Impact of fecal microbiota transplantation on chronic recurrent pouchitis in ulcerative colitis with ileo-anal anastomosis: study protocol for a prospective, multicenter, double-blind, randomized, controlled trial

Caroline Trang-Poisson, Elise Kerdreux, Alexandra Poinas, Lucie Planche, Harry Sokol, Pascale Bemer, Karine Cabanas, Eliane Hivernaud, Laetitia Biron, Laurent Flet, Emmanuel Montassier, Ghislaine Le Garcasson, Anne Chiffoleau, Alexandra Jobert, Didier Lepelletier, Jocelyne Caillon, Patrice Le Pape, Berthe-Marie Imbert, Arnaud Bourreille, Caroline Trang-Poisson, Elise Kerdreux, Alexandra Poinas, Lucie Planche, Harry Sokol, Pascale Bemer, Karine Cabanas, Eliane Hivernaud, Laetitia Biron, Laurent Flet, Emmanuel Montassier, Ghislaine Le Garcasson, Anne Chiffoleau, Alexandra Jobert, Didier Lepelletier, Jocelyne Caillon, Patrice Le Pape, Berthe-Marie Imbert, Arnaud Bourreille

Abstract

Background: Almost 15% of patients with ulcerative colitis (UC) will require a proctocolectomy with ileal pouch-anal anastomosis (IPAA) as a result of fulminant colitis, dysplasia, cancer, or medical refractory diseases. Around 50% will experience pouchitis, an idiopathic inflammatory condition involving the ileal reservoir, responsible for digestive symptoms, deterioration in quality of life, and disability. Though the majority of initial cases of pouchitis are easily managed with a short course of antibiotics, in about 10% of cases, inflammation of the pouch becomes chronic with very few treatments available. Previous studies have suggested that manipulating the composition of intestinal flora through antibiotics, probiotics, and prebiotics achieved significant results for treating acute episodes of UC-associated pouchitis. However, there is currently no established effective treatment for chronic antibiotic-dependent pouchitis. Fecal microbiota transplantation (FMT) is a novel therapy involving the transfer of normal intestinal flora from a healthy donor to a patient with a medical condition potentially caused by the disrupted homeostasis of intestinal microbiota or dysbiosis.

Methods: Our project aims to compare the delay of relapse of chronic recurrent pouchitis after FMT versus sham transplantation. Forty-two patients with active recurrent pouchitis after having undergone an IPAA for UC will be enrolled at 12 French centers. The patients who respond to antibiotherapy will be randomized at a ratio of 1:1 to receive either FMT or sham transplantation.

Discussion: On April 30, 2014, the World Health Organization published an alarming report on antibiotic resistance. Finding an alternative medical treatment to antibiotics in order to prevent relapses of pouchitis is therefore becoming increasingly important given the risk posed by multiresistant bacteria. Moreover, if the results of this study are conclusive, FMT, which is less expensive than biologics, could become a routine treatment in the future.

Trial registration: ClinicalTrials.gov, NCT03524352. Registered on 14 May 2018.

Keywords: Fecal microbiota transplantation; Ileal pouch–anal anastomosis; Pouchitis; Randomized controlled trials.

Conflict of interest statement

The authors declare that they have no competing interests. This study is considered to be externally funded as Dr. Trang-Poisson has been awarded government funding (via a funding body).

