Loss of Intestinal Core 1-derived O-glycans Causes Spontaneous Colitis in Mice

J Clin Invest. 2011 Apr;121(4):1657-66. doi: 10.1172/JCI45538. Epub 2011 Mar 7.

Abstract

Mucin-type O-linked oligosaccharides (O-glycans) are primary components of the intestinal mucins that form the mucus gel layer overlying the gut epithelium. Impaired expression of intestinal O-glycans has been observed in patients with ulcerative colitis (UC), but its role in the etiology of this disease is unknown. Here, we report that mice with intestinal epithelial cell-specific deficiency of core 1-derived O-glycans, the predominant form of O-glycans, developed spontaneous colitis that resembled human UC, including massive myeloid infiltrates and crypt abscesses. The colitis manifested in these mice was also characterized by TNF-producing myeloid infiltrates in colon mucosa in the absence of lymphocytes, supporting an essential role for myeloid cells in colitis initiation. Furthermore, induced deletion of intestinal core 1-derived O-glycans caused spontaneous colitis in adult mice. These data indicate a causal role for the loss of core 1-derived O-glycans in colitis. Finally, we detected a biosynthetic intermediate typically exposed in the absence of core 1 O-glycan, Tn antigen, in the colon epithelium of a subset of UC patients. Somatic mutations in the X-linked gene that encodes core 1 β1,3-galactosyltransferase-specific chaperone 1 (C1GALT1C1, also known as Cosmc), which is essential for core 1 O-glycosylation, were found in Tn-positive epithelia. These data suggest what we believe to be a new molecular mechanism for the pathogenesis of UC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Tumor-Associated, Carbohydrate / metabolism
  • Base Sequence
  • Colitis / etiology*
  • Colitis / genetics
  • Colitis / metabolism
  • Colitis / pathology
  • Colon / metabolism
  • DNA Primers / genetics
  • Disease Models, Animal
  • Galactosyltransferases / deficiency
  • Galactosyltransferases / genetics
  • Humans
  • Intestinal Mucosa / abnormalities
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / microbiology
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism
  • Mutation
  • Polysaccharides / deficiency*

Substances

  • Antigens, Tumor-Associated, Carbohydrate
  • C1GALT1C1 protein, human
  • Cosmc protein, mouse
  • DNA Primers
  • Molecular Chaperones
  • Polysaccharides
  • Tn antigen
  • C1galt1 protein, mouse
  • Galactosyltransferases