Altered O-glycosylation profile of MUC2 mucin occurs in active ulcerative colitis and is associated with increased inflammation

Larsson, Jessica M. Holmn; Karlsson, Hasse; Crespo, Jessica Gråberg; Johansson, Malin; Eklund, Lisbeth; Sjövall, Henrik; Hansson, Gunnar C.

doi:10.1002/ibd.21625

Cited by 269 publications

(239 citation statements)

References 48 publications

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“…Muc2 is a heavily O-glycosylated mucin, and the impact of its glycosylation was noted by a recent study examining different glycosylation patterns of Muc2 in mice and humans (49,50). In agreement with previous findings (13), we found that core 3 O-glycosylation plays a major role in protecting intestinal barrier function.…”

Section: Discussionmentioning

confidence: 99%

The Mucin Muc2 Limits Pathogen Burdens and Epithelial Barrier Dysfunction during Salmonella enterica Serovar Typhimurium Colitis

et al. 2013

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c Salmonella enterica serovar Typhimurium is a model organism used to explore the virulence strategies underlying Salmonella pathogenesis. Although intestinal mucus is the first line of defense in the intestine, its role in protection against Salmonella is 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 ␤1,3-N-acetylglucosaminyltransferase (C3GnT). Mice lacking these glycans still produce Muc2 but display a thinner intestinal mucus barrier. We began our investigations by comparing Salmonella-induced colitis and mucus dynamics in Muc2-deficient (Muc2 ؊/؊ ) mice, C3GnT ؊/؊ mice, and wild-type C57BL/6 (WT) mice. Salmonella infection led to increases in luminal Muc2 secretion in WT and C3GnT ؊/؊ mice. When Muc2 ؊/؊ mice were infected with Salmonella, they showed dramatic susceptibility to infection, carrying significantly higher cecal and liver pathogen burdens, and developing significantly higher barrier disruption and higher mortality rates, than WT mice. We found that the exaggerated barrier disruption in infected Muc2 ؊/؊ mice was invA dependent. We also tested the susceptibility of C3GnT ؊/؊ mice and found that they carried pathogen burdens similar to those of WT mice but developed exaggerated barrier disruption. Moreover, we found that Muc2 ؊/؊ mice were impaired in intestinal alkaline phosphatase (IAP) expression and lipopolysaccharide (LPS) detoxification activity in their ceca, potentially explaining their high mortality rates during infection. Our data suggest that the intestinal mucus layer (Muc2) and core 3 O-glycosylation play critical roles in controlling Salmonella intestinal burdens and intestinal epithelial barrier function, respectively.

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Section: Discussionmentioning

confidence: 99%

The Mucin Muc2 Limits Pathogen Burdens and Epithelial Barrier Dysfunction during Salmonella enterica Serovar Typhimurium Colitis

et al. 2013

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“…Mucus is impermeable to commensal bacteria, with the exception of that forming the outer layer in the colon (Johansson et al, , 2008(Johansson et al, , 2013. Mucins are highly glycosylated proteins produced and released by goblet cells that vary in structure, function and sites of expression (Fu et al, 2011;Johansson et al, 2013;Larsson et al, 2011;Sommer et al, 2014). For example, differences in their protein domains distinguish the transmembrane mucins anchored to the epithelial layer from the detached gel-forming mucins.…”

Section: Mucin Is An Extracellular Component Essential In Barrier Funmentioning

confidence: 99%

The mucosal barrier at a glance

Turner

2017

Journal of Cell Science

190

183

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Mucosal barriers separate self from non-self and are essential for life. These barriers, which are the first line of defense against external pathogens, are formed by epithelial cells and the substances they secrete. Rather than an absolute barrier, epithelia at mucosal surfaces must allow selective paracellular flux that discriminates between solutes and water while preventing the passage of bacteria and toxins. In vertebrates, tight junctions seal the paracellular space; flux across the tight junction can occur through two distinct routes that differ in selectivity, capacity, molecular composition and regulation. Dysregulation of either pathway can accompany disease. A third, tight-junction-independent route that reflects epithelial damage can also contribute to barrier loss during disease. In this Cell Science at a Glance article and accompanying poster, we present current knowledge on the molecular components and pathways that establish this selectively permeable barrier and the interactions that lead to barrier dysfunction during disease.

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“…These glycan chains are highly heterogeneous in chain length and composition even at homeostasis. Importantly, glycan structure can be influenced during parasitic infections, which aids host protection against pathogenesis (which will be discussed further below) 33, 34, 35, 36…”

Section: Muc2 Biosynthesismentioning

confidence: 99%

A sticky end for gastrointestinal helminths; the role of the mucus barrier

Sharpe

Thornton

Grencis

2018

Parasite Immunology

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SummaryGastrointestinal (GI) nematodes are a group of successful multicellular parasites that have evolved to coexist within the intestinal niche of multiple species. It is estimated that over 10% of the world's population are chronically infected by GI nematodes, making this group of parasitic nematodes a major burden to global health. Despite the large number of affected individuals, there are few effective treatments to eradicate these infections. Research into GI nematode infections has primarily focused on defining the immunological and pathological consequences on host protection. One important but neglected aspect of host protection is mucus, and the concept that mucus is just a simple barrier is no longer tenable. In fact, mucus is a highly regulated and dynamic‐secreted matrix, underpinned by a physical hydrated network of highly glycosylated mucins, which is increasingly recognized to have a key protective role against GI nematode infections. Unravelling the complex interplay between mucins, the underlying epithelium and immune cells during infection are a major challenge and are required to fully define the protective role of the mucus barrier. This review summarizes the current state of knowledge on mucins and the mucus barrier during GI nematode infections, with particular focus on murine models of infection.

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Altered O-glycosylation profile of MUC2 mucin occurs in active ulcerative colitis and is associated with increased inflammation

Abstract: In the majority of the active UC patients MUC2 mucin has an altered glycan profile as compared to inactive UC and control patients. Patients with strong alterations in the glycan pattern tended to have a more severe disease course.

Cited by 269 publications

References 48 publications

The Mucin Muc2 Limits Pathogen Burdens and Epithelial Barrier Dysfunction during Salmonella enterica Serovar Typhimurium Colitis

The Mucin Muc2 Limits Pathogen Burdens and Epithelial Barrier Dysfunction during Salmonella enterica Serovar Typhimurium Colitis

The mucosal barrier at a glance

A sticky end for gastrointestinal helminths; the role of the mucus barrier

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