Human inflammatory bowel diseases (IBD) such as Crohn’s Disease and ulcerative colitis (UC) are believed to involve inappropriate immune responses to the complex mix of microbes in the gut. A mucosal barrier made up of cells and secreted goodies normally keeps this plethora of pathogenic and normal bugs separated from the intestinal tissues.
It has long been known that this mucosal barrier is disrupted in IBD. However, the extent to which the mucin proteins that characterise this layer are involved in the chronic inflammatory cycle of IBD beyond simple physical protection is only just starting to become apparent.
Last year, Associate Professor Michael McGuckin and his team at the Mater Medical Research Institute (MMRI) in Brisbane published the first real in vivo evidence that mucins on the surface of the gut play an active and critical role in mucosal defence against infection and inflammation.
Now they have again led the field in establishing a functional link between mucin abnormalities and a novel mechanism underlying intestinal inflammation, not only in mice but also in human patients with a particular form of IBD.
At the Australian Health and Medical Research Congress in this week, McGuckin discussed his two mice strains, called Winnie and Eeyore, and explained just what they are teaching him about the gut.
McGuckin heads the Mucosal Diseases Program at the MMRI, focusing on mucosal barriers to infection and inflammation. He has close ties with several respiratory physicians and gastroenterologists around town, although he concentrates on epithelial mucins in the gastrointestinal tract, in collaboration with the director of gastroenterology at the adjacent Mater Hospital, Professor Tim Florin.
McGuckin has a long-standing interest in mucin glycoproteins, which are made by specialised cells found in all mucosal epithelial linings in the body.
These large molecules are about 70 per cent carbohydrate on a protein backbone and include mucins secreted into the extracellular matrix, as well as others that remain embedded in the apical membrane of mucosal epithelial cells and poke out into the lumen.
These cell surface-mucins form large disulphide-bonded polymers by virtue of characteristic cysteine-rich regions at either end of the protein structure. The polymers get together to form gel-like mucous layers covering the cell surface.
The most well know mucosal layer is of course in the gut, where the mucin proteins are made and secreted by the distinctive-looking goblet cells – so-called because of their flask-like appearance – dispersed throughout the gastrointestinal epithelia.
Exactly how these complex proteins actively participate in protecting the intestinal lining from infection, and how they contribute to the pathology associated with chronic infection and inflammation, are of prime interest to McGuckin’s team.
According to McGuckin, the field of mucin research is not all that popular, mainly because the genes are huge and the proteins are difficult to work with. “Howard Florey and Frank Macfarlane Burnet both dabbled in mucins and there have not been too many Aussies since,” he says.
“Macfarlane Burnet was the one who got mucins written up in the textbooks as an important part of primary defence, although this was based really on very little in terms of empirical data.”
