Journal of Pediatric Gastroenterology & Nutrition:
Davidovics, Zev H.; Sylvester, Francisco A.
Connecticut Children's Medical Center, Hartford, CT.
Address correspondence and reprint requests to Francisco A. Sylvester, MD, Professor of Pediatrics and Immunology, Connecticut Children's Medical Center, 282 Washington Street, Hartford, CT 06106 (e-mail: email@example.com).
Received 3 April, 2013
Accepted 4 April, 2013
The authors report no conflicts of interest.
See “Safety, Tolerability, and Clinical Response After Fecal Transplantation in Children and Young Adults With Ulcerative Colitis” by Kunde et al on page 597.
Significant alterations in intestinal microbial composition occur in patients with inflammatory bowel disease (IBD) (1) that may contribute to the initiation and perpetuation of an intestinal inflammatory response (2). Although the individual normal microbiota remains to be clearly delineated, in theory, infusion of healthy donor feces (“fecal transplantation”) can ‘normalize’ microbial composition and, perhaps more importantly, restore the microbial metabolic functions that maintain intestinal homeostasis. Fecal transplantation has become a valid option for the treatment of refractory Clostridium difficile infection (3,4), but few studies have evaluated fecal transplantation as a treatment for IBD (5).
In this issue, Kunde et al report on 10 patients, 7 to 21 years of age, with mild to moderate ulcerative colitis (UC) who received retention fecal enemas for 5 consecutive days to treat their UC (6). One 18-year-old patient was unable to retain the enema and another had fever and chills within 3 hours of an enema that cleared spontaneously. No other serious events were reported. Notably, 7 patients showed clinical response, and 3 achieved clinical remission 1 week post-treatment.
Although this and previous reports (7,8) provide evidence of feasibility and proof of principle for fecal transplantation in UC, many questions remain. First, standard protocols are needed for screening donors, patient preparation, and volume and route of fecal transfer. Second, the stability of colonization after fecal transfer (and consequently, the frequency of its administration) is not known in patients with IBD. Given the chronic, recurrent nature of UC, a single infusion of stool given periodically may prove more effective than repeated doses during a short period of time, but this remains to be studied. Therefore, key issues of patient safety and treatment design need to be resolved. Third, the underlying mechanisms by which fecal transplantation may be anti-inflammatory in UC are not known. For example, the specific role of beneficial microbes and fecal metabolites in the transplanted stool needs to be delineated. Knowing more about the key microbial components and metabolites responsible for anti-inflammatory effects of fecal transfer in UC will help tailor the treatments and minimize its health risks.
Several regulatory issues need attention. Should human stool be considered a “biologic” and therefore require Food and Drug Administration review as an investigational new drug, as the authors suggest? Or should an investigational new drug review be reserved to research settings and the use of stool transfer in IBD be left to practicing clinicians, as is the case with treatment for refractory C difficile infections?
In summary, Kunde et al have taken an important first step to demonstrate the potential efficacy of fecal transfer in children with UC. Although this therapeutic option is enticing for its relative ease of administration, reasonable cost, and increasing acceptance by practitioners and patients, further research is required before it finds its proper place in our therapeutic armamentarium. We believe that at this time, fecal transfer should only be used in the setting of well designed research protocols in pediatric IBD to try to resolve the important issues outlined above and presented by this seminal paper.
1. Frank DN, St Amand AL, Feldman RA, et al. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci U S A
2. Couturier-Maillard A, Secher T, Rehman A, et al. NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer. J Clin Invest
3. Mattila E, Uusitalo-Seppala R, Wuorela M, et al. Fecal transplantation, through colonoscopy, is effective therapy for recurrent Clostridium difficile
4. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile
. N Engl J Med
5. Anderson JL, Edney RJ, Whelan K. Systematic review: faecal microbiota transplantation in the management of inflammatory bowel disease. Aliment Pharmacol Ther
6. Kunde S, Pham A, Bonczyk S, et al. Safety, tolerability, and clinical response after fecal transplantation in children and young adults with ulcerative colitis. J Pediatr Gastroenterol Nutr
7. Bennet JD, Brinkman M. Treatment of ulcerative colitis by implantation of normal colonic flora. Lancet
8. Borody TJ, Warren EF, Leis S, et al. Treatment of ulcerative colitis using fecal bacteriotherapy. J Clin Gastroenterol