The gastrointestinal mucus system in health and disease

Abstract

Mucins--large, highly glycosylated proteins--are important for the luminal protection of the gastrointestinal tract. Enterocytes have their apical surface covered by transmembrane mucins and goblet cells produce the secreted gel-forming mucins that form mucus. The small intestine has a single unattached mucus layer, which in cystic fibrosis becomes attached, accounting for the intestinal manifestations of this disease. The stomach and colon have two layers of mucus; the inner layer is attached and the outer layer is less dense and unattached. In the colon, the outer mucus layer is the habitat for commensal bacteria. The inner mucus layer is impervious to bacteria and is renewed every hour by surface goblet cells. The crypt goblet cells have the ability to restitute the mucus layer by secretion, for example after an ischaemic challenge. Proteases of certain parasites and some bacteria can cleave mucins and dissolve the mucus as part of their pathogenicity. The inner mucus layer can, however, also become penetrable to bacteria by several other mechanisms, including aberrations in the immune system. When bacteria reach the epithelial surface, the immune system is activated and inflammation is triggered. This mechanism might occur in some types of ulcerative colitis.

Figure 1

Simplified model of a gel-forming mucin produced by goblet cells and transmembrane mucins attached to the apical membrane of enterocytes. Left: the MUC2 mucin polymer is packed in the granulae (blue) of the goblet cells and during secretion expands to form flat ring-like structures that stack under each other. The enlarged ring shows the oligomeric nature of the MUC2 polymer, and above the MUC2 monomer is shown with its central mucin domains and exemplified O-glycans. The MUC2 N-termini and C-termini are held together with numerous disulphide bonds. Right: the apical side of the intestinal enterocytes are covered by a glycocalyx made up of mucins that are anchored in the cell membrane. The long and extended mucin domains make up the glycocalyx. The cleaved and associated SEA and vWD domains are indicated as well as the mucin domain. Abbreviations: SEA: sea urchin-enterokinase-agrin domain; vWD, von Willebrand domain.

Figure 2

The organization of epithelium and mucus in the gastrointestinal tract. The squamous epithelium of the mouth and oesophagus is washed by mucus from the salivary glands. The stomach and colon have a two-layered mucus system with an inner, attached mucus and an outer, unattached, loose mucus layer. The small intestine on the other hand has only one type of mucus that is unattached and loose.

Figure 3

Mucus secretion from the colon surface epithelium and crypts during ischaemia and reperfusion. a ∣ Normal steady state renewal of the inner mucus layer by the surface goblet cells. This inner mucus layer is converted and expanded to the outer mucus layer. b ∣ Upon ischaemia the mucus layers are lost and bacteria can enter the crypt and epithelial cells. c ∣ Upon reperfusion, the crypt goblet cells release their stored mucins and a new inner and outer mucus layer are formed at the same time as the bacteria in the crypt are washed out. d ∣ After reperfusion, the crypt goblet cells remain emptied for several hours as repleneshing of the mucin granulae is slow. During this period, the tissue will be more vulnerable to another episode of ischemia.

Figure 4

Model of mechanisms that could affect the inner mucus layer properties and potentially cause ulcerative colitis. The inner mucus layer normally separates the bacteria from the epithelial cells. If this inner mucus layer is absent or penetrable to bacteria, the load of bacteria on the epithelium increases, which will trigger an immune reaction by the subepithelial immune system.