Researchers describe the cause of a defective intestinal barrier
In Germany alone there are around 300,000 patients who suffer from chronic inflammatory bowel disease. The quality of life of these often relatively young patients is reduced due to symptoms such as diarrhoea and severe stomach pains. Defects in the barrier function of the intestinal wall are considered one of the key elements that cause the disease. A European team of researchers led by the Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology at Universitätsklinikum Erlangen has now identified a new mechanism in the affected cells of the intestinal wall that explains the defects in the intestinal barrier. Their findings have recently been published in the Journal of Clinical Investigation.
Intestinal epithelial cells, the cells that cover the inside of the intestinal wall, form the first layer of the intestinal wall and prevent bacteria and other foreign substances in the intestine from entering the body. Problems with this barrier function can lead to inflammation. To ensure the intestinal barrier can maintain its protective function over time, the layer of intestinal epithelial cells continuously renews itself. The old epithelial cells are replaced and removed in a controlled process via bowel movements. Erlangen-based researchers Dr. Rocío López-Posadas, Dr. Imke Atreya and Prof. Dr. Markus Neurath – who are members of the Clinical Research Unit CEDER, funded by the German Research Foundation (DFG) – have now shown that the activated protein Rho-A and the signals that it emits are key to the stability of the intestinal epithelial cells.
The process of prenylation, which takes place inside the cells and causes targeted changes to the properties of proteins, is responsible for activating the Rho-A protein. The protein is attached to an isoprenoid rest, which enables Rho-A to enter the areas of the cells where it can activate the protein. The new findings demonstrate for the first time that the presence of Rho-A in intestinal epithelial cells and, in particular, Rho-A prenylation are crucial for stable epithelial cell formation in the intestine. In laboratory experiments, a lack of Rho-A or a deliberate inhibition of prenylation in the intestinal epithelium were shown to be accompanied by increased permeability of the intestinal barrier and thereby cause chronic inflammation of the bowel. Interestingly, the researchers were also able to demonstrate that the epithelial cells of patients who suffer from chronic inflammatory bowel disease are characterised by impaired prenylation and defective Rho-A signalling.
The question that now needs to be addressed is whether these findings can be used to develop new strategies to improve treatment for chronic inflammatory bowel disease.
The research was funded in part by the European Union (People Programme Marie Curie Actions, Grant 302170), the Interdisciplinary Centre for Clinical Research (IZKF) at Friedrich-Alexander-Universität Erlangen-Nürnberg, and the German Research Foundation (Clinical Research Unit KFO257 CEDER).
Original publication: Rocío López-Posadas, Christoph Becker, Claudia Günther, Stefan Tenzer, Kerstin Amann, Ulrike Billmeier, Raja Atreya, Gionata Fiorino, Stefania Vetrano, Silvio Danese, Arif B. Ekici, Stefan Wirtz, Veronika Thonn, Alastair J.M. Watson, Cord Brakebusch, Martin Bergö, Markus F. Neurath, and Imke Atreya: Rho-A prenylation and signaling link epithelial homeostasis to intestinal inflammation. Journal of Clinical Investigation, 11 January 2016.
Dr. Imke Atreya
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