Fecal Microbiota Transplantation: an Interest in IBD?

Manipulating the Gut Microbiome as a Therapy for IBD Lewis JD, Ruemmele FM, Wu GD (eds): Nutrition, Gut Microbiota and Immunity: Therapeutic Targets for IBD. Nestlé Nutr Inst Workshop Ser, vol 79, pp 101–114, ( DOI: 10.1159/000360715 ) Nestec Ltd., Vevey/S. Karger AG., Basel, © 2014 Fecal Microbiota Transplantation: An Interest in IBD? a, b a a, b Stacy A. Kahn · Sarah R. Goeppinger · David T. Rubin a b Inflammatory Bowel Disease Center, and MacLean Center for Clinical Medical Ethics, University of Chicago Medicine, Chicago, IL , USA Abstract Fecal microbiota transplantation (FMT) is a targeted microbiome-based therapy that has garnered a great deal of attention from the scientific, clinical, and lay communities. An increasing number of studies have demonstrated that FMT is a highly effective therapy for recurrent/refractory Clostridium difficile infection and appears safe in the short term. Uncontrolled reports suggest the possibility of benefit in a select group of IBD patients, but there is quite limited information so far. FMT for IBD raises significant issues and concerns that warrant further systematic investigation. In this review, we discuss the background and rationale for this innovative therapy, the current knowledge for FMT in IBD, the logistical issues, and the important issues regarding ethics, social acceptability, and regulation. © 2014 Nestec Ltd., Vevey/S. Karger AG, Basel Although we have only begun to understand the complex microbiology of the human body, there is little doubt that the microbiome plays a fundamental role in health and disease. Since its inception, the Human Microbiome Project (HMP) has supported research aimed at characterizing the bacteria in and on our bodies and has fostered thousands of other projects with a similar goal [1] . This large-scale initiative has not only revolutionized our understanding of disease pathogenesis, but it has fundamentally changed the way we think about developing novel therapies and treating disease. Numerous microbiome-based approaches to treating diseases are being investigated, but none has garnered as much attention or interest as fecal microbiota transplantation (FMT). FMT is neither a new concept nor a new treatment, with reports dating back to 4th century China [2] . Despite its long history, we have little to no data about which diseases FMT will be most effective in treating, optimal delivery methods and doses, how to identify and screen healthy donors, and the long-term implications and safety of FMT. Much of our current understanding of FMT is drawn from its use in treating recurrent or relapsing Clostridium difficile infection (CDI). For recurrent/relapsing CDI, FMT appears to be incredibly effective and safe regardless of the delivery method, dose, or donor [3–6] . The therapeutic potential of FMT has been proposed for a number of other diseases including IBD [7–9]. Unfortu- nately, to date, there have been no published controlled trials of FMT in IBD, and the current basis for this innovative therapy is based on animal studies [10, 11] , studies describing the variations in the commensal intestinal microbiota in patients with IBD [12–16] , and a few small case reports and series of FMT in IBD [8, 9, 17–19] . This paucity of data has not dampened enthusiasm; patients, physicians, scientists, and the media continue to demonstrate a great deal of interest in FMT for IBD [20–23] . Although this enthusiasm is important in driving this innovative research forward, we must temper our enthusiasm and acknowledge that currently FMT is an experimental and unproven therapy for IBD. In this regard, FMT is analogous to any other unproven therapy and must be evaluated in the same controlled systematic approach. Furthermore, we be- lieve that because of the availability of the ‘treatment’ (stool), FMT for IBD raises unique issues and concerns that require further investigation. It is clear that there is a gap in our knowledge and a need for more research on this prom- ising and innovative therapy. In this review, we will discuss the background and rationale for this innovative therapy, the current knowledge for FMT in IBD, the logistical issues, and the important issues regarding ethics, social acceptability, and regulation. Background and Rationale FMT is the delivery of an entire microbial community from a healthy individual to an individual with disease. Dysbiosis, a theory first outlined over a century ago by Nobel Laureate Élie Metchnikoff, is a disruption in the otherwise normal balance of protective and pathogenic commensal bacteria [24] . The rationale is that FMT restores balance and corrects the underlying dysbiosis associated with the disease state. FMT involves the following: • Identification of a donor who submits to extensive screening for infectious diseases. • Collection and preparation of the fecal matter. • Delivery of the preparation to the patient. 