Programmed cell death in Crohn’s disease

FAU scientists discover switch which drives intestinal cells to commit suicide

More than 300,000 people in Germany suffer from chronic inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis. Their lives can be affected by intense recurrent abdominal pain, diarrhoea and cramps – as a result of the illness there is also a higher risk of developing bowel cancer. As the cause of the disease is still largely unknown, despite a global research effort, scientists at Medical Clinic 1 of the university hospital and their cooperation partners have been exploring the molecular mechanisms that lead to such intestinal diseases. Over the course of their studies they noted that the absence of a certain enzyme intensifies cell death in the intestine. This excessive cell death results in gaps in the epithelial layer – a cell layer which should protect the intestinal wall against the penetration of harmful bacteria. This, in turn, leads to an inflammation of the intestinal mucosa. The results were published by the research team lead by Erlangen researchers Claudia Günther and Prof. Dr. Christoph Becker on 15 September 2011 in the renowned specialist publication, Nature.

“The focus of our work was the caspase 8 enzyme,” explained Christoph Becker, who holds a professorship in molecular gastroenterology at FAU and leads the research project. “We examined the role this enzyme plays in the development of inflammatory bowel diseases both in the experimental model and in affected patients. Caspase 8 is an extremely important enzyme for our bodies. It regulates apoptosis, a sort of “suicide programme”, which governs the number of cells in the intestine whilst ensuring that aging cells die without harming the surrounding tissue,” continues Becker.

“If caspase 8 levels are insufficient in the epithelial cells or the function of the protein is disturbed, this may result in the cells in the intestine living longer – this was our original theory,” says biologist Claudia Günther, who is writing her doctoral thesis at Medical Clinic 1. However, to the great surprise of the researchers, this theory proved to be incorrect. On the contrary: epithelial cells lacking caspase 8 were especially susceptible to cell death. Particularly affected were the Paneth cells, specialised epithelial cells, which produce substances with which bacteria can be stopped at a distance or even killed. “If these cells are absent, bacteria can penetrate the intestinal wall and trigger inflammatory reactions such as those in patients with chronic inflammatory bowel diseases,” explains Günther. The dying intestinal cells showed completely different properties to cells which die due to apoptosis. “The cells observed in our experiments died via necroptosis, a recently discovered form of cell death which we have now been able to verify for the first time in the intestines of patients with chronic inflammatory bowel disease,” says Prof. Becker. “The discovery that Paneth cells in the intestine die due to necroptosis is an important step to understanding the development of chronic inflammatory bowel disease,” says Becker.

On the basis of their research results, Prof. Becker and his team are now hoping to develop new treatment methods for the targeted manipulation of such cellular processes in order to better treat patients with chronic inflammatory bowel disease.

Paper:

Claudia Günther, Eva Martini, Nadine Wittkopf, Kerstin Amann, Benno Weigmann, Helmut Neumann, Maximilian Waldner, Stephen M. Hedrick, Stefan Tenzer, Markus F. Neurath, Christoph Becker: Caspase 8 regulates TNF-alpha induced epithelial necroptosis and terminal ileitis.
Nature, DOI: 10.1038/nature10400.

Further information for the media:

uni | media service | research No. 44/2011 on 15.9.2011