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Tales from the crypt organoid culture

Inflammatory bowel disease (IBD) affects 1 in 250 people in the UK. IBD, in the form of Crohn’s disease and ulcerative colitis, is a long term condition characterised by inflammation of the lining of the gastro-intestinal tract, but the exact triggers of this inflammation aren’t known.

The Institute of Food Research, strategically sponsored by the Biotechnology and Biological Sciences Research Council, has a programme of research investigating the lining of the gastrointestinal (GI)-tract to maintain health.

The gut lining is complex in structure, consisting of finger-like projections called villi, separated by pits known as crypts. At the base of each crypt are stem cells that give rise to a number of different types of cell line the GI tract, with specialised functions. For example, goblet cells secrete proteins called mucins that make a layer of mucus that coats the entire GI tract. These mucins are heavily decorated with sugars. The top layer of mucus in the colon provides an ideal environment for the trillions of bacteria that live in our gut and help us digest food and stay healthy. A mucus layer under this is firmer, and designed to prevent pathogenic and commensal bacteria invading our body. To further protect our body,   large populations of immune system cells are present in the tissue underlying the mucosal layer. γδ T lymphocyte cells form one of the first lines of defence of the immune system, but exactly how they function isn’t known. They have recently been implicated in protecting from bacteria invasion. Furthermore mice lacking these cells have been shown to be more prone to developing colitis.

OliviaKober

Olivia Kober

In a new study, published in the American Journal of Physiology-Gastrointestinal and Liver Physiology, Nathalie Juge and her PhD student Olivia Kober showed that γδ T cells play an important role in the maintaining the mucus layer and promoting goblet cell function.

To better understand these immune cells, the IFR researchers along with colleagues at the University of East Anglia have established a system to grow crypts outside the gut. The ability to grow and maintain these ‘organoid cultures’ gives the Norwich Research Park a significant advantage in its studies into gut health.

Small intestinal crypy organoid, image by Olivia Korber

Small intestinal crypt organoid, image by Olivia Kober

A lack of γδ T cells led to the reduction in the number of goblet cells. Using the organoid culture system, this could be partially reversed by adding a growth factor produced by γδ T cells. Goblet cell depletion is characteristic of ulcerative colitis, although it is not known whether it is a cause or a symptom of the condition.

Despite the depleted number of mucin-filled goblet cells, the mucus layer appears as thick as normal. However, there were distinct changes in the composition of the mucus layer in terms of mucin expression and glycosylation.

Changes to the composition of the mucus layer’s sugar profiles is likely to impact on the bacteria that colonise it, as these sugars  provide  bacteria with potential binding sites and nutrients. The researchers now want to characterise the changes in the gut microbiota associated a lack of γδ T cells. This may further add to these findings that the immune system cells play a role in establishing a healthy gut, and point to what goes wrong in the development of inflammatory bowel disease.

Reference: γδ T-cell-deficient mice show alterations in mucin expression, glycosylation and goblet cells but maintain an intact mucus layer, Kober O, et al, DOI: http://dx.doi.org/10.1152/ajpgi.00218.2013

Read more about this paper on the Gut Health and Food Safety programme website

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