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Grant Abstract: Contribution of X-linked TLR-Gut microbiota interaction to Juvenile Onset of Systemic Autoimmunity

Grant Number: 5R21AI136339-02
PI Name: Vasu
Project Title: Contribution of X-linked TLR-Gut microbiota interaction to Juvenile Onset of Systemic Autoimmunity

Abstract: Autoimmunity in Systemic Lupus Erythematosus (SLE) is believed to be the result of a complex interplay between varying degrees of genetic susceptibility and environmental factors, which include pathogens and commensal gut microbes, dietary components and toxic substances. Recent studies, including ours, have shown much interest in understanding the impact of interaction between environmental factors including gut microbes and dietary factors on autoimmunity. However, the potential contribution of inflammation initiated in the gut mucosa to systemic autoimmunity in lupus and the root cause of gut inflammation in lupus-susceptible background are largely unknown. Further, the potential of a scientific evidence-based dietary manipulation to establish and maintain a healthy gut microbiota for preventing/suppressing autoimmunity has yet to be realized. Using a spontaneous pre-clinical model of SLE which presents slow progressing disease and strong gender bias as seen in humans, we found that pro-inflammatory events are initiated in the gut mucosa at juvenile age, long before the onset of systemic autoimmunity and clinical disease. These studies show that higher expression of X-linked TLR genes in intestinal epithelial and immune cells of lupus-prone females as early as juvenile age compared to males as well as lupus-resistant strain and hyper-activation of TLR7 and TLR8 induces profoundly high expression of inflammatory factors including gut permeability protein pre-Hp2, leading to gut inflammation at juvenile age. These observations prompted us to hypothesize, in our parent project (R21AI136339), that “the systemic autoimmune process in lupus susceptible subjects is initiated and perpetuated, as gut inflammation at juvenile ages, by high-dose TLR7/8 - microbiota interaction”. We are currently defining the requirement of Xlinked TLRs in gut inflammation and lupus autoimmunity and determining the requirement of interaction with microbiota for, and the role of X-linked TLR activation in, juvenile onset of gut inflammation, pre-Hp2 protein dependent leaky-gut, and autoimmunity using lupus relevant germ-free (GF) and TLR-deficient mouse models. With relevance to the FOA PA-18-817, our independent studies using highly purified ß-glucan of yeast origin (YBG), a well-recognized dietary supplement, show that this agent has: 1) pre-biotic properties and alter gut microbiota composition, 2) can suppress pre-Hp2 protein expression as well as leaky-gut, and 3) prevent T1D in NOD mice. Since TLR7/8 hyper-activation dependent pre-Hp2 expression is the focus of our parent project R21AI136339, the proposed supplementary research will determine the potential of this complex natural dietary polysaccharides in promoting protection from TLR7 and TLR8 hyper-activation dependent gut inflammation, suppression of pre-Hp2 expression, enhancing immune regulation, and preventing juvenile onset of autoimmunity. This administrative supplement fund will help us not only address the molecular mechanism of ß-glucan dietary supplement mediated immune modulation but will also test the potential this dietary approach in preventing lupus autoimmunity in at risk-subjects.

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