THE ROLE OF MUCINS AND MUCUS IN THE DISEASES CYSTIC FIBROSIS, CELIAC DISEASE, AND ULCERATIVE COLITIS

The overall aim of this proposal is to explain how the mucus systems of the intestine and lung act as a first innate immune defense line to protect our mucosal surfaces. Mucins are of highly glycosylated proteins that build the mucus skeleton. We previously discovered that there are two mucus layers in the colon. The inner mucus layer built around the MUC2 mucin is attached and impenetrable to bacteria, thus separating the intestinal bacteria from the epithelial cells. However, how the dynamic colon mucus layers are formed and controlled is poorly understood.

We have established an international leading position in this research area and have now addressed fundamental and unresolved problems of high medical importance. The capacity of the inner mucus layer to separate bacteria from the epithelium is highly dependent on the luminal bacteria. Our results suggest specific bacteria signaling via smaller molecules or bacterial fragments to the host to increase protection. We have discovered that western diets quickly weakens the colon barrier and that such weaker protection is an early event in the development of ulcerative colitis. We have discovered a single sensory goblet cell protecting the colon crypts and recently specific goblet cells of the surface colon that are lost early during the development of ulcerative colitis and also in patients in remission.

We have transferred our leading edge knowledge of intestinal mucus structure and function to the respiratory tract. Normal trachea is cleared by mucus strands formed the tracheal glands, but these strands are trapped cystic fibrosis. We shown that in chronic lung diseases an attached mucus layer is formed, similar to the one described by us in colon. Understanding this attached mucus layer can explain the mucus accumulation in chronic lung diseases.

The proposed project has substantially increased our basic understanding of molecular mechanisms behind several mucus related diseases and pave the way for new treatments.

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.

We have fulfilled the plan and obtained the expected results.

Periodic Reporting for period 4 - MUC2GO (THE ROLE OF MUCINS AND MUCUS IN THE DISEASES CYSTIC FIBROSIS, CELIAC DISEASE, AND ULCERATIVE COLITIS)

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