Epithelial fucosylation regulates intestinal stem cell differentiation

The potential role of human milk oligosaccharides (HMOs) in regulating intestinal epithelial cell proliferation and differentiation in mammals has attracted considerable attention. Fucosylated HMO can provide fucosylated glycans to the intestine of newborns, an outcome similar to genetic overexpression of fucosyltransferase. However, how HMOs, such as 2'-fucosyllactose (2'-FL), may impact small intestinal fucosylation to regulate intestinal stem cell (ISC)-mediated intestinal epithelial development remains unknown. In the present study, we employed a model of small intestinal fucosylation inhibition in pups by orally administering a fucosylation inhibitor, 2 F-peracetyl-fucose (2 F-Fuc) from postnatal day 4 (PN4) to postnatal day 21 (PN21). Inhibition of jejunal fucosylation of pups during the breastfeeding stage significantly promoted ISC differentiation toward the secretory lineage by inhibiting Notch signaling pathways. Furthermore, fucosylation inhibition caused ISC differentiation deregulation in the jejunum that persisted until PN day 42, even though 2 F-Fuc was no longer administered after weaning at PN21. Supplementation of 1,2-fucosylated oligosaccharide by 2'-FL after weaning ameliorated the long-term effects of fucosylation inhibition in rats on ISC differentiation and changes in mucus-degrading microbiota. These results demonstrate that intestinal fucosylation in pups plays an important role in maintaining the balance between ISC proliferation and differentiation. Our study offers new insights into the interactions between intestinal fucosylation and ISC function. It also establishes a research foundation for using 2'-FL as a donor for α1,2-fucosylated glycans, enabling targeted modifications in intestinal fucosylation to enhance gut health, particularly small intestine health.NEW & NOTEWORTHY Inhibition of jejunal fucosylation of pups during the breastfeeding stage significantly promoted ISC differentiation toward the secretory lineage, and this effect persisted until PN day 42 via inhibiting Notch signaling pathways. In addition, supplementation with 2'-FL after weaning ameliorated the long-term effects of fucosylation inhibition in rats on ISC differentiation and the dysregulation of mucus-degrading microbiota.