Interleukin 10-deficient mice exhibit defective colonic Muc2 synthesis before and after induction of colitis by commensal bacteria.

Germ-free (GF) interleukin 10-deficient (IL-10) mice develop chronic colitis after colonization by normal enteric bacteria. Muc2 is the major structural component of the protective colonic mucus. Our aim was to determine whether primary or induced aberrations in Muc2 synthesis occur in GF IL-10 mice that develop colitis after bacterial colonization. GF IL-10 and wild-type mice were colonized with commensal bacteria for various intervals up to 6 weeks. Colitis was quantified by histologic score and IL-12 secretion. Muc2 synthesis, total level of Muc2, and Muc2 sulfation were measured quantitatively. GF IL-10 mice showed 10-fold lower Muc2 synthesis and Muc2 levels compared with GF wild-type mice, but Muc2 sulfation was not different. When bacteria were introduced, IL-10 mice developed colitis, whereas wild-type mice remained healthy. Muc2 synthesis was unchanged in wild-type mice, but IL-10 mice showed a peak increase in Muc2 synthesis 1 week after bacterial introduction, returning to baseline levels after 2 weeks. Total Muc2 levels decreased 2-fold in wild-type mice but remained at stable low levels in IL-10 mice. Upon introducing bacteria, Muc2 sulfation increased 2-fold in wild-type mice, whereas in IL-10 mice Muc2 sulfation decreased 10-fold. In conclusion, a primary defect in colonic Muc2 synthesis is present in IL-10 mice, whereas bacterial colonization and colitis in these mice led to reduced Muc2 sulfation. These quantitative and structural aberrations in Muc2 in IL-10 mice likely reduce the ability of their mucosa to cope with nonpathogenic commensal bacteria and may contribute to their susceptibility to develop colitis.

Fate of goblet cells in experimental colitis.

We sought to correlate the characteristic changes in goblet cell morphology in the chronically inflamed large intestine of 1L10-/- mice to specific changes in goblet cell gene expression. In healthy as well as IL10-/- mice, marked differences were found among the large intestinal regions in goblet cell morphology and gene expression. The mucin Muc2, which is a major determinant of goblet cell morphology, was expressed in most goblet cells, yet only in cells staining positive for both Alcian blue and high iron diamine. TFF3 was expressed in only a small subset of goblet cells. Inflamed colon of IL10-/- mice still contained high numbers of small, hypotrophic goblet cells with similar histochemical staining and Muc2 and TFF3 expression patterns, contradicting the often reported "goblet cell depletion" in colitis. Quantitatively, the Muc2 and TFF3 levels remained relatively stabile in IL10-/- mice. Muc2 in distal IL10-/- colon contained significantly less sulfate residues than in controls, which may compromise its protective properties.

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

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.