Gastroenterology

Gastroenterology

Volume 149, Issue 1, July 2015, Pages 223-237
Gastroenterology

AGA Section
Update on Fecal Microbiota Transplantation 2015: Indications, Methodologies, Mechanisms, and Outlook

https://doi.org/10.1053/j.gastro.2015.05.008Get rights and content

The community of microorganisms within the human gut (or microbiota) is critical to health and functions with a level of complexity comparable to that of an organ system. Alterations of this ecology (or dysbiosis) have been implicated in a number of disease states, and the prototypical example is Clostridium difficile infection (CDI). Fecal microbiota transplantation (FMT) has been demonstrated to durably alter the gut microbiota of the recipient and has shown efficacy in the treatment of patients with recurrent CDI. There is hope that FMT may eventually prove beneficial for the treatment of other diseases associated with alterations in gut microbiota, such as inflammatory bowel disease, irritable bowel syndrome, and metabolic syndrome, to name a few. Although the basic principles that underlie the mechanisms by which FMT shows therapeutic efficacy in CDI are becoming apparent, further research is needed to understand the possible role of FMT in these other conditions. Although relatively simple to perform, questions regarding both short-term and long-term safety as well as the complex and rapidly evolving regulatory landscape has limited widespread use. Future work will focus on establishing best practices and more robust safety data than exist currently, as well as refining FMT beyond current “whole-stool” transplants to increase safety and tolerability. Encapsulated formulations, full-spectrum stool-based products, and defined microbial consortia are all in the immediate future.

Section snippets

History of FMT

Fecal transplantation dates back to 4th century China, where human fecal suspension by mouth was used to cure food poisoning and severe diarrhea,8 and has been widely used in veterinary medicine to treat ruminal disorders since the 17th century.9 There were anecdotal reports of the use of parental feces to treat antibiotic-associated diarrhea in children, but these cases were largely unknown until the publication by Ben Eiseman, an American surgeon, of the first case series in 1958 of 4

Indications

In 2010, members of various specialty societies with an interest in FMT formed a workgroup for the purpose of creating a consensus on FMT for practitioners. As outlined by the workgroup,16 the primary indications for FMT are as follows:

  • 1.

    Recurrent or relapsing CDI:

    • a.

      Three or more episodes of mild to moderate CDI and failure to respond to a 6- to 8-week taper with vancomycin with or without an alternative antibiotic (eg, rifaximin, nitazoxanide, or fidaxomicin)

    • b.

      At least 2 episodes of CDI resulting in

Efficacy Data in CDI

FMT has been examined in both young and old patients with limited comorbidities as well as those considered to be immunocompromised,42 and the procedure has been shown to be safe, well tolerated, and effective. The role of FMT for the treatment of CDI in specific situations (eg, toxic megacolon) is as yet unclear; however, of the more than 500 cases reported to date,3 FMT has shown a rapid response and a cure rate of nearly 90%, with a negligible significant adverse event rate, regardless of

Mechanisms

C difficile is an opportunistic organism that generally causes disease in people with decreased diversity of the GI microflora (typically as a result of antibiotic use). Indeed, studies have shown that patients with recurrent CDI are deficient in phyla of bacteria normally dominant in the colon6, 44 (Figure 1). FMT represents one of the most efficacious treatments available for recurrent CDI, although the exact mechanism of effect remains to be elucidated.

The greatest risk factor for CDI is the

FMT for IBD

Although the microbial basis of IBD is far more complex and variable than that of recurrent/refractory CDI, microbiome-based therapies are an important area of investigation for these chronic and debilitating diseases. As early as the 1900s, physicians recognized that bacteria may play a pivotal role in colitis.54 With more than a century of research and progress, we are just beginning to understand the microbiological basis for IBD and how FMT and other microbial therapeutics may be useful for

Safety of FMT

Evidence regarding the safety of FMT is relatively limited because the very rapid adoption of FMT as a therapeutic modality for CDI occurred before the performance of large, long prospective trials that are typically conducted to assess the safety of new interventions. Potential adverse events can be categorized as short term and long term, and short-term events can further be divided into those related to the method of FMT delivery (eg, colonoscopy, sedation) and those related to the FMT

Patient Perceptions

Patients with recurrent CDI are desperate for a cure and may seek guidance from online communities. Many are willing to travel great distances to undergo FMT. Some have even resorted to performing home enemas of donor stool when they are unable to find a physician who is willing or able to perform FMT. In fact, a YouTube video describing do-it-yourself FMT has been viewed more than 45,000 times.102 Limited studies of patient perceptions regarding FMT performed to date report that patients

Pediatric Considerations

Data regarding the safety and efficacy of FMT in pediatric patients is quite limited to date. Currently, the literature is composed of a handful of case reports and studies that include a small number of children with CDI23, 28, 26, 107 and/or IBD66, 69, 73, 108, 109, 110 who were treated with FMT. Additional larger, controlled, and prospective studies are needed to clarify both the safety and efficacy of FMT in pediatric patients.

In 2010, Russell et al reported the first pediatric patient

Regulatory Issues

Worldwide, regulation of FMT varies greatly between countries. The Therapeutic Goods Administration in Australia, where FMT is not considered a drug or regulated for any indication, has provided no communications regarding FMT. Although several trials of FMT are ongoing in China, there has been no indication that the Ministry of Health intends to exercise authority over the procedure. In Europe, the European Medicines Agency has not regulated FMT for CDI thus far.111 However, Health Canada

Future of FMT and Microbial Therapeutics

The value of FMT in treating recurrent CDI is clear, but its potential long-term consequences, both beneficial and detrimental, are unknown. The gut microbiota is a complex consortium with many components that have never been characterized. A priori knowledge is not available regarding the impact of transferring these complex communities from one person to another, although many studies in mice indicate that the composition of the gut microbiota can affect host susceptibility to diseases.

Conclusions

The high therapeutic efficacy of FMT for recurrent CDI is an important proof of concept that substantial modification of the gut microbiota can be an effective modality of treatment in humans. Much as the discovery of Helicobacter pylori revolutionized the treatment of peptic ulcer disease, our greater understanding of the communities of microorganisms residing within the human gut and the role of dysbiosis in various disease states will certainly result in new therapeutics in the coming

Acknowledgments

The authors thank David J. Cheney for the illustration and the American Gastroenterological Association Gut Microbiome Center for Research and Education.

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    This article has an accompanying continuing medical education activity on page e16. Learning Objective: Upon completion of this activity, successful learners will be able to explain appropriate indications for fecal microbiota transplantation, review regulatory and safety concerns related to this therapy, and identify appropriate patients for fecal microbiota transplantation.

    Conflicts of interest These authors disclose the following: C.R.K. has received research support from Assembly Biosciences, has been a consultant and site investigator for a clinical trial (SER-109) for Seres Health, and has been an advisory board member for OpenBiome and the Fecal Transplant Foundation. G.D.W. has been a scientific advisory board member for Chr. Hansen, Janssen, and Rebiotix; has received research support from Nestle, and is cofounder of Microbiota Therapeutics, LLC. The remaining authors disclose no conflicts.

    Funding Supported by National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases grant 1R21DK093839-01A1 (to C.R.K.); funding from National Institutes of Health grant K08 DK100638 as well as the Global Probiotic Council, Minnesota Partnership for Biotechnology and Genomics, and Center for Individualized Medicine (Mayo Clinic) (P.K.); and National Institutes of Health/National Institute of General Medical Sciences grant R01 GM103591 (to G.W.). D.R. Grant support: Digestive Disease Research Core Center of the University of Chicago (DK42086).

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