Figures

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Study diagram

References

    1. Cosnes J, Gower-Rousseau C, Seksik P, Cortot A. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology. 2011;140:1785–1794.
    1. Van Assche G, Dignass A, Bokemeyer B, Danese S, Gionchetti P, Moser G, et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 3: special situations. J Crohns Colitis. 2013;7:1–33.
    1. Shen B, Fazio VW, Remzi FH, Brzezinski A, Bennett AE, Lopez R, et al. Risk factors for diseases of ileal pouch-anal anastomosis after restorative proctocolectomy for ulcerative colitis. Clin Gastroenterol Hepatol. 2006;4:81–89.
    1. Shen B. Acute and chronic pouchitis--pathogenesis, diagnosis and treatment. Nat Rev Gastroenterol Hepatol. 2012;9:323–333.
    1. Penna C, Tiret E, Kartheuser A, Hannoun L, Nordlinger B, Parc R. Function of ileal J pouch-anal anastomosis in patients with familial adenomatous polyposis. Br J Surg. 1993;80:765–767.
    1. Tjandra JJ, Fazio VW, Church JM, Oakley JR, Milsom JW, Lavery IC. Similar functional results after restorative proctocolectomy in patients with familial adenomatous polyposis and mucosal ulcerative colitis. Am J Surg. 1993;165:322–325.
    1. Dozois RR, Goldberg SM, Rothenberger DA, Utsunomiya J, Nicholls RJ, Cohen Z, et al. Restorative proctocolectomy with ileal reservoir. Int J Color Dis. 1986;1:2–19.
    1. Machiels K, Sabino J, Vandermosten L, Joossens M, Arijs I, de Bruyn M, et al. Specific members of the predominant gut microbiota predict pouchitis following colectomy and IPAA in UC. Gut. 2017;66:79–88.
    1. Morgan XC, Kabakchiev B, Waldron L, Tyler AD, Tickle TL, Milgrom R, et al. Associations between host gene expression, the mucosal microbiome, and clinical outcome in the pelvic pouch of patients with inflammatory bowel disease. Genome Biol. 2015;16:67.
    1. Landy J, Al-Hassi HO, McLaughlin SD, Knight SC, Ciclitira PJ, Nicholls RJ, et al. Etiology of pouchitis. Inflamm Bowel Dis. 2012;18:1146–1155.
    1. Packey CD, Sartor RB. Commensal bacteria, traditional and opportunistic pathogens, dysbiosis and bacterial killing in inflammatory bowel diseases. Curr Opin Infect Dis. 2009;22:292–301.
    1. Reiff C, Kelly D. Inflammatory bowel disease, gut bacteria and probiotic therapy. Int J Med Microbiol. 2010;300:25–33.
    1. Magro F, Gionchetti P, Eliakim R, Ardizzone S, Armuzzi A, Barreiro-de Acosta M, et al. Third European Evidence-based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 1: Definitions, Diagnosis, Extra-intestinal Manifestations, Pregnancy, Cancer Surveillance, Surgery, and Ileo-anal Pouch Disorders. J Crohns Colitis. 2017;11:649–670.
    1. Athayde J, Davies SC, Parker CE, Guizzetti L, Ma C, Khanna R, et al. Placebo Rates in Randomized Controlled Trials of Pouchitis Therapy. Dig Dis Sci. 2018;63:2519–2528.
    1. Dong J, Teng G, Wei T, Gao W, Wang H. Methodological Quality Assessment of Meta-Analyses and Systematic Reviews of Probiotics in Inflammatory Bowel Disease and Pouchitis. PLoS One. 2016;11:e0168785.
    1. Nguyen N, Zhang B, Holubar SD, Pardi DS, Singh S. Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis. Cochrane Database Syst Rev. 2019;5:CD001176.
    1. Bar N, Dubinsky V, Avraham Y, Reshef L, Banon L, Cohen NA, et al. 93 - Long Term Use of Ciprofloxacin and Metronidazole for Pouchitis – The Low Rate of Adverse Events and the High Association with Antibiotic Resistance. Gastroenterology. 2018;154:S-28.
    1. Mimura T, Rizzello F, Helwig U, Poggioli G, Schreiber S, Talbot IC, et al. Once daily high dose probiotic therapy (VSL#3) for maintaining remission in recurrent or refractory pouchitis. Gut. 2004;53:108–114.
    1. Gionchetti P, Rizzello F, Helwig U, Venturi A, Lammers KM, Brigidi P, et al. Prophylaxis of pouchitis onset with probiotic therapy: a double-blind, placebo-controlled trial. Gastroenterology. 2003;124:1202–1209.
    1. Pronio A, Montesani C, Butteroni C, Vecchione S, Mumolo G, Vestri A, et al. Probiotic administration in patients with ileal pouch-anal anastomosis for ulcerative colitis is associated with expansion of mucosal regulatory cells. Inflamm Bowel Dis. 2008;14:662–668.
    1. Gupta A, Khanna S. Fecal Microbiota Transplantation. JAMA. 2017;318:102.
    1. van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368:407–415.
    1. Kelly CR, Kahn S, Kashyap P, Laine L, Rubin D, Atreja A, et al. Update on Fecal Microbiota Transplantation 2015: Indications, Methodologies, Mechanisms, and Outlook. Gastroenterology. 2015;149:223–237.
    1. Wang S, Xu M, Wang W, Cao X, Piao M, Khan S, et al. Systematic Review: Adverse Events of Fecal Microbiota Transplantation. PLoS One. 2016;11:e0161174.
    1. DeFilipp Z, Bloom PP, Torres Soto M, Mansour MK, Sater MRA, Huntley MH, et al. Drug-resistant E coli bacteremia transmitted by fecal microbiota transplant. N Engl J Med. 2019;381:2043–2050.
    1. Paramsothy S, Paramsothy R, Rubin DT, Kamm MA, Kaakoush NO, Mitchell HM, et al. Faecal Microbiota Transplantation for Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. J Crohns Colitis. 2017;11:1180–1199.