102 Kahn · Goeppinger · Rubin In addition to the numerous logistical, screening, and safety issues that warrant the investigation outlined in this review, an equal number of questions ex- ist regarding the definition of a healthy donor and the potential implications of microbiota transplantation on other health related issues, such as allergy, obe- sity, and metabolism. A growing body of (uncontrolled) literature has demonstrated that FMT has unquestionable efficacy for the treatment of recurrent or relapsing CDI, with cure rates of over 90% and a favorable side effect profile, with no reports of seri- ous adverse events in children or adults [3, 5, 25, 26] . FMT also appears to be safe and effective in patients with severe fulminant CDI [27, 28] . Microbiological investigations to explore the mechanisms underlying this response have demonstrated that patients with CDI have dysbiosis that is corrected and sustained by treatment with FMT [5, 29, 30] . Having established that FMT treats dysbiosis, we must ask if FMT can treat other diseases associated with dysbiosis. IBD is a group of diseases with clinical features that overlap with CDI, but have a much more complex basis. Current etiological theories of IBD suggest that disease results through a complicated interaction between genes, immune dysregulation, and environmental and microbial factors [31] . With the widespread use of novel molecular techniques, we have increasing evidence that microbial factors such as dysbiosis are central to the development of IBD [12, 15, 16, 32] . As such, many theorize that repopulation of the commensal bacteria through FMT may help correct dysbiosis and downregulate the overwhelming inflammatory cascade in IBD [33–36] . Current Evidence for Fecal Microbiota Transplantation in IBD Unfortunately, current evidence for the utility of FMT in IBD is limited to a handful of abstracts, reports, and case series ( table 1 ) [9, 18, 19, 37–39] . The descriptions include variable amounts of data about the patients, donors, and delivery methods. Others have summarized the experiences through useful systematic reviews [40, 41] . The majority of the reports have been favorable; however, a few patients had no response or worsening of their IBD [37, 39, 42, 43] . It is unclear if there are specific biological or clinical factors that will predict a response or ‘intolerance’ to FMT, reaffirming the need for method- ical systematic investigations of FMT in different patient populations with IBD. The first reported use of FMT in IBD was by Bennet and Brinkman in 1989 [17] . Bennet, both a physician and a patient with medically refractory ulcerative colitis (UC), treated himself with large-volume retention enemas of donor flora. Fecal Microbiota Transplantation: An Interest in IBD? 103 Table 1. Studies investigating FMT for the treatment of IBD Study Year Disease Patients Delivery mode FMT Results and frequency donor Bennet 1989 severe UC 1 large-volume ? clinical remission, no active et al. [17] enemas for 1 week inflammation at 6 months Borody 1989 active UC 1 not described ? clinical, endoscopic, histological et al. [37] remission at 3 months small-bowel Crohn’s 1 clinical remission at 4 months disease plus stenosis total: IBD and/or IBS 55 20 of 55 ‘cured’ Borody 2001 quiescent UC 3 enema daily for ? clinical and endoscopic et al. [38] 5 days remission at 8–16 months Borody 2003 severe UC 6 enema daily family clinical and histological et al. [9] for 5 days or close remission at 1–13 years relation Borody 2012 active UC 62 not described ? 68% complete clinical remission, et al. [18] 24% clinical response, 8% no response; 12/21 ‘profound’ mucosal healing Vermeire 2012 medically refractory 4 nasojejunal infusion, ? no clinical or histological et al. [39] Crohn’s colitis and three doses over response at 8 weeks ileocolitis 36 h Kunde 2013 mild-to-moderate UC 10 enema daily for family 3/9: clinical remission at 1 week; et al. [19] (pediatric) 5 days or close 6/9: clinical response at 1 month; relation 1/10: unable to retain enema Some subjects may have been included in more than one report. ? = Donor not specified; IBS = irritable bowel syndrome. Flexible sigmoidoscopy at 3 months after transplant demonstrated chronic but no active inflammation, and, at 6 months after FMT, he was symptom-free and off all medications. The most convincing evidence for FMT in IBD is based on several case series from Borody’s group in Australia [8, 9, 18, 37, 38] . In 2006, Borody and col- leagues reported the results of daily FMT enemas for 5 days in 6 adults with se- verely active UC. Clinical improvement was noted as early as 1 week after FMT, and complete symptomatic remission was achieved in all patients by month 4. All subjects displayed no clinical, endoscopic, or histological evidence of active UC 1–13 years following treatment [9] . In March 2013, Kunde et al. [19] reported the first series of pediatric patients with IBD treated with FMT. They described 10 youths, aged 7–21 years, with mildly to moderately active UC treated with FMT enemas daily for 5 days.

Load more