The ulcerative colitis associated gene FUT8 regulates the quantity and quality of secreted mucins (original) (raw)
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Muc5ac Expression Protects the Colonic Barrier in Experimental Colitis
Inflammatory Bowel Diseases
Background The mucus gel layer (MGL) lining the colon is integral to exclusion of bacteria and maintaining intestinal homeostasis in health and disease. Some MGL defects allowing bacteria to directly contact the colonic surface are commonly observed in ulcerative colitis (UC). The major macromolecular component of the colonic MGL is the secreted gel-forming mucin MUC2, whose expression is essential for homeostasis in health. In UC, another gel-forming mucin, MUC5AC, is induced. In mice, Muc5ac is protective during intestinal helminth infection. Here we tested the expression and functional role of MUC5AC/Muc5ac in UC biopsies and murine colitis. Methods We measured MUC5AC/Muc5ac expression in UC biopsies and in dextran sulfate sodium (DSS) colitis. We performed DSS colitis in mice deficient in Muc5ac (Muc5ac-/-) to model the potential functional role of Muc5ac in colitis. To assess MGL integrity, we quantified bacterial-epithelial interaction and translocation to mesenteric lymph nod...
Mediators of Inflammation, 2015
Background. Patients with UC have shown an important defect in the secretion and maintenance of the mucosal barrier as part of inadequate expression of mucin genes. The aim of the present study was to determine the expression of MUC12, MUC16, and MUC20 in colonic tissue from patients with UC in regard to their clinical outcomes.Methods. We included a total of 40 patients with UC and 30 normal controls. Mucin gene expression was performed by RT-PCR and protein expression was detected by immunohistochemistry.Results. Patients with active UC showed no significant expression of MUC12 gene in mucosa compared to the group of patients with UC in remission and the normal control group. MUC16 gene expression was significantly increased in the UC active and remission groups compared to the normal control group (P=0.03). MUC20 gene expression was found significantly decreased in patients with active UC compared to both remission group (P=0.001) and normal controls (P=0.001). Furthermore, an as...
MUC2 is the prominent colonic mucin expressed in ulcerative colitis
Gut, 1996
Background-It has been shown that MUC2 is the prominent mucin synthesised in healthy colon. Aim-To identify the predominant mucins in ulcerative colitis (UC) and to study their biosynthesis. Methods and Results-Mucin was purified from UC resection specimens. This mucin on sodium dodecylsulphate polyacrylamide gel electrophoresis (SDS-PAGE) presented as one, high molecular weight, periodic acid/Schiff's reagent (PAS) stainable band. Amino acid composition showed a close resemblance to that of MUC2. Immunoprecipitation with a specific anti-MUC2 antiserum confirmed that this mucin was MUC2. In addition, on the mRNA level MUC2 was also the most prominent mucin expressed in UC. Polyclonal antiserum was elicited, mainly recognising mucin peptide epitopes of UC and normal colonic mucin.
Infection and Immunity, 2013
ABSTRACTSalmonella entericaserovar Typhimurium is a model organism used to explore the virulence strategies underlyingSalmonellapathogenesis. Although intestinal mucus is the first line of defense in the intestine, its role in protection againstSalmonellais still unclear. The intestinal mucus layer is composed primarily of the Muc2 mucin, a heavily O-glycosylated glycoprotein. The core 3-derived O-glycans of Muc2 are synthesized by core 3 β1,3-N-acetylglucosaminyltransferase (C3GnT). Mice lacking these glycans still produce Muc2 but display a thinner intestinal mucus barrier. We began our investigations by comparingSalmonella-induced colitis and mucus dynamics inMuc2-deficient (Muc2−/−) mice,C3GnT−/−mice, and wild-type C57BL/6 (WT) mice.Salmonellainfection led to increases in luminal Muc2 secretion in WT andC3GnT−/−mice. WhenMuc2−/−mice were infected withSalmonella, they showed dramatic susceptibility to infection, carrying significantly higher cecal and liver pathogen burdens, and ...
Quantitative Analysis of MUC2 Synthesis in Ulcerative Colitis
Biochemical and Biophysical Research Communications, 1996
MUC2 is the predominant mucin in the human colon responsible for the protective mucus layer. We developed methods to quantify MUC2 biosynthesis, which were used to study the regulation of MUC2 expression in the colon of normal individuals and of patients with ulcerative colitis. Colonic biopsies were metabolically labeled, and biosynthesis of MUC2 precursor was quantified using SDS-PAGE. Total MUC2 and MUC2 mRNA were quantified using blotting techniques. MUC2 precursor biosynthesis and total MUC2 levels were significantly decreased in ulcerative colitis patients with active inflammation compared to controls. In contrast, both these parameters returned to control values during remission of the inflammation, demonstrating that colonic biosynthesis and total amounts of MUC2 vary according to the activity of the disease. However, MUC2 mRNA levels were similar in all patients and independent of disease activity, indicating that these variations in MUC2 synthesis are post-transcriptionally regulated. ᭧ 1996 Academic Press, Inc.
