A double blinded randomised controlled trial to investigate the efficacy of faecal microbiota transplantation (FMT) in achieving and maintaining remission for patients with ulcerative colitis 13/179

Patients with inflammatory bowel disease (IBD) have reduced bacterial diversity compared to healthy individuals and at the phylum level a reduction in Firmicuites and a relative increase in Proteobacteria [2,9]. Recent data has suggested that alteration in the microbiome plays a central role in driving UC; studies highlight the importance of Roseburia hominid [10], Faecalibacterium prausnitzii [11] and Akkermansia muciniphila [12]. Probiotics have shown promise in UC [13,14]. Although data is limited to case series, there is evidence for a positive efficacy signal for FMT in IBD[15]. The inflammatory effects associated with the dysbiosis may be due to differential carbohydrate and protein fermentation [12], the metabolic end products of which modulate inflammatory pathways [17]. We have shown that major bacterial fermentation metabolites change during induction of remission in IBD using enteral nutrition treatment [3]. Thus the central role of colonic bacteria makes manipulation of the colonic microbiome a potentially fruitful endeavour in the treatment of IBD. Current data are limited but the signals are encouraging. Reports of FMT in IBD are generally individual case reports or small case series and this technique has not yet been subject to rigorous clinical trials. A recent meta-analysis reported that, from the small numbers studied, FMT achieved remission in over 50%. Encouragingly about three quarters of the patients were able, in the short term, to stop all other IBD related medication [19]. The majority of studies with FMT in IBD have been undertaken by delivering the transplant directly into the colon either through the colonoscope or using enemas. Delivery of the faecal transplant into the upper gut via a naso-gastric tube into the stomach is an alternative and C. difficile treatment studies have shown that use of either route seems equally effective [20]. Naso-gastric (NG) FMT has been used in one small cases series in UC [21]. In this study of patients with very severe disease 1 of 5 responded with a dramatic reduction in MAYO score from 11 to 3 and associated reduction in Enterobacteriaceae. Interim results from the only placebo controlled enema FMT RCT in UC [24] presented this year showed a 23% remission rate compared to placebo (7%). To summarise, data regarding FMT as a treatment for UC are limited at this time and furthermore numerous questions regarding treatment protocol remain to be answered; for example what is the optimum method of donor/ patient selection and preparation and the best route of delivery. In Birmingham we have the first HTA-approved treatment for C. difficile via the NG route and a well-developed protocol for donor screening and transplant preparation. We will use this to supply FMT and adapt it to study the two possible routes of FMT delivery. This becomes feasible with recent data demonstrating that freeze-thawing stool does not lead to deterioration in bacterial diversity and clinical efficacy for CDI over 12 weeks [20,26]. The proposal presented here is a two-stage study to investigate firstly the optimum route of FMT delivery for the treatment of UC and then the efficacy of one of these treatments in patients with UC which is refractory to standard treatment. On the basis of a suitable treatment effect and patient acceptability in the pilot, we propose to proceed with the chosen method to a randomised placebo-controlled trial with an efficacy outcome