Recent evidence indicates that Clostridium difficile infection, the leading cause of infectious diarrhea, impacts almost half a million people and was associated with approximately 29,000 deaths in 2011 (Lessa et al. 2015). The cumulative financial burden related to C. difficile is estimated at about $2 billion (McGlone et al. 2012).
The concept of fecal microbial transplant (FMT), defined as infusion of a fecal suspension from a healthy individual into the gastrointestinal tract of another person to cure a specific disease, has a long history and continues to gain medical favor in the treatment of those presenting recurrent C. difficile infection (RCDI) (Brandt and Aroniadis 2013). RCDI is defined as three or more recurrences with traditional antibiotic therapy (Surawicz et al. 2013; Debast, Bauer, and Kuijper 2014). Small studies on earlier approaches to reduce C. difficile disease suggest the concomitant introduction of some strains of probiotics with or without select antibiotics may be justified in some clinical presentations. The results of such studies are inconsistent, however (McFarland 2009; Gao, Mubasher, Fang, Reifer, and Miller 2010; Allen et al. 2013; Ollech, Shen, Crawford, and Ringel 2016).
A small study out of the Netherlands indicates that among RCDI patients, the initial administration of human stool via naso-duodenal route resulted in an 81% resolution, which increased to 94% following a subsequent infusion (van Nood et al. 2013). Multiple systematic reviews and meta-analyses suggest a potential resolution in about 90% of those presenting RCDI (Guo, Harstall, Louie, Van Zanten, and Dieleman 2012; Kassam, Lee, Yuan, and Hunt 2013; Sofi, Silverman, Khuder, Garborg, Westerink, and Nawras 2013).
An important aspect of FMT is the rate of RCDI and potential complications. One study with 70 patients treated with FMT via colonoscopy indicated the absence of complications after 12 months of follow-up (Mattila et al. 2012). A longer-term follow-up indicated resolution of diarrhea within three days for 74% of the patients and a secondary cure rate of 98% with no adverse effects (Brandt 2012).
FMT may be an alternative intervention in other gastrointestinal disorders, such as inflammatory bowel disease, obesity, and even metabolic syndrome (Pinn, Aroniadis, and Brandt 2015; Colman and Rubin 2014; Turnbaugh, Ley, Mahowald, Magrini, Mardis, and Gordon 2006). The latter were suggested by fecal-transplant interventions in rodents (Cho et al. 2012) and a few studies among humans (Vrieze et al. 2012).
Critical considerations in the FMT process are the inclusion and exclusion criteria regarding the health status of the donor and recipient. Both should undergo screening that includes a thorough health history, a review of dietary patterns, and an extensive evaluation of stool testing.
In 2013, the U.S. Food and Drug Administration notified the medical and scientific community that it intended to exercise enforcement discretion regarding FMT and acknowledged that FMT may be effective therapy in the management of C. difficile infection. Yet the consistency of efficacy and safety of this intervention demonstrated through clinical trials remain questionable.
From a Health Canada perspective, human stool is considered a “new biologic drug” or a therapeutic agent within the jurisdiction of the Biologic and Genetics Therapies Directorate (Allen-Vercoe et al. 2012). As a new biological drug, microbial ecosystem therapeutics would require a risk-benefit assessment as part of clinical trial application.
We seem to have entered the era of the microbiome. With it comes the hope that therapeutic manipulation of the microbiome may not only have a role in the management of RCDI, but in the effort to control pathologies such as insulin resistance, metabolic syndrome, morbid obesity, Parkinson disease, amyotrophic lateral sclerosis, and even autism.
What we do seem to know with confidence at this point is that stool is a very complicated entity that is composed of trillions of living organisms and their metabolic products, and it may be that only a select few of these components or some dynamic equilibrium of components are needed to treat C. difficile infection. Ongoing research to determine precisely which of the organisms and products in stool are needed for C. difficile therapy is key. Once the appropriate organism(s) can be identified, transplantation of stool would no longer be needed for treatment of C. difficile infection as patients could be given the curative organism in isolation.
Fecal microbial transplant appears to be a generally safe, relatively low-tech procedure that may be effective in managing recurrent C. difficile infection, and it shows promise in contributing to the treatment of unrelated disorders. Stay tuned!
Roger Clemens, DrPH, CFS, Contributing Editor
Adjunct Professor, Univ. of Southern California’s School of Pharmacy, Los Angeles, Calif.