Rigorous Donor Selection for Fecal Microbiota Transplantation in Active Ulcerative Colitis: Key Lessons From a Randomized Controlled Trial Halted for Futility.
[en] BACKGROUND & AIMS: Rigorous donor preselection on microbiota level, strict anaerobic processing, and repeated fecal microbiota transplantation (FMT) administration were hypothesized to improve FMT induction of remission in ulcerative colitis (UC). METHODS: The RESTORE-UC trial was a multi-centric, double-blind, sham-controlled, randomized trial. Patients with moderate to severe UC (defined by total Mayo 4-10) were randomly allocated to receive 4 anaerobic-prepared allogenic or autologous donor FMTs. Allogenic donor material was selected after a rigorous screening based on microbial cell count, enterotype, and the abundance of specific genera. The primary endpoint was steroid-free clinical remission (total Mayo ≤2, no sub-score >1) at week 8. A pre-planned futility analysis was performed after 66% (n = 72) of intended inclusions (n = 108). Quantitative microbiome profiling (n = 44) was performed at weeks 0 and 8. RESULTS: In total, 72 patients were included, of which 66 received at least 1 FMT (allogenic FMT, n = 30 and autologous FMT, n = 36). At week 8, respectively, 3 and 5 patients reached the primary endpoint of steroid-free clinical remission (P = .72), indicating no treatment difference of at least 5% in favor of allogenic FMT. Hence, the study was stopped due to futility. Microbiome analysis showed numerically more enterotype transitions upon allogenic FMT compared with autologous FMT, and more transitions were observed when patients were treated with a different enterotype than their own at baseline (P = .01). Primary response was associated with lower total Mayo scores, lower bacterial cell counts, and higher Bacteroides 2 prevalence at baseline. CONCLUSION: The RESTORE-UC trial did not meet its primary endpoint of increased steroid-free clinical remission at week 8. Further research should additionally consider patient selection, sterilized sham-control, increased frequency, density, and viability of FMT prior to administration. CLINICALTRIALS: gov, Number: NCT03110289.
Disciplines :
Gastroenterology & hepatology
Author, co-author :
Caenepeel, Clara; Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium, University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium.
Deleu, Sara; Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium.
Vazquez Castellanos, Jorge Francisco; Laboratory of Molecular Bacteriology, Department of Microbiology and Immunology, Rega Institute, KU Leuven, Leuven, Belgium, Center for Microbiology, VIB, Leuven, Belgium.
Arnauts, Kaline; Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium.
Braekeleire, Sara; Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium.
Machiels, Kathleen; Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium.
Baert, Filip; AZ Delta Roeselare, Department of Gastroenterology and Hepatology, Roeselare, Belgium.
Mana, Fazia; University Hospitals Brussels, Department of Gastroenterology and Hepatology, Brussels, Belgium.
Pouillon, Lieven; Imelda Hospital Bonheiden, Department of Gastroenterology and Hepatology, Bonheiden, Belgium.
Hindryckx, Pieter; Ghent University Hospital, Department of Gastroenterology, Ghent, Belgium.
Lobaton, Triana; Ghent University Hospital, Department of Gastroenterology, Ghent, Belgium, Department of Internal Medicine and Paediatrics, Ghent University, Gent, Belgium.
Louis, Edouard ; Université de Liège - ULiège > Département des sciences cliniques > Hépato-gastroentérologie
Franchimont, Denis; Erasmus Hospital Brussels, Department of Gastroenterology and Hepatology, Brussels, Belgium.
Verstockt, Bram; Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium, University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium.
Ferrante, Marc; Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium, University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium.
Sabino, João; Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium, University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium.
Vieira-Silva, Sara; Laboratory of Molecular Bacteriology, Department of Microbiology and Immunology, Rega Institute, KU Leuven, Leuven, Belgium, Institute of Medical Microbiology and Hygiene and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany, Institute of Molecular Biology (IMB), Mainz, Germany.
