Step-up fecal microbiota transplantation strategy: a pilot study for steroid-dependent ulcerative colitis
Bota Cui, Pan Li, Lijuan Xu, Youquan Zhao, Huiquan Wang, Zhaoyuan Peng, Hai'e Xu, Jie Xiang, Zhi He, Ting Zhang, Yongzhan Nie, Kaichun Wu, Daiming Fan, Guozhong Ji, Faming Zhang, Bota Cui, Pan Li, Lijuan Xu, Youquan Zhao, Huiquan Wang, Zhaoyuan Peng, Hai'e Xu, Jie Xiang, Zhi He, Ting Zhang, Yongzhan Nie, Kaichun Wu, Daiming Fan, Guozhong Ji, Faming Zhang
Abstract
Background: The strategy of using fecal microbiota transplantation (FMT) for refractory ulcerative colitis (UC) remains unclear if single FMT failed to induce remission. This study aimed to evaluate the efficacy and safety of a designed step-up FMT strategy for the steroid-dependent UC.
Methods: Fifteen patients with steroid-dependent UC were enrolled, and treated with step-up FMT strategy. Follow-up clinical data was collected for a minimum of 3 months. Fecal microbiota composition before and post FMT of patients and related donors were analyzed by 16S rRNA sequencing.
Results: Eight of fourteen (57.1 %) patients achieved clinical improvement and were able to discontinue steroids following step-up FMT. One patient was lost to follow-up. Among the 8 patients who responded, five (35.7 %) received one FMT therapy, one (7.1 %) received two FMTs, and two (14.2 %) received two FMTs plus a scheduled course of steroids. Four (28.6 %) of the 8 patients who responded maintained long-term remission during follow-up (3-18 months). Six patients (42.9 %) failed to meet the criteria of clinical improvement and maintained steroid dependence, though three experienced transient or partial improvement. Microbiota analysis showed that FMT altered the composition greatly, and a microbiota composition highly similar to that of the donor emerged in the patients with successful treatment. No severe adverse events occurred during treatment and follow-up.
Conclusions: Step-up FMT strategy shows promise as a therapeutic strategy for patients with steroid-dependent UC, likely due to the successful restructuring of gut microbial composition.
Trial registration: ClinicalTrials.gov, Number NCT01790061.
Figures
References
- Feuerstein JD, Cheifetz AS. Ulcerative colitis: epidemiology, diagnosis, and management. Mayo Clin Proc. 2014;89:1553–1563. doi: 10.1016/j.mayocp.2014.07.002.
- Sandborn WJ. Current directions in IBD therapy: what goals are feasible with biological modifiers? Gastroenterology. 2008;135:1442–1447. doi: 10.1053/j.gastro.2008.09.053.
- Marchioni Beery R, Kane S. Current approaches to the management of new-onset ulcerative colitis. Clin Exp Gastroenterol. 2014;7:111–132.
- Faubion WA, Jr, Loftus EV, Jr, Harmsen WS, Zinsmeister AR, Sandborn WJ. The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study. Gastroenterology. 2001;121:255–260. doi: 10.1053/gast.2001.26279.
- Stange EF, Travis SP, Vermeire S, Reinisch W, Geboes K, Barakauskiene A, Feakins R, Flejou JF, Herfarth H, Hommes DW, et al. European evidence-based consensus on the diagnosis and management of ulcerative colitis: definitions and diagnosis. J Crohns Colitis. 2008;2:1–23. doi: 10.1016/j.crohns.2007.11.001.
- Mehta SJ, Silver AR, Lindsay JO. Review article: strategies for the management of chronic unremitting ulcerative colitis. Aliment Pharmacol Ther. 2013;38:77–97. doi: 10.1111/apt.12345.
- Armuzzi A, Pugliese D, Danese S, Rizzo G, Felice C, Marzo M, Andrisani G, Fiorino G, Sociale O, Papa A, et al. Infliximab in steroid-dependent ulcerative colitis: effectiveness and predictors of clinical and endoscopic remission. Inflamm Bowel Dis. 2013;19:1065–1072. doi: 10.1097/MIB.0b013e3182802909.
- Armuzzi A, Pugliese D, Danese S, Rizzo G, Felice C, Marzo M, Andrisani G, Fiorino G, Nardone OM, De Vitis I, et al. Long-term combination therapy with infliximab plus azathioprine predicts sustained steroid-free clinical benefit in steroid-dependent ulcerative colitis. Inflamm Bowel Dis. 2014;20:1368–1374. doi: 10.1097/MIB.0000000000000115.
- Zhang F, Luo W, Shi Y, Fan Z, Ji G. Should we standardize the 1700-year-old fecal microbiota transplantation? Am J Gastroenterol. 2012;107:1755. doi: 10.1038/ajg.2012.251.
- Kunde S, Pham A, Bonczyk S, Crumb T, Duba M, Conrad H, Jr, Cloney D, Kugathasan S. Safety, tolerability, and clinical response after fecal transplantation in children and young adults with ulcerative colitis. J Pediatr Gastroenterol Nutr. 2013;56:597–601. doi: 10.1097/MPG.0b013e318292fa0d.
- Brandt L, Aroniadis O. Long-term follow-up study of fecal microbiota transplantation (FMT) for ulcerative colitis (UC) Am J Gastroenterol. 2012;107:S657. doi: 10.1038/ajg.2012.49.
- Borody T, Wettstein A, Campbell J, Leis S, Torres M, Finlayson S, Nowak A. Fecal microbiota transplantation in ulcerative colitis: review of 24 years experience. Am J Gastroenterol. 2012;107:S665.
