CDHR5 in intestinal barrier function and inflammation

Inflammatory bowel diseases such as Crohn`s disease or ulcerative colitis are on the advance worldwide and represent a risk factor for the development of colon cancer. According to the current state of knowledge, inflammatory bowel diseases arise from a co mplex interplay of genetic and environmental factors, a dysregulated immune response and pathogenic changes in the intestinal flora. However, it is currently unclear which factors are the cause or consequence of the disease. It has long been assumed that t he intestinal barrier (impermeability of the intestinal epithelium to germs) plays an important role in the prevention of inflammatory bowel diseases. An intact intestinal barrier depends on several factors. The access of germs to the intestinal epithelial cells is usually restricted by the production of mucus. Cell-cell connections prevent germs from being squeezed between two epithelial cells. Microvilli (superficial protuberances of the epithelial cell membrane) form a kind of brush border, which is supposed to prevent the penetration of germs into the epithelial cells. We suspect that changes in the brush border under stressful conditions can trigger intestinal inflammation. This hypothesis will be investigated in a mouse model without an intact brush border. If our hypothesis is confirmed, we would have discovered a causal mechanism for the development of intestinal inflammation.

In Austria, approximately 0.5% of the population suffers from chronic inflammatory bowel disease, and the incidence is increasing. The disease is associated with abdominal pain, nausea, and diarrhea, and those affected often have severe limitations in their daily lives. In severe cases, a part of the intestine even has to be surgically removed. The causes of chronic inflammatory bowel disease are still largely unknown, despite massive research efforts. A possible trigger has now been discovered as part of the FWF project P35069. The research group led by Robert Eferl from the Center for Cancer Research at the Medical University of Vienna has discovered that a specific protein called CDHR5 is reduced in chronic inflammatory bowel disease. This protein is located on the surface of intestinal epithelial cells in the so-called brush border. The brush border is a collection of cell protrusions, the microvilli, which massively enlarge the surface area of the intestine. A reduction in CDHR5 leads to a disorganization of the microvilli, thus facilitating the penetration of gut bacteria into the intestinal epithelium. In combination with an unhealthy diet, which impairs another barrier function of the intestine, namely the formation of a protective mucous layer, a disorganized brush border could lead to chronic inflammatory bowel disease. Indeed, the researchers were able to show that deletion of the CDHR5 protein in mice led to disorganization of the brush border and promotes the development of inflammatory bowel disease. This discovery offers a potential new starting point for the development of a therapy.