How the colon protects itself with a mucus layer

Professor Gunnar C. Hansson and his team have discovered an inner mucus layer in the colon that acts as a protective shield against all the commensal bacteria, a discovery that has implications for colon inflammation, as in the disease ulcerative colitis.

The colon, the last part of the digestive system, harbours a large amount of normal bacteria, which are necessary for a healthy life and provide us with vitamin K and extract energy from otherwise indigestible carbohydrates. The number of bacteria outnumbers the cells of the body by at least a factor of ten and is usually estimated to weigh about a kilogram. How the colon is able to cope with all these bacteria has not been understood until recently, as a majority of these are not possible to cultivate in the laboratory. Now, a research group at the Sahlgrenska Academy at the University of Gothenburg have discovered an inner layer of mucus in the colon, devoid of bacteria, with the bacteria only living in an outer mucus layer.

The discovery of this inner mucus layer was made by Malin Johansson of the Gothenburg group. The study was published in Proceedings of the National Academy of Sciences USA in a collaborative project with Uppsala University and Albert Einstein, New York. The Uppsala team had found that there were two layers of mucus in the colon that together created a millimetre-thick mucus layer. "At that time we believed that this must be important for protecting the large intestine, but we could not guess that the inner layer was such a good barrier," remarked Professor Holm.

Both mucus layers were shown to have an identical composition - where an enormous carbohydrate-rich protein called a mucin is the main constituent. This large protein - MUC2 - has more than five-thousand amino acids, and it's size is due to it being wrapped with five times its weight by carbohydrates. The Gothenburg group had dedicated twenty years of research on the study of the function of the MUC2 mucin and during this process they had made some breakthroughs.

The MUC2 mucin (and other components) is formed in the goblet cells where the MUC2 mucin is assembled in a complex two-step process into enormous net-like polymers that probably are among the largest proteins in the body. Stored in cells in a very condensed way, these complexes have to expand in volume at least 100-times to make the inner mucus layer when released. The released MUC2 mucin self-organises into layers, but also remains attached to the epithelia in an unknown way.

The inner mucus is continually re-made, oozing from the colon wall and spreading outward, then released from its anchor after a tenth of a millimetre and expanding to at least four times the original size. The volume expansion of the now-formed outer mucus layer allows the bacteria to penetrate and have their habitat here. Whilst the bacteria use the MUC2 mucin as an attachment site, they can chow on the carbohydrates of the mucin. This is a real symbiotic relation between us and our bacteria. Later, the bacteria and mucus are transported away together with other intestinal non-digestible content like a mucus conveyer.

Crucial, the inner mucus layer is a barrier for the bacteria and there is a sharp borderline between the two mucus layers, indicating that the two layers have different functions.

As the PhD student at the time, Malin Johansson puts it: "When I discovered where the intestinal bacteria were located, it was observed that the inner mucus layer was devoid of bacteria and that all bacteria were in the outer layer. It was really fascinating to find that inner mucus layer lacked bacteria and that it was such a sharp border between the inner and outer mucus layers." The colon's protective system builds up the MUC2 mucin into a dense network that creates a physical barrier that the bacteria cannot penetrate: thus, it never has the opportunity to reach and affect the intestinal cells.

The research group also looked into the effects upon mice that lacked the MUC2 mucin. Here the bacteria were in direct contact with the intestinal cells, and even worse the bacteria penetrated down into the crypts and also managed to get into the epithelial cells, which caused considerable damage to the health of the animals.

"These animals got a severe inflammation and later still - because of the longstanding inflammation they could develop colon cancer, a scenario that is similar to the human disease ulcerative colitis. Ulcerative colitis is a serious human disease that affects a couple of people per 1000, but we still do not understand the cause of this disease.

We believe that the solution to this puzzle is to be found in defects in the inner mucus layer that protects the large intestine," said Professor Gunnar C. Hansson. "A large number of reasons for how defects in the inner mucus layer can be created are easily envisaged."

Hopefully, the study can commence understanding and development of treatments for ulcerative colitis.

For more information on the research, contact Gunnar Hansson at gunnar.hansson@medkem.gu.se

Published: Thursday, 4th March 2010 by Tom Freeman

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