Sunday, May 11, 2025
5/11/2025
Reducing innate inflammation in new onset T1D with Lactobacillus plantarum - PROJECT SUMMARY Type 1 diabetes (T1D) arises through T-cell mediated killing of the pancreatic beta-cells. It has a strong genetic component, but environmental factors likely influence disease triggering as well as the post-onset disease course. In human T1D families, we have identified an elevated inflammatory state that is consistent with exposure to microbial antigens. In healthy siblings of probands, this familial innate inflammation is supplanted by an age-dependent regulatory state that includes temporal increases in peripheral activated regulatory T-cell frequencies. We have identified a similar inflammatory state in the BioBreeding DR rat model of T1D. DR rats are not spontaneously diabetic, however T1D can be triggered in young animals by viral infection. Importantly, the innate inflammatory state in DR rats is temporally supplanted by an IL-10/TGF-β- mediated regulatory state that coincides with the inability of virus to induce T1D in older animals. In line with studies that implicate an altered gastrointestinal microbiota in T1D pathogenesis, modulation of the microbiota in healthy siblings of T1D probands or DR rats partially normalizes the underlying inflammatory state. In BioBreeding rats, such treatments prevent development of T1D. Our studies suggest that T1D progression is promoted when the genetically controlled but environmentally influenced familial innate state is augmented by additional inflammatory signals prior to the establishment of robust counter-regulatory mechanisms. Our studies have also focused on the persistence of insulin secretion after T1D onset, which is clinically significant as even modest residual beta cell function is associated with reduced risk of complications. These studies have utilized a plasma-based transcriptional bioassay that quantitatively captures inflammatory: regulatory balance. Importantly, new onset T1D patients with short post-onset partial remissions, exhibit plasma based signatures with predictively higher inflammatory bias, as well as reduced peripheral regulatory T-cell abundances. In genetically susceptible healthy subjects and T1D patients, we hypothesize that levels of immune activity are in part governed by composition of the microbiota and systemic microbial antigen exposure. This in turn influences the rate of T1D progression as measured by duration of the post- onset partial remission. With our large patient population and expertise, we are well-positioned to test the hypothesis that the inflammatory state associated with T1D and T1D susceptibility can be partially normalized through probiotic supplementation. We propose the following specific aims. 1. Determine whether Lactobacillus plantarum 299v supplement reduces systemic inflammation and prolongs residual β-cell function in new onset T1D. 2. Define how L. plantarum 299v supplementation alters immune activity in new onset T1D.
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