HE-4 might help design better aspartic protease inhibitors in the future. Finally, we can say this is the first report to establish that HE-4 is a highly stable protein which shows cross-class protease inhibition. A broad spectrum protease inhibition points towards a role in innate immunity CCT 018159 conferring protection against microbial virulence factor of proteolytic nature. Seminal fluid HE-4 might be different from HE-4 found in other Cilastatin sodium tissues like ovarian cancer cells because of alternative splicing or different glycosylation. Its ability to trimerize might not be present in all the isoforms. Increased translocation of bacteria has been associated with increased risk of developing IBD which is thought to be due primarily to dysregulation of the epithelial barrier. In IBD patients many pro-inflammatory cytokines, such as tumor necrosis factor, interferon gamma, interleukin -6, IL-17 and members of the IL-12 family, are produced in excess in response to the translocated intestinal microbiota and these responses have been shown to be instrumental to the progression of disease. Confounding this exaggerated inflammatory response to bacteria in the submucosal compartment is the inhibition of epithelial repair by TNF-induced upregulation of apoptosis. Here, we discuss and provide data showing how TNF induced inflammation and microbial alterations contribute to the progression of IBD in a mouse model. The human gut is the largest reservoir of microbes in the body. Many studies have indicated that the gut microbiota plays an active and integral role in maintaining host health. The Human Microbiome Project has allowed us to obtain an overview of the healthy gut microbial community that is comprised of microbes belonging to a limited number of phyla but includes hundreds to thousands of species. Perturbation of the gut microbiota contributes to a myriad of disease conditions, such as obesity, diabetes, metabolic syndrome, inflammation, as well as certain cancers. In IBD, dysbiosis in the gut microbiota may contribute to the development of CD in susceptible individuals emerged. IBD-related microbial dysbiosis is characterized by a decrease in overall alpha diversity, decrease in the abundances of members of the phyla Firmicutes and Bacteroidetes, and increases in Gammaproteobacteria. The only bacterial genus that is significantly higher in adult and pediatric IBD patients is the Escherichia-Shigella group. In humans, studies are confounded by environmental and behavioral variables, thus model animal studies are best suited to examine the interactions between the gut microbiota and disease in order to elucidate the potential role these microbes play in IBD pathogenesis. TNF is a pleiotropic cytokine, considered to be a master regulator of cytokine production. This cytokine is elevated in both the serum and mucosa of IBD patients. The current, and arguably one of the most effective treatments for CD, is the use of TNF functional inhibitor drugs ; however, this treatment can cause adverse reactions, has a relatively large percentage of incomplete or non-responders and cannot be used in areas where certain infections are common.