Frontiers in Immunology, 2020
Throughout the gastrointestinal (GI) tract, a distinct mucus layer composed of highly glycosylated proteins called mucins plays an essential role in providing lubrication for the passage of food, participating in cell signaling pathways and protecting the host epithelium from commensal microorganisms and invading pathogens, as well as toxins and other environmental irritants. These mucins can be broadly classified into either secreted gel-forming mucins, those that provide the structural backbone for the mucus barrier, or transmembrane mucins, those that form the glycocalyx layer covering the underlying epithelial cells. Goblet cells dispersed among the intestinal epithelial cells are chiefly responsible for the synthesis and secretion of mucins within the gut and are heavily influenced by interactions with the immune system. Evidence from both clinical and animal studies have indicated that several GI conditions, including inflammatory bowel disease (IBD), colorectal cancer, and numerous enteric infections are accompanied by considerable changes in mucin quality and quantity. These changes include, but are not limited to, impaired goblet cell function, synthesis dysregulation, and altered post-translational modifications. The current review aims to highlight the structural and functional features as well as the production and immunological regulation of mucins and the impact these key elements have within the context of barrier function and host defense in intestinal inflammation.
PLoS Pathog, 2010
Despite recent advances in our understanding of the pathogenesis of attaching and effacing (A/E) Escherichia coli infections, the mechanisms by which the host defends against these microbes are unclear. The goal of this study was to determine the role of goblet cell-derived Muc2, the major intestinal secretory mucin and primary component of the mucus layer, in host protection against A/E pathogens. To assess the role of Muc2 during A/E bacterial infections, we inoculated Muc2 deficient (Muc2 2/2 ) mice with Citrobacter rodentium, a murine A/E pathogen related to diarrheagenic A/E E. coli. Unlike wildtype (WT) mice, infected Muc2 2/2 mice exhibited rapid weight loss and suffered up to 90% mortality. Stool plating demonstrated 10-100 fold greater C. rodentium burdens in Muc2 2/2 vs. WT mice, most of which were found to be loosely adherent to the colonic mucosa. Histology of Muc2 2/2 mice revealed ulceration in the colon amid focal bacterial microcolonies. Metabolic labeling of secreted mucins in the large intestine demonstrated that mucin secretion was markedly increased in WT mice during infection compared to uninfected controls, suggesting that the host uses increased mucin release to flush pathogens from the mucosal surface. Muc2 also impacted host-commensal interactions during infection, as FISH analysis revealed C. rodentium microcolonies contained numerous commensal microbes, which was not observed in WT mice. Orally administered FITC-Dextran and FISH staining showed significantly worsened intestinal barrier disruption in Muc2 2/2 vs. WT mice, with overt pathogen and commensal translocation into the Muc2 2/2 colonic mucosa. Interestingly, commensal depletion enhanced C. rodentium colonization of Muc2 2/2 mice, although colonic pathology was not significantly altered. In conclusion, Muc2 production is critical for host protection during A/E bacterial infections, by limiting overall pathogen and commensal numbers associated with the colonic mucosal surface. Such actions limit tissue damage and translocation of pathogenic and commensal bacteria across the epithelium. Citation: Bergstrom KSB, Kissoon-Singh V, Gibson DL, Ma C, Montero M, et al. (2010) Muc2 Protects against Lethal Infectious Colitis by Disassociating Pathogenic and Commensal Bacteria from the Colonic Mucosa. PLoS Pathog 6(5): e1000902.
Mucins Dynamics in Physiological and Pathological Conditions
International Journal of Molecular Sciences, 2021
Maintaining intestinal health requires clear segregation between epithelial cells and luminal microbes. The intestinal mucus layer, produced by goblet cells (GCs), is a key element in maintaining the functional protection of the epithelium. The importance of the gut mucus barrier is highlighted in mice lacking Muc2, the major form of secreted mucins. These mice show closer bacterial residence to epithelial cells, develop spontaneous colitis and became moribund when infected with the attaching and effacing pathogen, Citrobacter rodentium. Furthermore, numerous observations have associated GCs and mucus layer dysfunction to the pathogenesis of inflammatory bowel disease (IBD). However, the molecular mechanisms that regulate the physiology of GCs and the mucus layer remain obscured. In this review, we consider novel findings describing divergent functionality and expression profiles of GCs subtypes within intestinal crypts. We also discuss internal (host) and external (diets and bacter...