New Clues to the Causes of Gut Inflammation

9 April 2019

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3D Intestinal Organoids

Researchers at our partners the Quadram and Earlham Institutes have discovered new details about the consequences of an imparied key cellular process, called Autophagy, in gut cells.

Paneth cells are found at the bottom of crypts in the lining of the gut. They help defend against pathogenic microbes, as well as protecting the integrity of the lining of the gut. Carrying out these functions relies on them being able to secrete antimicrobial factors and other molecules that ensure a balanced gut microbiome and functioning stem cells that regenerate the gut lining. Given their vital role, it’s not surprising that abnormalities in Paneth cells are associated with gut conditions such as Crohn’s disease.

Similar symptoms are seen when a cellular process called autophagy is dysfunctional. Cells use autophagy to remove defective and potentially harmful proteins within themselves by surrounding the offending object in a membrane “bag” that is then tagged for destruction. Paneth cells also use this mechanism to bag up antimicrobial molecules for export from the cell in response to attack by pathogenic microbes.

This new study aimed to fill a gap in our understanding of the effects of autophagy impairment on Paneth cells, and was led by Dr Tamas Korcsmaros, a research fellow at the Quadram Institute and the Earlham Institute, which are strategically funded by the Biotechnology and Biological Sciences Research Council.

Tamas assembled an interdisciplinary team from across the Norwich Research Park to explore the molecular changes seen when autophagy in Paneth cells is blocked, and also what wider effects these changes might have. This involved integrating a number of different data sets and using network analysis and computational biology to interpret how these changes impact on different functions within cells.

Using cells from mice, the researchers grew organoid cultures in the lab. These are three dimensional collections of cells that grow and organise themselves into crypts, as they would in the lining of the gut. In some of these, a central gene needed for autophagy was knocked out. By comparison to organoids with the fully functioning gene, the team could then, for the first time, work out the molecular mechanisms and cellular processes affected by impaired autophagy in Paneth cells.

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