FEATURE ARTICLE

Fecal microbiota transplantation and metagenomic medicine

Arthur Ling (Meds 2015) Faculty Reviewer: Dr. David Colby, MSc, MD, FRCPC (Departments of Microbiology and Immunology, Medi- cine and School of Dentistry)

INTRODUCTION was in 1958, when a team of physicians in Colorado successfully treated four patients with pseudomembranous colitis.6 At the time, three of these Have you ever had a gut feeling that you were not alone? Before you get patients had severe life threatening post-operative colitis that was unre- up to lock the doors, consider that our , in particular sponsive to conventional treatments. In a final attempt, the physicians the distal colon, is home to trillions of bacteria and other microorgan- pioneered the FMT procedure and the patients miraculously recovered isms collectively referred to as the microbiome. Fortunately, most of the and were discharged after several days. It would be much later in 1978 microbiota are not harmful, but instead provide physiological functions when C. difficile was identified to be a cause of antibiotic-associated such as and immune system development. Importantly, the in- diarrhea/colitis, which was then followed by the first report of a success- testinal microbiome acts as a front line defense against potential patho- ful FMT in a CDI case in 1981.6,7 While FMT was originally performed gens entering our gut. An important clinical example that highlights this by a crude colonic retention enema of homogenized stool samples ob- is an infection by a bacterium called Clostridium difficile, which usu- tained from closely related or intimate donors, the procedure has been ally causes a diarrheal/colitis syndrome, but in some cases may progress refined through the 1990s. Nowadays, most studies use standardized do- into a life-threatening pseudomembranous colitis or a colonic disten- nor screening and stool collection, cryoprotectant processing and freezer sion called toxic megacolon. Although healthy individuals are resistant storage, and instillation with a nasogastric/nasoduodenal tube or guided to the ingested spores, cases of C. difficileinfection (CDI) are on the rise infusion with a colonoscope or upper tract endoscope.2,8,9 However, the because of antibiotic treatments that disrupt the protective microbiota.1 basic engraftment principle applied in 1958 is so simple that there are To compound this problem, there are reports of increased incidence and even published ‘do-it-yourself’ guidelines that rely on easily acquired mortality rates, metronidazole resistance, and the emergence of hyper- items (e.g. kitchen blender, enema bag) and a healthy friend.10 virulent strains (e.g. BI/NAP1/PCR 027).1,2 This ‘epidemic’ has forced us to critically evaluate how we manage CDI cases, especially taking Today, the main indication for FMT is severe refractory CDI or into consideration the inherent dilemma that antibiotic therapy itself is chronic disease with a history of recurrence and a failure of multiple an- causing this infection. tibiotic regimens. While the evidence is limited to case series and reports of chronic CDI, recent systematic reviews have found an astounding What can be done? The standard treatment includes discontinuation 89-92% clinical resolution of the diarrheal syndrome in over 300 cases of the inciting antibiotics and adding other antibiotics (metronidazole, reported in the literature.2,3,11 These numbers are encouraging, but only vancomycin). Other additional therapies now include oral bacteriother- recently has there been interest in conducting a randomized controlled apy/probiotics, toxin binders, vaccination, and even performing surgical trial (FECAL trial, 2008 - ongoing).12 bowel resection.2–4 However, despite additional medical therapy, there are some patients (15 - 35%) that continue to have chronic recurring One possible objection to FMT is the concern for safety as there is disease or a severe presentation.5 For these patients, there has been a the possibility for transmitting infections during the procedure. This is last ditch protocol that focuses on replacing the disrupted microbiome a valid concern for any attempt to administer foreign microbiota as evi- through a procedure called fecal microbiota transplantation (FMT). denced in trials of Saccharomyces boulardii probiotic treatment in CDI Although this procedure has been around for over 50 years, it is not a patients, which had rare reports of sepsis and fungemia.13 Surprisingly, mainstream practice even though it has been found to provide safe, rela- in a systematic review of 376 cases of FMT in cases of CDI and other in- tively inexpensive, and rapid relief with potential long term protection. dications, there has not been a report of a major adverse event including This is likely due to disinterest from patients (the ‘yuck’ factor), physi- transmitted infection.3 Still, the possibility has been taken into consider- cians (‘natural’ approaches without good evidence tend to be presump- ation by developing protocols such as extensive donor screening in order tively dismissed), and researchers. In this article, I will provide a fresh to prevent transmission of enteric pathogens and provide reconstitution perspective of FMT and discuss how it is becoming an increasingly at- of ‘healthy’ microbiota. 8,14 tractive option in light of our improved understanding of the colonic FMT TREATMENT FOR OTHER DISEASES microbiome. (UC) and Crohn’s disease are both types of idiopathic MI CACA ES SU CACA inflammatory bowel disease (IBD) that are possible candidates for FMT FMT works on the principle of taking the bacteria in a healthy donor’s treatment because of the possible pathophysiologic role of the colonic stools and introducing them into the patient’s colon in order to restore bacteria. The first report of FMT in UC treatment was 1989 by Bennet a ‘healthy’ intestinal microbiota population. Historically, FMT has been and Brinkmann, in which Bennet, who suffered from persistent UC, suc- studied and performed in veterinary medicine to treat various disorders cessfully treated himself.15 Another report near the same time used FMT in farm animals (transfaunation).2 The first instance of FMT in humans to treat a variety of non-CDI associated colitis syndromes with some

