Commensal Lachnospiraceae bacterium mitigates colitis-induced mucin fucosylation deficits through ILC3/IL-22 axis

Flagellins from commensal bacteria are potent modulators of intestinal immunity, yet their strain-specific functions, particularly in promoting homeostasis in ulcerative colitis (UC), remain poorly defined. We investigate whether flagellin from the commensal Lachnospiraceae bacterium 3–1-57 FAA CT1 ( L. 3–1-57 Fla) plays a role in UC pathogenesis and mucin fucosylation deficits. Clinically, compared with healthy controls and patients with UC in remission, patients with active UC exhibit reduced abundance of L. 3–1-57 , which inversely correlates with disease severity. In mouse colitis models, we show that live L. 3–1-57 or L. 3–1-57 Fla attenuates intestinal inflammation and mucus barrier dysfunction, whereas E. coli flagellin exacerbates disease. Mechanistically, L. 3–1-57 Fla directly binds TLR5 with high affinity and activates dendritic cells to produce IL-23. This cascade expands IL-22 + group 3 innate lymphoid cells, drives fucosyltransferase 2-mediated MUC2 fucosylation, and restores mucus integrity. Crucially, genetic ablation of Tlr5 , inhibition of α-1,2-fucosylation, or IL-22 neutralization abolishes these benefits, confirming that the TLR5–IL-23–IL-22 immune axis and fucosylation are indispensable for protection. Our study establishes L. 3–1-57 flagellin as a key mediator of intestinal homeostasis via a TLR5–IL-23–IL-22-dependent mucin fucosylation pathway. These findings nominate L. 3–1-57 as a candidate next-generation probiotic, its flagellin as a potential postbiotic therapy for UC, and its fecal depletion as a potential noninvasive auxiliary diagnostic biomarker.