The mucus covering our mucosal surfaces is an intimate part of the innate immune system and the first line of defense against microbial challenges. This is especially prominent in the lower parts of the intestine where we have to protect ourselves at the same time as we live in a symbiotic relation without trigger an overt immune response. In a trend-setting publication (PNAS, 2008) we could shown that colon has a double- layered mucus layer built around the MUC2 mucin. The inner of these act as a barrier and does not allow bacteria to penetrate. With an absence of MUC2 or defects in the mucus, bacteria reach the epithelial cells, penetrate into the crypts, and into the epithelial cells. In experimental colitis the bacteria can penetrate this inner dense mucus layer further proving that this is the key to an understanding of intestinal inflammation and ulcerative colitis. We will now study how the mucus layers are formed and built by the use of biochemical methods, especially mass spectrometry, and the use of various types of gene knock-out animals that are colonized with bacteria or germ-free. By studies on the growth of the mucus layers from biopsies we will characterize the alterations causing ulcerative colitis. The mucus properties will be manipulated by recombinant mucus proteins and pharmacological agents. Expected results are novel ways to improve the protection of colon and by this novel principle for treatment of the disease ulcerative colitis.
Aim 1. To obtain a functional understanding of how the mucus and its main component, the MUC2 mucin, protect the mucosal surfaces of the colon and small intestine. Secretion, formation and components of the loose and firm colonic mucus in the large intestine and its transition This includes an understanding of biosynthesis, 0-glycosylation, unpacking/secretion, volume expansion, attachment to epithelia, and regulation by immune system.
Aim 2. To unravel the role of the MUC2 mucin and its glycans in the selection of our colonic commensal bacterial flora and effects of bacteria on the inner mucus layer.
Aim 3. To unravel the role of the inner colonic mucus layer in the disease Ulcerative Colitis (UC).

Public Health Relevance

Ulcerative colitis is a relatively common disease that causes personal suffering as well as high costs for the health care system. Our discovery of an inner mucus layer in colon that separates the large amount of bacteria in the colon from the epithelial cells has provided a new model for the initiation of this disease as we know that defects in this barrier and epithelial contact with bacteria triggers inflammation as observed in this disease

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI095473-02
Application #
8304120
Study Section
Special Emphasis Panel (ZAI1-WFD-I (M2))
Program Officer
Rothermel, Annette L
Project Start
2011-07-22
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$222,264
Indirect Cost
$16,464
Name
Goteborg University
Department
Type
DUNS #
350582359
City
Gothenburg
State
Country
Sweden
Zip Code
SE-40-530
Lang, Tiange; Klasson, Sofia; Larsson, Erik et al. (2016) Searching the Evolutionary Origin of Epithelial Mucus Protein Components-Mucins and FCGBP. Mol Biol Evol 33:1921-36
Bergstrom, K; Fu, J; Johansson, M E V et al. (2016) Core 1- and 3-derived O-glycans collectively maintain the colonic mucus barrier and protect against spontaneous colitis in mice. Mucosal Immunol :
Recktenwald, Christian V; Hansson, Gunnar C (2016) The Reduction-insensitive Bonds of the MUC2 Mucin Are Isopeptide Bonds. J Biol Chem 291:13580-90
Bergström, Joakim H; Birchenough, George M H; Katona, Gergely et al. (2016) Gram-positive bacteria are held at a distance in the colon mucus by the lectin-like protein ZG16. Proc Natl Acad Sci U S A 113:13833-13838
Birchenough, George M H; Nyström, Elisabeth E L; Johansson, Malin E V et al. (2016) A sentinel goblet cell guards the colonic crypt by triggering Nlrp6-dependent Muc2 secretion. Science 352:1535-42
Arike, Liisa; Hansson, Gunnar C (2016) The Densely O-Glycosylated MUC2 Mucin Protects the Intestine and Provides Food for the Commensal Bacteria. J Mol Biol 428:3221-9
Magnusson, M K; Brynjólfsson, S F; Dige, A et al. (2016) Macrophage and dendritic cell subsets in IBD: ALDH+ cells are reduced in colon tissue of patients with ulcerative colitis regardless of inflammation. Mucosal Immunol 9:171-82
Gustafsson, Jenny K; Lindén, Sara K; Alwan, Ala H et al. (2015) Carbachol-induced colonic mucus formation requires transport via NKCC1, K⁺ channels and CFTR. Pflugers Arch 467:1403-15
Birchenough, G M H; Johansson, M E V; Gustafsson, J K et al. (2015) New developments in goblet cell mucus secretion and function. Mucosal Immunol 8:712-9
Ermund, Anna; Meiss, Lauren N; Scholte, Bob J et al. (2015) Hypertonic saline releases the attached small intestinal cystic fibrosis mucus. Clin Exp Pharmacol Physiol 42:69-75

Showing the most recent 10 out of 56 publications