Abstract Background Ulcerative colitis (UC) is a refractory inflammatory bowel disease with limited treatment options for moderate-to-severe cases. While fecal microbiota transplantation (FMT) demonstrates therapeutic potential through gut microbiota remodeling, its core mechanisms involving key bacterial strains and metabolites remain unclear. This study aims to evaluate FMT’s efficacy and safety in moderate-to-severe UC and elucidate its mechanism of action. Methods This self-controlled study evaluated FMT in moderate-to-severe UC patients through discovery (n = 16) and validation (n = 40) cohorts. Clinical response was assessed using Mayo scores, with integrated multi-omics identifying key bacteria and metabolic pathways. Mechanistic studies confirmed candidate bacteria produced FMT-related metabolites and exhibited anti-inflammatory effects in colon organoids. Metabolites were tested in inflamed intestinal epithelium, with conditioned medium applied to macrophage models. In vivo validation used germ-free honeybees and DSS-colitis mice. Results FMT significantly improved clinical outcomes in UC patients, reducing Mayo scores with high response rates and only mild adverse events. Post-FMT, tryptophan metabolism shifted: urinary indole-3-carboxylic acid and indolelactic acid increased, while fecal tryptophan, tryptamine, and kynurenine decreased, and indole-3-carboxaldehyde (IAld) increased. Transcriptomics confirmed this metabolic shift from the kynurenine to the IAld pathway alongside reduced inflammation. Metagenomics pinpointed the donor-derived bacterium Bacteroidescoprocola, whose abundance correlated with reduced enzymatic gene abundance in tryptophan metabolism. In vitro, B. coprocola produced tryptophan/tryptamine and consumed kynurenine. Crucially, both the bacterium and these key tryptophan metabolites activated the AHR receptor and suppressed NF-κB/pSTAT3 signaling. This mechanism alleviated inflammation and restored barrier integrity across diverse models, evidenced by suppressed pro-inflammatory cytokines (IL-6, IL-1β, TNF-α), elevated anti-inflammatory factors (IL-10, TGF-β, IL-22) and tight junction proteins (Claudin-1, Occludin, ZO-1), and promoted M2 macrophage polarization. Histology confirmed the alleviation of mucosal damage. Conclusion FMT safely achieves clinical remission and mucosal healing in moderate-to-severe ulcerative colitis. The study demonstrates that donor-derived Bacteroidescoprocola and its tryptophan metabolites activate the AHR pathway, thereby suppressing NF-κB/STAT3 signaling, modulating macrophage polarization, and enhancing intestinal barrier function. These results define a multi-level mechanism for FMT and establish a foundation for developing precision microecological therapies. Conflict of interest: Dr. Chi, Xiaoyan: No conflict of interest Ren, Rongrong: No conflict of interest Yang, Yunsheng: No conflict of interest
Chi et al. (Thu,) studied this question.