Autoimmunity, the aberrant regulation of the immune system, affects an astounding 23.5 million Americans. Autoimmune disease such as Type 1 diabetes (T1D) and Inflammatory Bowel Diseases (IBD) are major causes of chronic illness and are expected to rise with increasing prevalence across all ethnic groups. Disruptions in gut microbial communities (dysbiosis) are highly associated with both T1D and IBD; however, the importance of gut microbes as regulators of disease pathophysiology has only recently been highlighted. The interleukin-10 deficient (IL10KO) mouse is a well-established model of IBD; however germ-free (GF) IL10KO mice never develop colonic inflammation. We made the novel discovery that GF IL10KO mice instead develop pancreatic infiltration that remarkably resembles clinical T1D insulitis. The IL10KO model is an exciting opportunity to investigate the role of gut microbes as regulators of immunopathology that mediate T1D and/or the complex interplay between host-microbial interactions and immunological regulation in disease. Determine whether GF IL10KO mice exhibit an increased risk for insulitis associated with Type 1 diabetes and identify the immune mediators in GF IL10KO compared to conventionally-raised counterparts ; [2] Determine the role of gut microbes and mucosal immune function in protection against insulitis in IL10 KO mice. A multidisciplinary approach using immunological, histological, and molecular strategies will identify (1) the window of time insulitis is initiated, (2) specific immune cell types involved in immunopathology, as well as potential biomarkers of disease, and (3) the impact of insulitis on islet architecture and host blood glucose homeostasis. In vivo approaches will test the IBD phenotypes, demonstrating Two central aims are proposed: [1] transferability of autoimmune-mediated pathophysiology via adoptive transfer models and whether introduction of specific microbes at an early window of life protects against insulitis. This model has the potential to open many avenues to discovery in the fields of metabolism, autoimmunity, genetics, and microbiome; and warrants further characterization to investigate mechanisms of disease. The proposed research will provide fundamental information about autoimmune initiation and progression in the pancreas and the premise for preventative probiotic therapies to decrease the incidence of T1D.

Public Health Relevance

Type 1 diabetes (T1D) and Inflammatory Bowel Diseases (IBD) are major causes of chronic illness and are expected to rise with increasing prevalence across all ethnic groups. The present application will utilize an IBD mouse model, the interleukin-10 knockout (IL10KO), with novel applications in T1D under germ-free conditions, to investigate the role of gut microbiota as modifiers of host autoimmune responses and glucose homeostasis. This work will contribute towards a better understanding of T1D pathogenesis and probiotic therapies for disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZDK1)
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Rivers, Robert C
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University of Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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