Sialylated Milk Oligosaccharides as Regulators of Mucosal Immunity

摘要

The mucosal immune system acts as the first line of defense against invading microorganisms. Improper development of mucosal immunity accounts for susceptibility of a person to various diseases. A key role in maturation and modulation of mucosal immunity is attributed to maternal milk. Breastfed infants have a lower incidence of diarrheal diseases and respiratory tract infections when compared to those raised on infant formulas. Moreover, the emerging evidence points to the long-term protective action of breastfeeding in relation to chronic disorders in adults. Many components including secretory IgA, bioactive proteins, lipids and oligosaccharides account for the beneficial effects of human milk. Oligosaccharides act as soluble receptors for different pathogens, thereby limiting pathogen dissemination in the gastrointestinal tract of infants. Milk oligosaccharides also act as prebiotics promoting colonization of beneficial bacteria in the gut. However, the contributions of individual maternal milk oligosaccharides to regulation of the mucosal immune system are still vague. The limited structural diversity of mouse milk oligosaccharides, consisting only of sialyl(α2,3)lactose (3SL) and sialyl(α2,6)lactose (6SL), simplifies characterization of the specific contribution of these molecules to intestinal homeostasis.\udIn the present study we investigated the role of 3SL in development of mucosal immunity in connection with chronic inflammatory disorders of the gastrointestinal tract. We based our study on St3gal4-/- mice that lack 3SL in milk and have reduced α2,3-sialylation in the gut in two mouse models. In the first model we induced chronic intestinal inflammation in wild-type (C57Bl/6) and St3gal4-/- mice by dextran sulfate sodium treatment. In the second model we assessed the contribution of 3SL to spontaneous colitis development in Il10-/- mice crossed into a St3gal4-/- background. We showed that the progression of chronic colitis was delayed in the absence of St3gal4 in both models. Exposure of newborn mice to milk-derived 3SL increased susceptibility to colitis in adulthood, while exclusion of 3SL from maternal milk reduced inflammation. Similarly, postnatal supplementation with pure 3SL resulted in enhanced development of colitis in mice. Moreover, short-term supplementation of pure 3SL to the adult Il10-/- mice dramatically aggravated colitis pointing to the ability of the trisaccharide to directly modulate the mucosal immune system. We found that 3SL but not 6SL was a potent activator of CD11c+ dendritic cells that facilitated differentiation of T-cells towards TH1 and TH17 phenotype. The absence of 3SL-stimulation in Tlr4-deficient dendritic cells indicated that sensing of the trisaccharide occurs through the TLR4-signaling pathway. Collectively, our study demonstrated the important role of milk-derived 3SL in development of mucosal immunity and intestinal homeostasis.