1751-P: Human Islet Response to Selected Type 1 Diabetes Associated Bacteria

Abstract

Type 1 diabetes (T1D) is a chronic autoimmune disease that results from destruction of pancreatic β-cells. A role of gut bacteria in T1D has been suggested. However, the nature of that role remains largely unknown. Bacterial blooms are reported to be increased in gut prior to incidence of autoimmunity. One hypothesis is that these bacteria might elicit a response from human islets associated with immune cells recruitment. We have tested this hypothesis using 3 bacteria, namely Bacteroides dorei (BD), Ruminococcus gnavus (RG), both increased before T1D and Escherichia coli (EC), ubiquitous bacteria. Briefly, human islets were exposed to one of these bacteria for 6 and 24h. After that, RNA-Seq analysis was performed. The three bacteria altered expression of a number of genes at 6 and 24h. Additionally, each bacteria displayed a unique set of differentially expressed genes (DEG). Ingenuity pathway analysis of DEG revealed that top activated pathways and diseases included Th17 activation and inflammatory response respectively. A common set of DEG was also noted among different treatments at both 6 and 24h. The commonly upregulated genes were mostly cytokines (42.5%) including members of C-C and C-X-C motif chemokines followed by enzymes (13%) e.g., PTGS2 and SOD2, suggesting a selective effect of gut bacteria on islet immune and biosynthetic pathways. Immunoblotting for NAMPT, SOD2 and TRAF3IP2 revealed similar trends to those observed in RNA-Seq. From the list of tested cytokines, only CXCL8 was significantly increased, with its release being highest in EC. When injected into the pancreas through the bile ducts of normal mice, each bacteria elicited a unique pattern of islet inflammation. However, diabetes doesn’t not result from these injections, indicating other missing factors e.g., genetics or environment. Our data reveal several details about islet response to T1D associated bacteria. Understanding the changes induced by host-microbiome interaction could help for diabetes prevention by their reversal. Disclosure A.M. Abdellatif: None. N.E. Sarvetnick: None. Funding National Institute of Allergy and Infectious Diseases; The Leona M. and Harry B. Helmsley Charitable Trust; JDRF; J.W. Kieckhefer Foundation