Falony, Gwen; Laboratory of Molecular Bacteriology, Department of Microbiology and Immunology, Rega Institute, KU Leuven, Leuven, Belgium, Center for Microbiology, VIB, Leuven, Belgium, Institute of Medical Microbiology and Hygiene and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
Raes, Jeroen; Laboratory of Molecular Bacteriology, Department of Microbiology and Immunology, Rega Institute, KU Leuven, Leuven, Belgium, Center for Microbiology, VIB, Leuven, Belgium.
Vermeire, Séverine; Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium, University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium. Electronic address: severine.vermeire@uzleuven.be.
Rigorous Donor Selection for Fecal Microbiota Transplantation in Active Ulcerative Colitis: Key Lessons From a Randomized Controlled Trial Halted for Futility.
Vieira-Silva, S., Sabino, J., Valles-Colomer, M., et al. Quantitative microbiome profiling disentangles inflammation- and bile duct obstruction-associated microbiota alterations across PSC/IBD diagnoses. Nat Microbiol 4 (2019), 1826–1831.
Schmidt, T.S.B., Raes, J., Bork, P., The human gut microbiome: from association to modulation. Cell 172 (2018), 1198–1215.
Moayyedi, P., Surette, M.G., Kim, P.T., et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology 149 (2015), 102–109.e6.
Rossen, N.G., Fuentes, S., Van Der Spek, M.J., et al. Findings from a randomized controlled trial of fecal transplantation for patients with ulcerative colitis. Gastroenterology 149 (2015), 110–118.e4.
Costello, S.P., Hughes, P.A., Waters, O., et al. Effect of fecal microbiota transplantation on 8-week remission in patients with ulcerative colitis: a randomized clinical trial. JAMA 321 (2019), 156–164.
Paramsothy, S., Kamm, M.A., Kaakoush, N.O., et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet 389 (2017), 1218–1228.
Shabat, C.S., Scaldaferri, F., Zittan, E., et al. Use of faecal transplantation with a novel diet for mild to moderate active ulcerative colitis: the CRAFT UC randomised controlled trial. J Crohns Colitis 16 (2022), 369–378.
Haifer, C., Paramsothy, S., Kaakoush, N.O., et al. Lyophilised oral faecal microbiota transplantation for ulcerative colitis (LOTUS): a randomised, double-blind, placebo-controlled trial. Lancet Gastroenterol Hepatol 7 (2022), 141–151.
Kump, P.K., Gröchenig, H.-P., Lackner, S., et al. Alteration of intestinal dysbiosis by fecal microbiota transplantation does not induce remission in patients with chronic active ulcerative colitis. Inflamm Bowel Dis 19 (2013), 2155–2165.
Vermeire, S., Joossens, M., Verbeke, K., et al. Donor species richness determines faecal microbiota transplantation success in inflammatory bowel disease. J Crohns Colitis 10 (2016), 387–394.
Bénard, M.V., Arretxe, I., Wortelboer, K., et al. Anaerobic feces processing for fecal microbiota transplantation improves viability of obligate anaerobes. Microorganisms, 11, 2023, 2238.
Orenstein, R., Dubberke, E., Hardi, R., et al., PUNCH CD Investigators. Safety and durability of RBX2660 (microbiota suspension) for recurrent clostridium difficile infection: results of the PUNCH CD study. Clin Infect Dis 62 (2016), 596–602.
Feuerstadt, P., Louie, T.J., Lashner, B., et al. SER-109, an oral microbiome therapy for recurrent clostridioides difficile infection. N Engl J Med 386 (2022), 220–229.
Cammarota, G., Ianiro, G., Tilg, H., et al., European FMT Working Group. European consensus conference on faecal microbiota transplantation in clinical practice. Gut 66 (2017), 569–580.
Vandeputte, D., Kathagen, G., D'Hoe, K., et al. Quantitative microbiome profiling links gut community variation to microbial load. Nature 551 (2017), 507–511.
Caenepeel, C., Falony, G., Machiels, K., et al. Dysbiosis and associated stool features improve prediction of response to biological therapy in inflammatory bowel disease. Gastroenterology 166 (2023), 483–495.
