Grant Abstract: Contribution of Gut Symbiotic Bacteria to Autoimmunity

Grant Number: 5R21AI133798-02
PI Name: Vasu
Project Title: Contribution of Gut Symbiotic Bacteria to Autoimmunity

Abstract: In addition to infections, gut commensal microbes influence the pathogenesis of autoimmune diseases. Bacteroides fragilis (BF) is a gram-negative anaerobe and an integral component of the human gut symbiotic microflora. However, this is also the most commonly isolated organism from clinical cases of intra-abdominal abscess. Recent studies have used BF as a model for studying the commensal bacteria-human host interactions. Using experimental models, studies have demonstrated many beneficial effects of BF and its major capsular component, polysaccharide A (PSA) including enhancement of gut and systemic immune regulation through activating regulatory T cells under normal circumstances. However, employing this organism and autoimmune susceptible mice as models, we observed that gut commensal microbes can produce deleterious effects upon gaining access to systemic circulation. While orally administered, heat-killed BF caused protection from spontaneous autoimmune diabetes, i.v. administration of small amounts of this bacterium led to rapid onset of the disease. These observations suggest that systemic exposure to this, and perhaps other similar, commensal bacteria due to transient or persistent enhanced gut permeability could trigger or accelerate autoimmunity in individuals who are genetically susceptible to the disease. Therefore, in the parental application we hypothesized that while gut colonization by BF promotes protection of at-risk subjects from T1D, translocation of this symbiont to systemic compartment, due to compromised gut integrity, triggers and/or perpetuates autoimmunity. We are currently testing this novel hypothesis by determining the impact of systemic access of BF components on autoimmunity in T1D using specific pathogen free (SPF) and germ free (GF) non-obese diabetic (NOD) mouse model of T1D under normal and leaky-gut conditions. Our independent studies using two structurally different ?- glucan (BGs) dietary supplements show that they have pre- biotic properties, can suppress leaky-gut, and prevent gut inflammation in colitis model as well as prevent T1D in NOD mice. Therefore, the proposed supplemental research will determine the potential of oral consumption of these complex natural polysaccharide dietary supplements in promoting protection from leaky-gut and enhancing BF mediated gut immune regulation, and suppression of autoimmunity.

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