Though previously considered fringe medicine and the "last resort" for patients with Clostridium difficile infection, fecal microbiota transplantation (FMT) has certainly reached a tipping point. The surge in interest in FMT among physicians and researchers over the past 2-3 years is evident by increasing numbers of publications and registered clinical trials. The lay press is full of stories of lives saved by fecal transplant. There are guidebooks for patients, online resources such as "The Power of Poop," and even YouTube videos describing "do it yourself" FMT.
Dr. Colleen Kelly
It’s a rather simple procedure: identify a donor, process the stool, and administer it to the patient. However, each of these steps has generated many questions and some debate and there is currently no standard FMT protocol. Indeed, the optimum methods may vary depending on the clinical situation. The evidence is mounting in support of FMT for recurrent C. difficile infection (r- CDI). A recent systematic review of over 500 patients (J. Clin. Gastroenterol. 2014. epub Jan 2014) showed that 87% experienced clinical resolution after FMT with no serious adverse events reported. The first randomized controlled trial, published last year, (N. Engl. J. Med. 2013;368:407-15) confirmed the safety and efficacy of FMT for r-CDI. The data are growing on the mechanisms of effect. A recent study of 14 patients treated with FMT showed that, prior to FMT, these patients lacked the gut microbial diversity seen in their donors (PLoS One 2013;8:e81330). Post-FMT, they became more similar to their donors, with increased diversity, increased numbers of butyrate-producing organisms, and decreased Proteobacteria.
Despite good efficacy, ease of administration, and the lack of therapeutic alternatives for many patients, there are challenges to widespread implementation. Though FMT appears safe, prospective data are lacking. There have been case reports of fevers, bacteremia, and inflammatory bowel disease flares after FMT and theoretical concerns exist about transmitting risk factors for other conditions associated with dysbiosis, such as obesity and autoimmune disease. Many patients have difficulty identifying a healthy donor, screening protocols may be cumbersome, and long turn-around time in donor screening and laboratory testing limits use in emergent cases. Furthermore, relying on the availability of fresh material to treat patients presents obvious logistical difficulties. In terms of reimbursement, questions remain about who should pay for donor screening (donor vs. recipient insurance), how to bill for FMT delivery, and whether some insurers will pay given that most consider it an experimental procedure.
The regulatory landscape is rapidly evolving. The Food and Drug Administration announced at a public workshop last May that an investigational new drug application (IND) was required in order to treat patients with FMT. The IND process presents a large administrative burden to the average practitioner as INDs must include a detailed protocol, safety monitoring, and reporting plans, and annual reports. After outcry from patients and providers, the agency amended this policy and determined it would exercise "enforcement discretion." Providers would be permitted to administer FMT to individual patients with CDI not responding to standard therapies as long as they provide informed consent stating that FMT is investigational and discuss potential risks.
In the near future, physicians will not have to identify donors or rely on fresh stool to perform FMT. Stool banks, such as OpenBiome, have centralized donor screening and stool processing and hope to supply physicians with material to treat patients and researchers conducting clinical trials on applications of FMT. Commercialized preparations of minimally modified stool (which would be stored and shipped to providers when needed) are in clinical trials. Defined microbiota ecosystems, in which the species responsible for therapeutic effects are isolated and delivered, have been effective in animal and human trials. Ultimately, encapsulated formulations would be the easiest delivery method and enable thousands of patients to be treated, perhaps earlier in the course of disease. Dr. Thomas Louie at the University of Calgary reported successfully treating 27 patients with orally administered capsules containing fresh donor stool. Seres Health (Cambridge, Mass.) has developed an encapsulated formulation comprised of the "essential organisms" found in FMT. This product is currently in clinical trials, and efficacy has been observed in doses greater than 10,000-fold below the bacterial dose given in a conventional FMT.
In conclusion, there is good evidence supporting FMT for treatment of r-CDI and we are beginning to understand the mechanisms of therapeutic effect. Challenges remain and regulation is necessary, though agencies must recognize the unique nature of FMT and adapt policies as microbial therapeutics emerges.
Dr. Kelly, FACG, is assistant professor of medicine, Alpert School of Medicine, Brown University, Providence, R.I. Her comments were made during the ASGE and AGA joint Presidential Plenary at the annual Digestive Disease Week.
