Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 43, Pages 17444-17449Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1306322110
Keywords
carbohydrate; glycan; prebiotics; mouse innate immunity
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Funding
- Zurich Center for Integrative Human Physiology
- Swiss National Foundation
- Hartmann Muller-Stiftung
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Breast milk oligosaccharides shape the intestinal environment by affecting mucosal immunity and bacterial colonization. To clarify the role of milk oligosaccharide sialyl(alpha 2,3) lactose (3SL) in intestinal physiology and disease, we investigated colitis development in II10(-/-) mice exposed to normal or 3SL-deficient milk during lactation. Onset and progression of intestinal inflammation were delayed in II10(-/-) mice deficient for the a2,3 sialyltransferase 4 (ST3GAL4) responsible for 3SL biosynthesis. The proinflammatory role of 3SL was confirmed by showing that oral supplementation of newborn II10(-/-); St3gal4(-/-) mice with 3SL increased colitis severity. Conversely, fostering of newborn II10(-/-) mice to lactating St3gal4(-/-) mothers reduced colitis severity. 3SL directly stimulated mesenteric lymph node CD11c(+) dendritic cells and induced production of cytokines required for expansion of T(H)1 and T(H)17 T cells. The stimulatory effect of 3SL was attenuated in Tlr4-deficient CD11c(+) cells, demonstrating that 3SL induces inflammation through Toll-like receptor 4 (TLR4) signaling. Thus, 3SL directly modulates mucosal immunity, which increases susceptibility to colitis.
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