2'-Fucosyllactose promotes intestinal epithelial development via modulating gut microbial metabolism in neonatal mice

2'-fucosyllactose (2'-FL), a major human milk oligosaccharide, has been demonstrated to support early-life gut maturation and microbial balance. However, the association between 2'-FL, intestinal epithelial development, and gut microbiota remains unclear. In this study, 3-d-old murine model was established to investigate intestinal epithelial differentiation, variations in gut microbes and metabolism. The results showed that 2'-FL enhanced intestinal barrier function by upregulating the expression of tight junction proteins and increasing goblet cell density (P < 0.01) in the duodenum, in addition to promoting Mucin-2 secretion. Furthermore, 2'-FL stimulated the Lgr5+ intestinal stem cell-Paneth cell axis, resulting in a 4-fold increase in Lgr5 expression (P < 0.01) and upregulation of the Paneth cell marker Lysozyme (P < 0.01) as well as the progenitor cell marker Musashi (P < 0.001), thereby accelerating epithelial regeneration. Microbiota analysis revealed the enrichment of Lactobacillus and Bifidobacterium, accompanied by a significant enhancement in the accumulation of l-arginine (P < 0.0001) and ornithine (P < 0.0001) accumulation, which have been shown to promote intestinal development. These results suggest that 2'-FL promotes intestinal stem cell proliferation and barrier maturation by modulating gut microbial metabolism. These findings provide important insights into the role of 2'-FL in promoting infant gut homeostasis.