Loss of intestinal core 1–derived O-glycans causes spontaneous colitis in mice
Jianxin Fu, Bo Wei, Tao Wen, Malin E.V. Johansson, Xiaowei Liu, Emily Bradford, Kristina A. Thomsson, Samuel McGee, Lilah Mansour, Maomeng Tong, J. Michael McDaniel, Thomas J. Sferra, Jerrold R. Turner, Hong Chen, Gunnar C. Hansson, Jonathan Braun, Lijun Xia
Jianxin Fu, Bo Wei, Tao Wen, Malin E.V. Johansson, Xiaowei Liu, Emily Bradford, Kristina A. Thomsson, Samuel McGee, Lilah Mansour, Maomeng Tong, J. Michael McDaniel, Thomas J. Sferra, Jerrold R. Turner, Hong Chen, Gunnar C. Hansson, Jonathan Braun, Lijun Xia
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Research Article Gastroenterology

Loss of intestinal core 1–derived O-glycans causes spontaneous colitis in mice

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.

Authors

Jianxin Fu, Bo Wei, Tao Wen, Malin E.V. Johansson, Xiaowei Liu, Emily Bradford, Kristina A. Thomsson, Samuel McGee, Lilah Mansour, Maomeng Tong, J. Michael McDaniel, Thomas J. Sferra, Jerrold R. Turner, Hong Chen, Gunnar C. Hansson, Jonathan Braun, Lijun Xia

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Figure 6

Absence of core 1–derived O-glycans impairs the levels of intestinal mucins and the integrity of intestinal barrier function.

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Absence of core 1–derived O-glycans impairs the levels of intestinal muc...
(A) Representative images of immunohistochemical staining (brown) with O-glycosylation–independent antibodies to different mucins in colon sections of WT and TM-IEC C1galt1–/– mice 5 days after TM. Scale bars: 100 μm. (B) Serum concentrations of FITC-dextran were measured 4 hours after oral administration to WT and TM-IEC C1galt1–/– mice at different time points after TM induction (mean ± SD, n = 6). *P < 0.008. (C) Relative amount of bacterial 16S rDNA detected by real-time PCR using two independent sets of 16S universal primers. Data are expressed as the fold difference between WT and TM-IEC C1galt1–/– mice (mean ± SD, n = 6). The average 16S rDNA value of WT mice was expressed as 1. **P < 0.02. (D) Colon sections of 7-week-old mice 10 days after TM induction were probed with an Alexa Fluor 555–conjugated general bacterial 16S rDNA probe for FISH (red) and costained with a FITC-labeled glycosylation-independent polyclonal antibody to Muc2 (green). Dashed lines mark epithelial surfaces. Scale bar: 20 μm. (E) Quantification of immunofluorescence images of 7-week-old WT and TM-IEC C1galt1–/– colon sections stained with mAbs to myeloid cells (Gr1) and TNF (mean ± SD, n = 5). †P < 0.001.