The study, published in the latest online issue of Nature, shows that the transcription factor NF-kappaB is vital to maintaining the integrity of the gut lining. If this lining breaks down, bacteria can escape into the gut wall and the subsequent immune system reaction causes the severe inflammation observed in IBD sufferers. According to the authors, new treatments could be developed to target this mechanism and prevent gut inflammations. Inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis, impairs the lives of more than 4m people worldwide. Current therapies involve the administration of anti-inflammatory drugs, such as steroids, and immunosuppression drugs. The gut lining is formed from a thin continuous layer of epithelial cells that line the intestinal surface, creating a physical barrier that expresses antimicrobial peptides and separates gut bacteria from the underlying immune cells. If gut bacteria penetrate this layer, they can become harmful and cause disease, as well as instigating the immune responses that cause inflammation of the stomach. The researchers, led by Professor Manolis Pasparakis of the University of Cologne and Professor Markus Neurath of the University of Mainz, investigated the role that the NF-kappaB pro-inflammatory signalling regulator plays in the guts response to environmental stress. The researchers engineered mice to not express the NF-kappaB activating molecule or 'essential modulator' , NEMO (1kappaB kinase-gamma). The lack of NEMO in virtually all epithelial cells was confirmed by southern blot DNA analysis and immunostaining. Even at a young age, the mice showed runting, diarrhoea and rectal bleeding - indicating IBD. The mice also all developed chronic inflammation of the colon, which was very similar to colitis in humans. "A close look at the mice revealed that their gut epithelium was damaged," said Pasparakis. "NF-kappaB acts as a survival signal for cells. Without the molecule cells are much more likely to die and this is what happened in the intestines of our mice; individual epithelial cells died, disrupting the gut lining." The NF-kappaB signalling pathway has previously been shown to regulate antimicrobial peptide expression in colonic epithelium. Mice lacking NEMO were shown to only produce reduced levels of beta-defensin-3. Bacteria induce the formation of beta-defensin-3 in mouse colonic epithelial cells. Reduced levels of the human equivalent, beta-defensin-2, has been recently linked with a predisposition towards the development of colonic Crohn's disease in humans. The researchers also found that in two week old mice bred without NEMO, a number of pro-inflammatory genes were up-regulated - IL-1beta, IL-6, TNF and MCP-1 genes in the colon. The normally harmless bacteria can then penetrate the epithelium lining of the gut to reach the intestinal immune system, which is the largest in the body. The bacteria set off a strong immune response to fight the bacteria, secreting a cocktail of signals that cause the inflammation. "This is where the vicious cycle closes, inflammatory signals also reach the epithelial cells that due to the lack of NF-kappaB are very sensitive to them and die. The death of more epithelial cells creates bigger gaps in the gut lining so that more bacteria enter," said Neurath. "The result is a constant immune response leading to chronic inflammation as we know it from inflammatory bowel diseases in humans." According to the research, NEMO-deficient cells not only lack the ability to activate NF-kappaB but are also sensitive to apoptosis induced by immune response cytokines such as TNF. TNF-blockade has been used as an effective therapy for IBD. To test whether TNF signalling contributes to the development of colitis, the NEMO deficient mice were crossed onto a TNF receptor-1 (TNFR1)-deficient background. The resulting double NEMO/TNFR1-deficient mice did not show macroscopic or histological signs of colitis even after 10 weeks. TNF administration to the NEMO/TNFR1-deficient mice caused increased apoptosis of colon epithelial cells, compared with TNF deficient and wild-type mice. The authors believe that these results suggest a key mechanism by which TNF signalling induces colon inflammation in NEMO-deficient mice is by killing the NF-kappaB deficient epithelial cells resulting in the disruption of the epithelium. Because of the close similarities between the immune systems of mice and humans, the insights gained through studies using mouse models provide a better understanding of the mechanisms that cause human inflammatory bowel diseases and may pave the way for novel therapeutic approaches.