Role of mucins in inflammatory bowel disease: important lessons from experimental models

Abstract

Inflammatory bowel disease (IBD) is characterized by a chronically inflamed mucosa of the gastrointestinal tract, caused by an underlying immune imbalance and triggered by luminal substances, including bacteria. Mucus forms a gel layer covering the gastrointestinal tract, acting as a semi-permeable barrier between the lumen and the epithelium. Mucins, the building blocks of the mucus gel, determine the thickness and properties of mucus. In IBD in humans, alterations in both membrane-bound and secretory mucins have been described involving genetic mutations in mucin genes, changes in mucin mRNA and protein levels, degree of glycosylation, sulphation, and degradation of mucins. As mucins are strategically positioned between the vulnerable mucosa and the bacterial contents of the bowel, changes in mucin structure and/or quantity probably influence their protective functions and therefore constitute possible aetiological factors in the pathogenesis of IBD. This hypothesis, however, is difficult to prove in humans. Animal models for IBD permit detailed analysis of those aspects of mucins necessary for protection against disease. These models revealed pertinent data as for how changes in mucins, in particular in MUC2, imposed by immunological or microbial factors, may contribute to the development and/or perpetuation of chronic IBD, and shed some light on possible strategies to counteract disease.

Muc-2–Deficient Mice Display a Sex-Specific, COX-2–Related Impairment of Gastric Mucosal Repair

“…6 The Muc2 gene has been implicated as crucial in colonic mucosal defense, based on observations that Muc-2-deficient mice exhibit lowgrade mucosal inflammation in the basal state, and have an increased susceptibility to colitis. 11,22,29,30 MUC-2 is not a major form of mucin in the healthy stomach of humans or rodents, but has been shown to be expressed in gastric carcinoma. 9,10 The results of the present study, however, clearly demonstrate that Muc-2-deficient mice exhibit impaired gastric mucosal repair.…”

DMBT1 functions as pattern‐recognition molecule for poly‐sulfated and poly‐phosphorylated ligands

“…Nutritional compounds, bacterial pathogens, and the endogenous bacterial microflora have been considered as environmental factors contributing to the etiology of CD [1,2]. The putative involvement of bacteria is also reflected at the level of susceptibility genes for CD, of which some appear to exert important functions in innate mucosal immunity [1,3,4]. Genetic variants of the gene nucleotide-binding oligomerization domain 2/Caspase recruitment domain 15 (NOD2/CARD15) at the IBD1 locus, for example, have been shown to be associated with an increased risk for CD [5][6][7].…”

Combined defects in epithelial and immunoregulatory factors exacerbate the pathogenesis of inflammation: mucin 2-interleukin 10-deficient mice

“…They are thought to be caused by combined genetic, environmental, immunoregulatory and epithelial factors. 1,2 Interleukin (IL)-10 contributes to maintaining intestinal homeostasis by suppressing pro-inflammatory cytokine production. 1,3,4 IL-10-deficient (IL-10 À/À ) mice spontaneously develop chronic colitis, of which severity is dependent on both strain background and environmental factors.…”