Crohn's disease (CD) is a debilitating condition of unknown etiology that affects up to 1 million individuals in North America. An accepted hypothesis suggests that CD may represent a dysregulated immune response to antigens derived from the commensal flora in a genetically predisposed host. Our recent studies have shown that SAMP1/YitFc (SAMP) mice are able to develop an attenuated form of ileitis and spontaneous colitis when raised under germ-free conditions. This suggests that mechanisms independent of the intestinal flora may also be involved in the pathogenesis of CD. The present renewal application will therefore focus on the mechanisms of chronic intestinal inflammation in SAMP mice lacking colonization with commensal flora. The central hypothesis of this proposal is that normal intestinal bacteria are important, but not essential for the initiation and perpetuation of immune responses in the gut of SAMP mice, and that this model provides a unique opportunity to characterize bacterial-independent mechanisms of chronic intestinal inflammation. We have developed three specific aims designed to explore this hypothesis: 1. Characterize the effect of dietary antigens on the development of disease in SAMP mice. We will define and manipulate the antigenic composition of the diet of these mice through comparison of regular diet with elemental and ultra-filtered diets, to determine which elements are important in the development and severity of disease in germ-free (GF) mice. 2. Determine the possible role of autoimmunity in the pathogenesis of gut inflammation in SAMP mice. We will perform a series of experiments to test the presence of auto- antibodies and intestinal self-antigens in the intestinal mucosa of SAMP mice, as well as performing passive transfer experiments to prove a direct role of auto-antibodies in pathogenicity. These studies will help us to understand how auto-antigens may induce chronic gut inflammation in this model. 3. Determine the role of the regulatory component of the immune system in SAMP mice. We will perform a series of adoptive transfer experiments and mono-association studies with specific bacterial strains, to precisely define the components of the commensal flora that are important in the development of T regs. The overall objective in this research proposal is to further understand the basic mechanism(s) underlying chronic intestinal inflammation in CD, with the ultimate goal of beginning to develop a cure for this devastating disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-DIG-C (03))
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Hamilton, Frank A
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Case Western Reserve University
Internal Medicine/Medicine
Schools of Medicine
United States
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Cominelli, Fabio; Arseneau, Kristen O; Rodriguez-Palacios, Alexander et al. (2017) Uncovering Pathogenic Mechanisms of Inflammatory Bowel Disease Using Mouse Models of Crohn's Disease-Like Ileitis: What is the Right Model? Cell Mol Gastroenterol Hepatol 4:19-32
Corridoni, D; Rodriguez-Palacios, A; Di Stefano, G et al. (2017) Genetic deletion of the bacterial sensor NOD2 improves murine Crohn's disease-like ileitis independent of functional dysbiosis. Mucosal Immunol 10:971-982
Bamias, Giorgos; Pizarro, Theresa T; Cominelli, Fabio (2016) Pathway-based approaches to the treatment of inflammatory bowel disease. Transl Res 167:104-15
De Salvo, Carlo; Wang, Xiao-Ming; Pastorelli, Luca et al. (2016) IL-33 Drives Eosinophil Infiltration and Pathogenic Type 2 Helper T-Cell Immune Responses Leading to Chronic Experimental Ileitis. Am J Pathol 186:885-98
Grivennikov, Sergei I; Cominelli, Fabio (2016) Colitis-Associated and Sporadic Colon Cancers: Different Diseases, Different Mutations? Gastroenterology 150:808-10
Basson, Abigail; Trotter, Ashley; Rodriguez-Palacios, Alex et al. (2016) Mucosal Interactions between Genetics, Diet, and Microbiome in Inflammatory Bowel Disease. Front Immunol 7:290
Rodriguez-Palacios, Alexander; Aladyshkina, Natalia; Retuerto, Mauricio et al. (2016) Clinical Effects of Gamma-Radiation-Resistant Aspergillus sydowii on Germ-Free Mice Immunologically Prone to Inflammatory Bowel Disease. J Pathog 2016:5748745
Jia, Li-Guo; Bamias, Giorgos; Arseneau, Kristen O et al. (2016) A Novel Role for TL1A/DR3 in Protection against Intestinal Injury and Infection. J Immunol 197:377-86
Di Martino, Luca; Dave, Maneesh; Menghini, Paola et al. (2016) Protective Role for TWEAK/Fn14 in Regulating Acute Intestinal Inflammation and Colitis-Associated Tumorigenesis. Cancer Res 76:6533-6542
Xu, Rong; Wang, QuanQiu (2016) Towards understanding brain-gut-microbiome connections in Alzheimer's disease. BMC Syst Biol 10 Suppl 3:63

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