Milk oligosaccharide sialyl(α2,3)lactose activates intestinal CD11c+ cells through TLR4

Proc Natl Acad Sci U S A. 2013 Oct 22;110(43):17444-9. doi: 10.1073/pnas.1306322110. Epub 2013 Oct 7.

Abstract

Breast milk oligosaccharides shape the intestinal environment by affecting mucosal immunity and bacterial colonization. To clarify the role of milk oligosaccharide sialyl(α2,3)lactose (3SL) in intestinal physiology and disease, we investigated colitis development in Il10(-/-) mice exposed to normal or 3SL-deficient milk during lactation. Onset and progression of intestinal inflammation were delayed in Il10(-/-) mice deficient for the α2,3 sialyltransferase 4 (ST3GAL4) responsible for 3SL biosynthesis. The proinflammatory role of 3SL was confirmed by showing that oral supplementation of newborn Il10(-/-);St3gal4(-/-) mice with 3SL increased colitis severity. Conversely, fostering of newborn Il10(-/-) 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 TH1 and TH17 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.

Keywords: carbohydrate; glycan; mouse innate immunity; prebiotics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Bacteria / classification
  • Bacteria / genetics
  • Bacteria / immunology
  • CD11c Antigen / immunology*
  • CD11c Antigen / metabolism
  • Cells, Cultured
  • Colitis / genetics
  • Colitis / immunology
  • Colitis / metabolism
  • Cytokines / genetics
  • Cytokines / immunology
  • Cytokines / metabolism
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Female
  • Flow Cytometry
  • Gastrointestinal Tract / immunology
  • Gastrointestinal Tract / microbiology
  • Gastrointestinal Tract / pathology
  • Gene Expression / immunology
  • Immunity, Mucosal / genetics
  • Immunity, Mucosal / immunology
  • Interleukin-10 / deficiency
  • Interleukin-10 / genetics
  • Interleukin-10 / immunology
  • Intestinal Mucosa / metabolism
  • Intestines / cytology
  • Intestines / immunology*
  • Lactation / immunology
  • Lactose / analogs & derivatives*
  • Lactose / immunology
  • Lactose / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Milk / chemistry
  • Milk / immunology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sialic Acids / immunology*
  • Sialic Acids / metabolism
  • Sialyltransferases / deficiency
  • Sialyltransferases / genetics
  • Sialyltransferases / immunology
  • Toll-Like Receptor 4 / immunology*
  • Toll-Like Receptor 4 / metabolism

Substances

  • CD11c Antigen
  • Cytokines
  • Sialic Acids
  • Toll-Like Receptor 4
  • Interleukin-10
  • N-acetylneuraminoyllactose
  • Sialyltransferases
  • beta-galactoside alpha-2,3-sialyltransferase
  • Lactose