Tanner Walker

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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2. DiMeglio LA, Evans-Molina C, Oram RA. Type 1 diabetes. Lancet. 2018;391(10138):2449-2462. doi:10.1016/S0140-6736(18)31320-5
3. Zhou H, Sun L, Zhang S, Zhao X, Gang X, Wang G. Evaluating the Causal Role of Gut Microbiota in Type 1 Diabetes and Its Possible Pathogenic Mechanisms. Front Endocrinol (Lausanne). 2020;11:125. Published 2020 Mar 24. doi:10.3389/fendo.2020.00125
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6. Joshi, S., 2021. Who Will Win The Regenerative Medicine For Diabetes Race?. [online] Cellandgene.com. Available at: <https://www.cellandgene.com/doc/who-will-win-the-regenerative-medicine-for-diabetes-race-0001> [Accessed 1 May 2021].
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8. Hayes TON, Tara O’Neill HayesDirector of Human Welfare PolicyTara O’Neill Hayes is the Director of Human Welfare Policy at the American Action Forum., Tracker: Paycheck Protection Program LoansThomas Wade, et al. Insulin Cost and Pricing Trends. AAF. https://www.americanactionforum.org/research/insulin-cost-and-pricing-trends/. Published April 2, 2020. Accessed May 13, 2021.