Human Milk-Derived Synbiotics Attenuate DSS-Induced Colitis in Mice via Promoting Intestinal Colonization of Lachnospira

Abstract 2′-Fucosyllactose (2′-FL) exhibits prebiotic properties, but its ability to enhance probiotic efficacy in ulcerative colitis (UC) is incompletely understood. Here, we show that 2′-FL effectively enhances the protective effect of Bifidobacterium bifidum B-67 against DSS-induced colitis in mice. Combination therapy outperformed individual treatments, suppressing pro-inflammatory cytokines and restoring mucosal integrity. Mechanistically, 2′-FL remodeled the gut microbiota, enriched butyrate-producing Lachnospira, promoted SCFA production, and upregulated epithelial adhesion molecules HAS1 and GPC-1, which are associated with enhanced Lachnospira adhesion. In vitro coculture further indicated that B. bifidum B-67 acts as the primary degrader of 2′-FL and supports Lachnospira growth, suggesting a cross-feeding effect. Untargeted metabolomics revealed distinct metabolic alterations, including in bile acid-related pathways, associated with the combination intervention. These findings indicate that 2′-FL potentiates B. bifidum via both metabolic cross-feeding and enhanced bacterial retention, supporting this synbiotic combination as a promising strategy for UC intervention.