Gut Dysbiosis in Type 1 Diabetes: Islet Cell Cytokine Response to Co-Culture with Bacteroides Dorei
Introduction. Type 1 diabetes (T1D) is a chronic autoimmune disease, affecting 1.6 million Americans, that destroys β cells in the pancreas resulting in chronic hyperglycemia if left untreated with daily exogenous insulin 1 – 4. With 64,000 Americans being newly diagnosed each year, a juvenile onset, and a clearly increasing healthcare cost to insulin, many have investigated potential cures to T1D outside of typical exogenous insulin therapy 4,6,7,8. The leaky gut hypothesis, the theory that bacteria in the microbiome influence and trigger onset of T1D through a permeable gut epithelium, has been revisited with renewed interest due to the Dias et al work – demonstrating an upregulation in Bacteroides dorei months before seroconversion in high-risk Finnish neonates 5. Dias et al and others theorized that the reason for bacteria upregulation was tied to a specific gene or cytokine. This led Sarvetnick et al to co-culture islets with previously implicated bacteria in the pathogenesis of T1D, searching for a potentially causative agent 1. Methods. Islets were co-cultured with either R. gnavus, E. coli, B. dorei, or IL-1β. Their supernatants were collected at 6 and 24 hours post co-culture. These supernatant samples were tested using both RNA Sequencing and cytokine elisa enzyme linked immunosorbent assays (ELISAs) 1. Results. Islets co-cultured with bacteria significantly decreased in viability by ~10% after 6 hours. There was no significant difference between the viability of islets at 6 and 24 hours. The genes identified by RNA sequencing to be differentially expressed in islets exposed to B. dorei included: ADM2, ASNS, and CHAC1 1. These genes are known to alter insulin sensitivity, islet cell metabolism, and glutathione metabolism previously linked to diabetes respectively 1. Notably, the ELISA data demonstrated an upregulation in the amount of IL-8 cytokines in the 6 hour and 24 hour samples for all bacterial conditions. For the two previously diabetes-linked bacteria (B. dorei and R. gnavus), the IL-8 cytokine was the only cytokine to show a significant and specific response. However, all cytokines reported were upregulated in the E. coli condition 1. Conclusions. While both R. gnavus and B. dorei demonstrated a statistically significant specific and time-dependent upregulation in IL-8, more data is needed on different bacteria to draw correlative or causative conclusions 1. Even still, the implications of this research demonstrates a possible clinical need to downregulate certain bacteria in high-risk neonatal populations for delaying or preventing seroconversion 1,5.
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