- Cui B, Feng Q, Wang H, Wang M, Peng Z, Li P, Huang G, Liu Z, Wu P, Fan Z, et al. Fecal microbiota transplantation through mid-gut for refractory Crohn’s disease: safety, feasibility, and efficacy trial results. J Gastroenterol Hepatol. 2015;30:51–58. doi: 10.1111/jgh.12727.
- Gordon H, Harbord M. A patient with severe Crohn’s colitis responds to faecal microbiota transplantation. J Crohns Colitis. 2014;8:256–257. doi: 10.1016/j.crohns.2013.10.007.
- Zhang FM, Wang HG, Wang M, Cui BT, Fan ZN, Ji GZ. Fecal microbiota transplantation for severe enterocolonic fistulizing Crohn’s disease. World J Gastroenterol. 2013;19:7213–7216. doi: 10.3748/wjg.v19.i41.7213.
- Kao D, Hotte N, Gillevet P, Madsen K. Fecal microbiota transplantation inducing remission in Crohn’s colitis and the associated changes in fecal microbial profile. J Clin Gastroenterol. 2014;48:625–628. doi: 10.1097/MCG.0000000000000131.
- Rossen NG, MacDonald JK, de Vries EM, D’Haens GR, de Vos WM, Zoetendal EG, Ponsioen CY. Fecal microbiota transplantation as novel therapy in gastroenterology: a systematic review. World J Gastroenterol. 2015;21:5359–5371. doi: 10.3748/wjg.v21.i17.5359.
- van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JF, Tijssen JG, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368:407–415. doi: 10.1056/NEJMoa1205037.
- Satsangi J, Silverberg MS, Vermeire S, Colombel JF. The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut. 2006;55:749–753. doi: 10.1136/gut.2005.082909.
- Dubberke ER, Burdette SD. Clostridium difficile infections in solid organ transplantation. Am J Transplant. 2013;13(Suppl 4):42–49. doi: 10.1111/ajt.12097.
- Bakken JS, Borody T, Brandt LJ, Brill JV, Demarco DC, Franzos MA, Kelly C, Khoruts A, Louie T, Martinelli LP, et al. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol. 2011;9:1044–1049. doi: 10.1016/j.cgh.2011.08.014.
- Kelly CR, Ihunnah C, Fischer M, Khoruts A, Surawicz C, Afzali A, Aroniadis O, Barto A, Borody T, Giovanelli A, et al. Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am J Gastroenterol. 2014;109:1065–1071. doi: 10.1038/ajg.2014.133.
- Brandt L, Aroniadis O, Greenberg A, Borody T, Finlayson S, Furnari V, Kelly C. Safety of fecal microbiota transplantation (FMT) in immunocompromised (Ic) patients with inflammatory bowel disease (IBD) Am J Gastroenterol. 2013;108:S556.
- Colman RJ, Rubin DT. Fecal microbiota transplantation as therapy for inflammatory bowel disease: a systematic review and meta-analysis. J Crohns Colitis. 2014;8:1569–1581. doi: 10.1016/j.crohns.2014.08.006.
- Kump PK, Grochenig HP, Lackner S, Trajanoski S, Reicht G, Hoffmann KM, Deutschmann A, Wenzl HH, Petritsch W, Krejs GJ, et al. Alteration of intestinal dysbiosis by fecal microbiota transplantation does not induce remission in patients with chronic active ulcerative colitis. Inflamm Bowel Dis. 2013;19:2155–2165. doi: 10.1097/MIB.0b013e31829ea325.
- De Leon LM, Watson JB, Kelly CR. Transient flare of ulcerative colitis after fecal microbiota transplantation for recurrent Clostridium difficile infection. Clin Gastroenterol Hepatol. 2013;11:1036–1038. doi: 10.1016/j.cgh.2013.04.045.
- Weingarden AR, Hamilton MJ, Sadowsky MJ, Khoruts A. Resolution of severe Clostridium difficile infection following sequential fecal microbiota transplantation. J Clin Gastroenterol. 2013;47:735–737. doi: 10.1097/MCG.0b013e31829004ae.
- Manichanh C, Borruel N, Casellas F, Guarner F. The gut microbiota in IBD. Nat Rev Gastroenterol Hepatol. 2012;9:599–608. doi: 10.1038/nrgastro.2012.152.
- Mukhopadhya I, Hansen R, El-Omar EM, Hold GL. IBD-what role do Proteobacteria play? Nat Rev Gastroenterol Hepatol. 2012;9:219–230. doi: 10.1038/nrgastro.2012.14.
- Chinen T, Rudensky AY. The effects of commensal microbiota on immune cell subsets and inflammatory responses. Immunol Rev. 2012;245:45–55. doi: 10.1111/j.1600-065X.2011.01083.x.
- Gorkiewicz G, Thallinger GG, Trajanoski S, Lackner S, Stocker G, Hinterleitner T, Gully C, Hogenauer C. Alterations in the colonic microbiota in response to osmotic diarrhea. PLoS One. 2013;8:e55817. doi: 10.1371/journal.pone.0055817.
- Chebli LA, Chaves LD, Pimentel FF, Guerra DM, Barros RM, Gaburri PD, Zanini A, Chebli JM. Azathioprine maintains long-term steroid-free remission through 3 years in patients with steroid-dependent ulcerative colitis. Inflamm Bowel Dis. 2010;16:613–619. doi: 10.1002/ibd.21083.
- Van Assche G, Dignass A, Bokemeyer B, Danese S, Gionchetti P, Moser G, Beaugerie L, Gomollon F, Hauser W, Herrlinger K, 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. doi: 10.1016/j.crohns.2012.09.005.
Source: PubMed