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

Periodic Reporting for period 2 - MUC2GO (THE ROLE OF MUCINS AND MUCUS IN THE DISEASES CYSTIC FIBROSIS, CELIAC DISEASE, AND ULCERATIVE COLITIS)

Reporting period: 2018-03-01 to 2019-08-31

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 are now addressing 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 address how this signaling take place, important for understanding increased western world diseases including ulcerative colitis. Of special interest is our recent finding of a single sensory goblet cell protecting the colon crypts.

We are transfering our leading edge knowledge of intestinal mucus structure and function to the respiratory tract. Normal trachea seems to be cleared by mucus strands formed the tracheal glands, but these strands are trapped cystic fibrosis. We will also reveal how the attached mucus layer, as described by us in colon, could explain the mucus accumulation in chronic lung diseases.

The proposed project will substantially increase our basic understanding of molecular mechanisms behind several mucus related diseases and pave the way for new treatments.
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. In control patients ro ulcerative colitis patients in remission the same levels of such crosslinks were observed, but lower levels in patients with active ulcerative colitis.

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.

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.

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 still do not know the mechanism for this attachment and how the mucus bundles or mucus layer can be detached. 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.