Faecal Microbiota Transplantation for the Treatment of Active Ulcerative Colitis

Abstract

Introduction Ulcerative colitis (UC) is an inflammatory bowel disease that has high rates of persistent or relapsing symptoms despite available therapies. Many of these therapies also have the potential for unacceptable side effects including allergy, intolerance, serious infection and malignancy due to long-term immunosuppression. It is for these reasons that new therapies for UC are required; particularly therapies that target novel pathways and do not suppress the immune system. Faecal microbiota transplantation (FMT) has demonstrated efficacy in the treatment of recurrent and refractory Clostridium difficile infection (CDI) and has been proposed as a novel therapy for UC. Aims The aims of this thesis were to: 1. establish a stool bank of screened donor stool containing viable organisms 2. assess the efficacy and safety of FMT for the induction of remission of UC 3. explore the mechanisms by which FMT may alter the disease process of UC. Methods Methods of stool donor recruitment and screening as well as anaerobic stool processing were developed and optimised. The viability of culturable organisms was validated after 6 months of frozen storage. A double-blind randomised controlled trial of a short duration of FMT using anaerobically prepared stool for the induction of remission of mild to moderate UC was undertaken with clinical and endoscopic remission assessed at 8 weeks and 12 months. Exploratory immunological, microbiological and metabolomic analyses were undertaken. A systematic review and meta-analysis was undertaken to assess the broader evidence for FMT as therapy for the induction of remission of UC. Results A stool bank of anaerobically prepared donor stool was established; 14 (31%) of 44 respondents to donor recruitment questionnaires were eligible. Bacterial viability was similar to baseline at both 2 and 6 months in specimens stored with saline and 10% glycerol and at 2 months in stool stored only in saline, but was reduced by >1 log at 6 months for aerobes, coliforms and lactobacilli in saline alone. In patients undergoing FMT with stool frozen for 2–10 months in 10% glycerol, the cure rate for rCDI was 88% after a single FMT. In mild to moderate active UC, clinical and endoscopic remission was achieved in 12 of the 38 participants (32%) who received pooled donor FMT, compared with 3 of the 35 (9%) who received autologous FMT (odds ratio [OR] 5.0 [95% CI 1.2–20.1]; P = 0.03). A number of bacterial species were associated with the observed donor FMT treatment effect. Neither lamina propria mononuclear cell populations nor short-chain fatty acid levels were associated with the donor FMT treatment effect. Meta-analysis of randomised controlled trials of FMT for UC demonstrated that clinical remission was achieved in 39 of 140 (28%) patients in the donor FMT groups, compared with 13 of 137 (9%) patients in the placebo groups (OR 3.67 [95% CI 1.82– 7.39]; P < 0.01]. Conclusions Establishing a bank of anaerobically prepared frozen donor stool facilitates the delivery of FMT for clinical and clinical trial purposes. Anaerobic stool processing with normal saline and glycerol results in viability of bacteria in frozen storage for 6 months. Donor FMT is an effective therapy for the induction of remission of UC. Further research is required to assess the efficacy and safety of FMT as maintenance therapy for UC and to establish the mechanism of treatment effect.