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 #
3U01AI095473-03S1
Application #
8912143
Study Section
Special Emphasis Panel (ZAI1-WFD-I (M2))
Program Officer
Rothermel, Annette L
Project Start
2011-07-22
Project End
2015-06-30
Budget Start
2014-08-14
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
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
Pelaseyed, Thaher; Bergström, Joakim H; Gustafsson, Jenny K et al. (2014) The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system. Immunol Rev 260:8-20
Johansson, Malin E V; Hansson, Gunnar C (2014) Is the intestinal goblet cell a major immune cell? Cell Host Microbe 15:251-2
Schütte, André; Ermund, Anna; Becker-Pauly, Christoph et al. (2014) Microbial-induced meprin ? cleavage in MUC2 mucin and a functional CFTR channel are required to release anchored small intestinal mucus. Proc Natl Acad Sci U S A 111:12396-401
Johansson, Malin E V (2014) Mucus layers in inflammatory bowel disease. Inflamm Bowel Dis 20:2124-31
Xiao, F; Yu, Q; Li, J et al. (2014) Slc26a3 deficiency is associated with loss of colonic HCO3 (-) secretion, absence of a firm mucus layer and barrier impairment in mice. Acta Physiol (Oxf) 211:161-75
Nilsson, Harriet E; Ambort, Daniel; Bäckström, Malin et al. (2014) Intestinal MUC2 mucin supramolecular topology by packing and release resting on D3 domain assembly. J Mol Biol 426:2567-79
Bergström, Joakim H; Berg, Katarina A; Rodríguez-Piñeiro, Ana M et al. (2014) AGR2, an endoplasmic reticulum protein, is secreted into the gastrointestinal mucus. PLoS One 9:e104186
Johansson, Malin E V; Gustafsson, Jenny K; Holmen-Larsson, Jessica et al. (2014) Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis. Gut 63:281-91
Wenzel, Ulf A; Magnusson, Maria K; Rydström, Anna et al. (2014) Spontaneous colitis in Muc2-deficient mice reflects clinical and cellular features of active ulcerative colitis. PLoS One 9:e100217
Holmén Larsson, Jessica M; Thomsson, Kristina A; Rodríguez-Piñeiro, Ana M et al. (2013) Studies of mucus in mouse stomach, small intestine, and colon. III. Gastrointestinal Muc5ac and Muc2 mucin O-glycan patterns reveal a regiospecific distribution. Am J Physiol Gastrointest Liver Physiol 305:G357-63

Showing the most recent 10 out of 18 publications