[Frontiers in Bioscience 6, d1321-1357, October 1, 2001]


Anthony P. Corfield, Daniel Carroll, Neil Myerscough and Christopher S.J. Probert

Mucin Research Group, Division of Medicine, Bristol Royal Infirmary, Bristol BS2 8HW, UK


1. Abstract
2. Introduction
3. The normal protective mucus barrier in the gastrointestinal tract
3.1. Mucins
3.1.1. Genes and peptide structure
3.1.2. Glycosylation
3.1.3. Biosynthesis and secretion
3.1.4.Degradation and turnover
3.1.5. Sites of production
3.1.6. Mucus barrier thickness and rheology
3.1.7. Foetal and neonatal expression
3.2. Non-Mucin components
3.2.1. Electrolytes and lipids
3.2.2. Defensive proteins Lysozyme Lactoferrin Secretory IgA Protease inhibitors Growth factors Defensins Beta-Galectins Trefoil factor peptides IgG gamma Fc binding protein Heparin and Heparan Sulfate Lipopolysaccharide binding protein Serum Amyloid A protein
4. The mucus barrier in gastrointestinal disease
4.1. Esophageal disease
4.2 Intestinal metaplasia, gastric ulcer and Helicobacter pylori infection
4.3. Gastric cancer
4.4. Inflammatory bowel disease
4.4.1. Ulcerative colitis and Crohn's disease
4.4.2. Diversion colitis
4.5. Ileoanal pouch
4.6. Colorectal cancer
4.7. Paediatric disease
5. Summary and perspective
6. Acknowledgments
7. References


Mucins form part of the dynamic, interactive mucosal defensive system active at the mucosal surface of the gastrointestinal tract. They are carbohydrate rich glycoproteins with unique molecular structure and chemical properties. The family of mucin (MUC) genes has 13 members that can be divided into secreted and membrane-associated forms each with characteristic protein domains and tissue specific glycosylation. Biosynthetic pathways have been described for the secreted and membrane-associated mucins and their eventual degradation and turnover. Mucins are present at all mucosal surfaces throughout the body in typical combinations and relate to the demands of organ function. Patterns of MUC gene expression with gastrointestinal site specific glycosylation are clearly important but are not yet well defined. Mucin production during fetal development shows distinct patterns that may correlate in many cases with neoplastic expression in adult life.

An increasing number of protective proteins have been identified that appear in the adherent mucus layer at the mucosal surface. These proteins are co-secreted with mucins in some cases, interact with mucins at a molecular level through peptide and carbohydrate sites or benefit from the viscoelastic, aqueous environment afforded by the mucus gel to effect their defensive roles. The mechanism of many of these interaction remains to be elucidated but is clearly part of an integrated innate and adaptive mucosal defensive system relying on the mucins as an integral component to provide a mucus gel.

Recent improvements in the description of MUC gene expression and mature mucin synthesis in the healthy gastrointestinal tract has formed a basis for assessment of mucosal disease at sites throughout the tract. Pathological patterns of mucin expression in disease appear to follow tissue phenotype, so that gastric and intestinal types can be defined and appear in metaplasia in e.g. esophagus and stomach. Adaptation of previous mucin based, histochemical classification of intestinal metaplasia to assess MUC gene expression has proved helpful and promises greater value if reliably combined with mucin linked glycosylation markers. Few changes in MUC gene expression or polymorphism have been detected in inflammatory bowel diseases in contrast to malignant transformation. Glycosylation changes however, are evident in both types of disease and appear to be early events in disease pathogenesis. Review of the major mucosal diseases affecting the gastrointestinal tract in childhood reveals parallel patterns to those found in adult pathology, but with some novel conditions arising through the developmental stages at lactation and weaning. The impact of bacterial colonization and nutrition at these stages of life are important in the evaluation of mucosal responses in pediatric disease.