UWOMJ | 81:2 | Fall 2012 11 FEATURE ARTICLE degree of success.16 In 2003, there was a landmark study on treating UC, REFERENCES which documented a case series of six patients with chronic UC who 1. Heinlen, L. & Ballard, J.D. Clostridium difficile Infection. Am J Med Sci. 17 underwent FMT. All of the patients in the study went into remission 2010;340(3):247-252. and at 1-13 years of follow-up, none of the patients had any evidence of active disease, indicating that the FMT treatments were associated 2. Brandt, L.J. & Reddy, S.S. Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection. J Clin Gastroenterol. 2011;45(Suppl):159-167. with a lengthy remission period or possible cure. While the evidence is far from definitive, it does support the idea that FMT can be used to 3. Borody, T.J. & Khoruts, A. Fecal microbiota transplantation and emerging treat other diseases that involve the colonic microbiota. These diseases applications. Nature reviews. 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To start off, consider the question: what makes each person pseudomembranous colitis due to toxin-producing clostridia. N Engl J Med. unique? Of course, many would say that it is a combination of genet- 1978;298(10):531-4. ic, epigenetic, and environmental factors, but traditionally few would 7. Bowden TA, Mansberger AR, L.L. Pseudomembranous enterocolits: mecha- consider the microbiome as a significant influence. Yet, while genetic nism of restoring floral homeostasis. Am Surg. 1981;47178-183. sequence variations between individuals comprise a miniscule fraction of our genome, the differences in microbiota populations have been esti- 8. Hamilton, M.J., Weingarden, A.R., Sadowsky, M.J. & Khoruts, A. Standard- ized Frozen Preparation for Transplantation of Fecal Microbiota for Recur- mated to be as high as 50%.21 Moreover, the microbiome is easily ame- rent Clostridium difficile Infection. 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Diabetologia. 2010;53(4):606-13. ing that patients may not be as adverse to the idea as what we might think.26 With any luck, we may see substantial developments in the years 21. Yong, E. Microbiome sequencing offers hope for diagnostics [Internet]. Na- ture News. 2012 Mar 23 [cited 2012 May 21]. Available from: http://www.na- to come. ture.com/news/microbiome-sequencing-offers-hope-for-diagnostics-1.10299

12 UWOMJ | 81:2 | Fall 2012 FEATURE ARTICLE . 22. Arumugam, M. et al. Enterotypes of the human gut microbiome. Nature. 2011;473(7346):174-80. 23. Yatsunenko, T. et al. Human gut microbiome viewed across age and geogra- phy. Nature. 2012;486(7402):222-7. 24. Mai, V., Ukhanova, M. & Baer, D.J. Understanding the Extent and Sources of Variation in Gut Microbiota Studies; a Prerequisite for Establishing Associa- tions with Disease. Diversity. 2010;2(9):1085-1096. 25. Lepage, P. et al. A metagenomic insight into our gut’s microbiome. Gut. 2012; doi:10.1136 26. Kahn, S., Gorawara-Bhat, R. & Rubin, D.T. Fecal bacteriotherapy for ul- cerative colitis: Patients are ready, are we? Inflammatory Bowel Diseases. 2012;18(4):676-684.

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