Mechanistic insights into FMT for the treatment of ulcerative colitis: analysis of the STOP-Colitis trial

Abstract Background and Aims Faecal microbiota transplantation (FMT) is a promising therapy for ulcerative colitis, but variable responses and unclear mechanisms limit its efficacy. We aimed to compare nasogastric versus colonic FMT delivery and define the microbial and immunological changes associated with clinical response. Methods In this prospective, open-label, randomised pilot trial (STOP-Colitis), 30 adults with active ulcerative colitis were randomised to receive multi-dose FMT via nasogastric tube or colonoscopy with subsequent enemas. Key endpoints were clinical outcomes at week 8 and longitudinal multi-omic analyses of stool and biopsies to define changes in microbial composition (16S rRNA and shotgun metagenomics), short-chain fatty acids, mucosal T-cells, and host gene expression. Results Colonic FMT was superior to nasogastric delivery, with a higher clinical response rate at week 8 (75% [9/12] vs 25% [2/8]; RR 2·94, 95% CI 0·84–10·30—per protocol analysis). Response was underpinned by successful microbial engraftment, leading to significantly increased faecal microbial diversity and enrichment of SCFA-producing taxa, including Oscillospiraceae and Christensenellaceae. This correlated with reduced faecal calprotectin. Responders showed a significant increase in mucosal regulatory T cells (P = 0·01), with a concurrent decrease in Th17 (P = 0·03) and CD8 + T cells. This anti-inflammatory shift was confirmed by mucosal transcriptomics, which revealed upregulation of metabolic pathways and downregulation of proinflammatory defence pathways in responders. (Trial registration: ISRCTN13636129). Conclusion Colonic FMT is a more effective delivery route than nasogastric administration. Clinical response is driven by the engraftment of immunomodulatory bacteria that restore a healthy host-microbe dialogue, providing rationale for developing targeted microbial therapeutics.