Caldeira, L. de F., Borba, H.H., Tonin, F.S., et al. Fecal microbiota transplantation in inflammatory bowel disease patients: a systematic review and meta-analysis. PLoS One, 15, 2020, e0238910.
Vandeputte, D., Falony, G., Vieira-Silva, S., et al. Stool consistency is strongly associated with gut microbiota richness and composition, enterotypes and bacterial growth rates. Gut 65 (2016), 57–62.
Kedia, S., Virmani, S., K Vuyyuru, S., et al. Faecal microbiota transplantation with anti-inflammatory diet (FMT-AID) followed by anti-inflammatory diet alone is effective in inducing and maintaining remission over 1 year in mild to moderate ulcerative colitis: a randomised controlled trial. Gut 71 (2022), 2401–2413.
Moayyedi, P., Yuan, Y., Baharith, H., et al. Faecal microbiota transplantation for Clostridium difficile-associated diarrhoea: a systematic review of randomised controlled trials. Med J Aust 207 (2017), 166–172.
Březina, J., Bajer, L., Wohl, P., et al. Clinical medicine fecal microbial transplantation versus mesalamine enema for treatment of active left-sided ulcerative colitis-results of a randomized controlled trial. J Clin Med, 10, 2021, 2753.
Lopetuso, L.R., Deleu, S., Godny, L., et al. The first international Rome consensus conference on gut microbiota and faecal microbiota transplantation in inflammatory bowel disease. Gut 72 (2023), 1642–1650.
Singh, P., Alm, E.J., Kelley, J.M., et al. Effect of antibiotic pretreatment on bacterial engraftment after fecal microbiota transplant (FMT) in IBS-D. Gut Microbes, 14, 2022, 2020067.
Costea, P.I., Hildebrand, F., Arumugam, M., et al. Enterotypes in the landscape of gut microbial community composition. Nat Microbiol 3 (2017), 8–16.
Ding, T., Schloss, P.D., Dynamics and associations of microbial community types across the human body. Nature 509 (2014), 357–360.
Vandeputte, D., De Commer, L., Tito, R.Y., et al. Temporal variability in quantitative human gut microbiome profiles and implications for clinical research. Nat Commun, 12, 2021, 6740.
Prest, E.I., Hammes, F., Kötzsch, S., et al. Monitoring microbiological changes in drinking water systems using a fast and reproducible flow cytometric method. Water Res 47 (2013), 7131–7142.
Sabino, J., Vieira-Silva, S., Machiels, K., et al. Primary sclerosing cholangitis is characterised by intestinal dysbiosis independent from IBD. Gut 65 (2016), 1681–1689.
Kozich, J.J., Westcott, S.L., Baxter, N.T., et al. Development of a dual-index sequencing strategy and curation pipeline for analyzing amplicon sequence data on the MiSeq Illumina sequencing platform. Appl Environ Microbiol 79 (2013), 5112–5120.
Tito, R.Y., Cypers, H., Joossens, M., et al. Brief report: dialister as a microbial marker of disease activity in spondyloarthritis. Arthritis Rheumatol 69 (2017), 114–121.
Hildebrand, F., Tadeo, R., Voigt, A., et al. LotuS: an efficient and user-friendly OTU processing pipeline. Microbiome, 2, 2014, 30.
Vandeputte, D., Kathagen, G., D'hoe, K., et al. Quantitative microbiome profiling links gut community variation to microbial load. Nature 551 (2017), 507–511.
McMurdie, P.J., Holmes, S., phyloseq: an R package for reproducible interactive analysis and graphics of microbiome census data. PLoS One, 8, 2013, e61217.
Lomolino, M.V., Ecology's most general, yet protean pattern: the species-area relationship. J Biogeogr 27 (2000), 17–26.
Dengler, J., Flottbek, K., Which function describes the species–area relationship best? A review and empirical evaluation. J Biogeogr 36 (2009), 728–744.
Holmes, I., Harris, K., Quince, C., Dirichlet multinomial mixtures: generative models for microbial metagenomics. PLoS One, 7, 2012, e30126.
