Mechanistic insights into fecal microbiota transplantation for the treatment of ulcerative colitis: analysis of the STOP-Colitis trial.
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Quraishi Mohammed Nabil, Moakes Catherine A, Yalchin Mehmet, Blackwell Claire, Segal Jonathan, Ives Natalie J, Magill Laura, Manzoor Susan E, Gerasimidis Konstantinos, McMullan Christel, Mathers Jonathan, Horniblow Richard, Loi Shrushma, Kaur Manjinder, Loman Nicholas J, Sharma Naveen, Hawkey Peter, McCune Victoria, Quick Joshua, Nicholls Samuel, McMurray Claire, Nichols Ben, Svolos Vaios, Raguideau Sebastien, Kerbiriou Caroline, Oo Ye H, Beggs Andrew D, Crees Nicola, Hansen Richard, Hart Ailsa L, Gaya Daniel R, Quince Christopher, Iqbal Tariq H
Аннотация
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.