    1. Moayyedi P, Surette MG, Kim PT, Libertucci J, Wolfe M, Onischi C, et al. Fecal Microbiota Transplantation Induces Remission in Patients With Active Ulcerative Colitis in a Randomized Controlled Trial. Gastroenterology. 2015;149:102–109.
    1. Rossen NG, Fuentes S, van der Spek MJ, Tijssen JG, Hartman JHA, Duflou A, et al. Findings From a Randomized Controlled Trial of Fecal Transplantation for Patients With Ulcerative Colitis. Gastroenterology. 2015;149:110–118.
    1. Imdad A, Nicholson MR, Tanner-Smith EE, Zackular JP, Gomez-Duarte OG, Beaulieu DB, et al. Fecal transplantation for treatment of inflammatory bowel disease. Cochrane Database Syst Rev. 2018;11:CD012774.
    1. Landy J, Walker AW, Li JV, Al-Hassi HO, Ronde E, English NR, et al. Variable alterations of the microbiota, without metabolic or immunological change, following faecal microbiota transplantation in patients with chronic pouchitis. Sci Rep. 2015;5:12955.
    1. Fang S, Kraft CS, Dhere T, Srinivasan J, Begley B, Weinstein D, et al. Successful treatment of chronic Pouchitis utilizing fecal microbiota transplantation (FMT): a case report. Int J Color Dis. 2016;31:1093–1094.
    1. Stallmach A, Lange K, Buening J, Sina C, Vital M, Pieper DH. Fecal Microbiota Transfer in Patients With Chronic Antibiotic-Refractory Pouchitis. Am J Gastroenterol. 2016;111:441–443.
    1. El-Nachef N, Lucey K, Somsouk M, Ma A, Berthe M, Leon K, et al. Su1747 Fecal Microbiota Transplant Improves Symptoms in Patients with Pouchitis and Induces Changes in the Microbiome: Preliminary Results of an Open Label Trial. Gastroenterology. 2016;150(Suppl 1):S544.
    1. Nishida A, Imaeda H, Inatomi O, Bamba S, Sugimoto M, Andoh A. The efficacy of fecal microbiota transplantation for patients with chronic pouchitis: A case series. Clin Case Rep. 2019;7:782–788.
    1. Herfarth H, Barnes EL, Long MD, Isaacs KL, Leith T, Silverstein M, et al. Combined Endoscopic and Oral Fecal Microbiota Transplantation in Patients with Antibiotic-Dependent Pouchitis: Low Clinical Efficacy due to Low Donor Microbial Engraftment. Inflamm Intest Dis. 2019;4:1–6.
    1. Selvig D, Piceno Y, Terdiman J, Zydek M, Umetsu SE, Balitzer D, et al. Fecal Microbiota Transplantation in Pouchitis: Clinical, Endoscopic, Histologic, and Microbiota Results from a Pilot Study. Dig Dis Sci. 2020;65:1099–1106.
    1. El-Nachef N, Piceno YM, Kassam Z, Zydek M, Ablaza A-J, Leith T, et al. Fecal Microbiota Transplantation is Safe and Effective in Chronic Pouchitis Patients. Gastroenterology. 2017;152:S1009.
    1. Agence Nationale de sécurité du Médicament. La transplantation de microbiote fécal et son encadrement dans les essais cliniques. Novembre 2016 (Actualisation de la version de juin 2015). . Accessed Nov 2019.
    1. Chan A-W, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža-Jerić K, et al. SPIRIT 2013 Statement: Defining Standard Protocol Items for Clinical Trials. Ann Intern Med. 2013;158:200.
    1. Costello SP, Conlon MA, Vuaran MS, Roberts-Thomson IC, Andrews JM. Faecal microbiota transplant for recurrent Clostridium difficile infection using long-term frozen stool is effective: clinical efficacy and bacterial viability data. Aliment Pharmacol Ther. 2015;42:1011–1018.
    1. Lee CH, Steiner T, Petrof EO, Smieja M, Roscoe D, Nematallah A, et al. Frozen vs Fresh Fecal Microbiota Transplantation and Clinical Resolution of Diarrhea in Patients With Recurrent Clostridium difficile Infection: A Randomized Clinical Trial. JAMA. 2016;315:142–149.
    1. Hamilton MJ, Weingarden AR, Sadowsky MJ, Khoruts A. Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection. Am J Gastroenterol. 2012;107:761–767.
    1. Carroll IM, Ringel-Kulka T, Siddle JP, Klaenhammer TR, Ringel Y. Characterization of the fecal microbiota using high-throughput sequencing reveals a stable microbial community during storage. PLoS One. 2012;7:e46953.
    1. Youngster I, Russell GH, Pindar C, Ziv-Baran T, Sauk J, Hohmann EL. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA. 2014;312:1772–1778.
    1. Sandborn WJ, Tremaine WJ, Batts KP, Pemberton JH, Phillips SF. Pouchitis after ileal pouch-anal anastomosis: a Pouchitis Disease Activity Index. Mayo Clin Proc. 1994;69:409–415.
    1. Peyrin-Biroulet L, Cieza A, Sandborn WJ, Coenen M, Chowers Y, Hibi T, et al. Development of the first disability index for inflammatory bowel disease based on the international classification of functioning, disability and health. Gut. 2012;61:241–247.
    1. International Committee of Medical Journal Editors (ICMJE) International Committee of Medical Journal Editors (ICMJE): Uniform Requirements for Manuscripts Submitted to Biomedical Journals: writing and editing for biomedical publication. Haematologica. 2004;89:264.
    1. World Health Organization . WHO’s first global report on antibiotic resistance reveals serious, worldwide threat to public health. Geneva: WHO; 2014.

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