Multi donor intense faecal microbiota transplantation is an effective treatment for resistant ulcerative colitis: A randomised placebocontrolled trial and microbiota analysis

Abstract

Background: The gut microbiota is the antigenic drive in ulcerative colitis (UC), but the efficacy of microbial manipulation using faecal microbiota transplantation (FMT) is unclear. Preliminary studies in active UC have suggested benefit, but the value of FMT in patients with conventional-drug resistant colitis, the dosing of treatment, and the importance of specific donors are unknown. The mechanism of benefit remains to be elucidated. Method: In this double-blind, 3-centre study, patients with active UC (Mayo score 4-10) resistant to standard treatments were randomised to receive a single FMT or placebo colonoscopic infusion on day 1 followed by FMT or placebo enemas 5 days per week for 8 weeks. Each active enema was derived from 3 to 7 unrelated donors. Patients on corticosteroids underwent mandatory weaning and cessation. The primary endpoint was steroid-free clinical remission together with endoscopic remission or response (total Mayo score ≤2 points with subscores ≤1 for each of rectal bleeding, stool frequency and endoscopic appearance, and ≥1 point reduction from baseline in endoscopy subscore) at week 8. Secondary endpoints included steroid free clinical remission (combined total score of ≤1 for both rectal bleeding and stool frequency Mayo subscores) and response, endoscopic remission (UCEIS score ≤ 1) and response, quality of life and safety. All analyses were intention to treat. At blinded therapy conclusion, placebo- treated patients were offered 8 weeks of open label active treatment. 16S ribosomal RNA faecal and colonic biopsy analysis was undertaken at multiple time points to examine microbial changes associated with treatment. Results: Clinical trial. Of 81 patients, the primary endpoint was achieved in 11 of 41 (27%) patients receiving FMT versus 3 of 40 (8%) patients receiving placebo (p = 0.02). Steroid free clinical remission and clinical response rates were 44% vs. 20% (p = 0.02) and 54% vs. 23% (p<0.01), respectively. Steroid free endoscopic remission and endoscopic response rates were 17% vs. 8% (p = 0.19) and 37% vs. 10% (p<0.01), respectively. There was no difference in adverse events between the study arms. Thirty-seven patients initially randomised to placebo progressed to open label FMT, of whom 10 (27%) met the primary endpoint, 17 (46%) experienced clinical remission and 9 (24%) experienced endoscopic remission, consistent with the blinded FMT outcomes. Three serious adverse events occurred during blinded therapy comprising worsening of colitis [2 active FMT treatment (including 1 patient who required colectomy for severe UC) and 1 placebo]. Microbiota analysis. Increased microbial α-diversity pre-treatment was associated with a higher chance of remission with FMT. There was increased faecal and colonic microbial diversity at all FMT treatment time points relative to baseline (p<0.005); this persisted 8 weeks after FMT. FMT significantly influenced patient microbial profiles, with the shift towards healthy donor microbiota most notable at the genus and OTU levels. Specific taxa were consistently significantly associated with FMT outcomes: taxa within Barnesiella were associated with remission, while OTUs within Fusobacterium and Sutterella were associated with lack of remission. Conclusion: This largest controlled trial of FMT has demonstrated that intense, multi-donor, colonoscopic and enema FMT is effective in inducing strictly defined clinical and endoscopic remission in patients with resistant active ulcerative colitis. Baseline patient microbial diversity in UC is predictive of therapeutic response to FMT. Intensive FMT is associated with increased microbial diversity, with the greatest diversity in patients achieving remission. Specific bacterial taxa are transplanted or displaced by FMT, some of which are associated with treatment outcome. These microbial findings may be important in both understanding the pathophysiology of the microbiota in UC and shaping future bacterial therapy.L612983521 <br />