability and understanding will require more standardized methods with randomization to safely and reasonably use FMT as a clinical therapeutic for IBD. Specific questions must include microbial analysis to appreciate the specific donor and recipient profiles that are required for clinical success.