Mucin-type O-glycans are primary components of the colonic mucus gel layer. Altered intestinal O- glycosylation has been observed in patients with ulcerative colitis (UC), but whether this alteration is an etiological factor is unknown. O-glycans consist mainly of core 1- and core 3-derived O-glycans. The biosynthesis of these two types of O-glycans is controlled by core 11,3-galactosyltransferase (T-synthase) and Core 31,3-glucosaminyltransferase (C3GnT), respectively. T-synthase function requires a specific chaperone, Cosmc. Human Cosmc is on the X-chromosome, increasing the significance of somatic mutations in this gene. In preliminary studies, we detected somatic mutations in the Cosmc gene in DNA, isolated from colonic epithelial cells, expressing abnormal O-glycans from UC patients. We hypothesize that altered O-glycans impair mucus barrier function, which in turn allows intestinal microflora to interact abnormally with epithelium and mucosal immune cells, thus causing colitis. To test this hypothesis, we developed mice lacking either core 1- or combined core 1- and core 3-derived O-glycans (IEC T-syn-/- and DKO mice, respectively). In addition, we have also developed mice with tamoxifen (TM) inducible deletion of T-syn in intestinal epithelial cells (TM-IEC T-syn-/-). These mice develop spontaneous colitis, which is associated with a massive granulocyte infiltration and cryptic abscesses, closely resembling active human UC. Significantly, IEC T-syn-/- and DKO mice in the Rag1-/- background, who lack adaptive immunity, manifested similarly severe colitis, suggesting an essential role for innate immune cells such as granulocytes in colitis development. This supports an etiological role for O-glycans in colitis and provides a unique model system to test whether altered O-glycans is a potential molecular mechanism in the pathogenesis of human UC. We propose to 1) analyze how abnormal O-glycosylation impairs the expression of intestinal mucins and add additional patient samples to improve the statistical power of our preliminary observations that Cosmc mutations cause abnormal expression of colon epithelial O-glycans in UC patients;2) determine the role of O- glycans in intestinal barrier function, investigate changes in bacterial variety or density in O-glycan-deficient mice before and after disease onset by phylogenetic analysis, and test definitively the role of microbiota in colitis development by developing germ-free O-glycan-deficient mice;and 3) identify mechanisms initiating granulocyte infiltration and determine the role of granulocytes in colitis. Our proposed studies will reveal novel insights into the pathogenesis of colitis and may lead to new therapies.

Public Health Relevance

Ulcerative colitis (UC) is a chronic inflammation of the large intestine with an unknown cause or cure that can last years to decades. UC often leads to physical as well as psychological discomfort and even disability. Altered expression of large sugar molecules called O-glycans in the large intestine is seen in UC patients. However, whether this alteration causes the disease is unknown. The proposed project is poised to provide novel insights into the role of intestinal mucin-type O-glycans in intestinal mucus barrier function and in pathogenesis of the common human disease. This work may lead to a novel therapy for patients with UC.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
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Grey, Michael J
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Oklahoma Medical Research Foundation
Oklahoma City
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Chugh, Seema; Barkeer, Srikanth; Rachagani, Satyanarayana et al. (2018) Disruption of C1galt1 Gene Promotes Development and Metastasis of Pancreatic Adenocarcinomas in Mice. Gastroenterology 155:1608-1624
Jacobs, Jonathan P; Lin, Lin; Goudarzi, Maryam et al. (2017) Microbial, metabolomic, and immunologic dynamics in a relapsing genetic mouse model of colitis induced by T-synthase deficiency. Gut Microbes 8:1-16
Song, Kai; Fu, Jianxin; Song, Jianhua et al. (2017) Loss of mucin-type O-glycans impairs the integrity of the glomerular filtration barrier in the mouse kidney. J Biol Chem 292:16491-16497
Chandrakesan, Parthasarathy; Yao, Jiannan; Qu, Dongfeng et al. (2017) Dclk1, a tumor stem cell marker, regulates pro-survival signaling and self-renewal of intestinal tumor cells. Mol Cancer 16:30
Bergstrom, K; Fu, J; Johansson, M E V et al. (2017) Core 1- and 3-derived O-glycans collectively maintain the colonic mucus barrier and protect against spontaneous colitis in mice. Mucosal Immunol 10:91-103
Gao, Nan; Bergstrom, Kirk; Fu, Jianxin et al. (2016) Loss of intestinal O-glycans promotes spontaneous duodenal tumors. Am J Physiol Gastrointest Liver Physiol 311:G74-83
Bergstrom, Kirk; Liu, Xiaowei; Zhao, Yiming et al. (2016) Defective Intestinal Mucin-Type O-Glycosylation Causes Spontaneous Colitis-Associated Cancer in Mice. Gastroenterology 151:152-164.e11
Chang, Baojun; Tessneer, Kandice L; McManus, John et al. (2015) Epsin is required for Dishevelled stability and Wnt signalling activation in colon cancer development. Nat Commun 6:6380
Jacobs, Jonathan; Braun, Jonathan (2014) Host genes and their effect on the intestinal microbiome garden. Genome Med 6:119
Sommer, Felix; Adam, Nina; Johansson, Malin E V et al. (2014) Altered mucus glycosylation in core 1 O-glycan-deficient mice affects microbiota composition and intestinal architecture. PLoS One 9:e85254

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