Abstract
BACKGROUND AND AIMS: Fecal 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, randomized pilot trial (STOP-Colitis), 30 adults with active ulcerative colitis were randomized to receive multidose 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 (SCFAs), 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]; risk ratio 2.94, 95% CI 0.84-10.30-per protocol analysis). Response was underpinned by successful microbial engraftment, leading to significantly increased fecal microbial diversity and enrichment of SCFA-producing taxa, including Oscillospiraceae and Christensenellaceae. This correlated with reduced fecal calprotectin. Responders showed a significant increase in mucosal regulatory T cells (P = .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 defense pathways in responders. (Trial registration: ISRCTN74072945). 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.