When the mucus proteome from more than 100 UC patients and controls were analyzed we observed lower levels of core mucus proteins (MUC2, FCGBP) in active ulcerative colitis than in remission. Some patients with an altered mucus proteome and active colitis lacked local inflammation as supported by normal calprotectin levels. Sentinel goblet cells, discovered by us in mice, have now been shown also in humans. In active ulcerative colitis patients, there were almost no Sentinel cells left due to their activation and depletion. This is caused by a defective inner mucus layer allowing bacteria to come in contact with the epithelium. This leaves the crypt opening without the guarding cells.
We recently discovered a new set of goblet cells that we call the intercrypt goblet cells or siGC. These are important for the anchoring of the inner mucus layer as these are secreting a different mucus than the mucus plume at the crypt opening. These two mucus combine to form the inner mucus layer. The icGC are organized around the crypt opening and they are declined in ulcerative colitis, also for patients without inflammation. This is the first observation of an alteration also in remission of ulcerative colitis, suggesting that the start of ulcerative colitis should be studied in these cells.
Bacteria in the intestinal lumen affect the mucus properties of the colon inner mucus layer. This is assumed to be caused by bacterial metabolites. One way to affect the bacterial composition and metabolism is the diet. We have now shown that a ‘Western’ type diet, low in polysaccharide polymers (‘fiber’) and high in fat and sugar already after three days renders the inner colon mucus layer more penetrable to bacteria. This could be partly reversed by adding the polysaccharide inulin. We have further observed that the Western diet also alters the mucus of the mid small intestine, further proving the importance of diet to mucus properties.
The MUC2 mucin of the colon mucus layers contains several isopeptide bonds formed by transglutaminases between the side-chains of Lys or Gln within or between MUC2 monomers. We have now shown that the the transglutaminase 3 is required for a stable inner mucus layer. Furthermore, the gluten peptide has been shown to require the MUC2 mucin for its uptake and presentation to the immune system as an initiator of celiac disease.
Pig and human lungs have numerous submucosal glands that are efficiently forming thick mucus bundles based on >1,000 linear MUC5B polymers. These bundles are sweeping and cleaning the tracheo-broncial surface from bacteria. In cystic fibrosis, these bundles are immobile as they are more firmly anchored closer to the epithelial surface. Interestingly, the normal neurotransmittor acetylcholine transiently stops the bundle movement and drugs utilized for treating COPD are mobilizing these stopped bundles.
The non-moving mucus bundles are anchored to the surface goblet cells, in part by the MUC5AC mucin. In chronic lung diseases as Cystic Fibrosis and COPD, a surface mucus layer is firmly anchored to the goblet cells. We now know that a non-mucin protein is mediating the attachment and that its removal detaches the mucus. We are actively working on understanding and testing different pharmacological approaches to mobilize non-moving mucus bundles and the attached mucus layer in chronic lung diseases. We are currently successfully exploring a pharmacological removal of calcium ions from the mucus/mucins for the treatment of chronic lung diseases.
