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Grant Abstract: Role of microbiota-TLR7/8 Interaction in systemic lupus erythematosus

Grant Number: 5R01AI138511-02
PI Name: Vasu
Project Title: Role of microbiota-TLR7/8 Interaction in systemic lupus erythematosus

Abstract: Unhealthy changes in the gut microbiota (dysbiosis) can trigger the pathogenesis of autoimmune diseases including systemic lupus erythematosus (SLE) in at-risk subjects. Recent studies have suggested that dysbiosis and aberrant production of microbial metabolites, prior to the clinical disease onset, contribute to disease progression in SLE. Therefore, we believe that SLE patients and at-risk subjects harbor pro-inflammatory, disease-promoting gut microbes and hypothesize that evidence-based microbiota manipulation could be employed to prevent SLE autoimmunity in at-risk subjects. In this regard, our recent studies pertinent to the parent project (R01AI138511) showed that pro-inflammatory events initiated in the gut mucosa as a result of gut microbiota-TLR7/8 interaction, long before the onset of systemic autoimmunity, are the initiators and perpetuators of autoimmunity in SLE. To address this notion, our parent project is currently studying SLE patients, at-risk subjects, and healthy controls for differences in pro-inflammatory biomarkers of gut mucosa and gut permeability-associated pro-inflammatory features of the systemic compartment. This project also employs lupus-prone germ-free, specific pathogen free, and various knockout mice to determine the role of microbiota in promoting SLE through TLR7 and TLR8, and the efficacy of blocking this interaction in preventing the disease. Our independent studies show that complex dietary polysaccharides, ß-glucans (BG) are not only immunologically active, but also have pre-biotic properties. We found that two structurally distinct BGs, yeast glucan and paramylon, can suppress gut permeability as well as shape the human gut microbiota to increase host beneficial communities and metabolites. We also found that human gut microbiota cultured with BG in vitro produced SCFA and could delay autoimmune diabetes in GF mice. In this regard, although BGs derived from different food sources are widely being used as dietary supplements, the impacts of BG degradation on human gut microbiota and autoimmunity are unknown. Based on our preliminary observations, we hypothesize that “BG degradation process can eliminate the pro-lupus properties of gut microbiota in SLE patients and at-risk subjects”. This notion will be tested by taking advantage of the readily available, precious human samples that have been collected and unique lupus-prone germ-free mice that was generated for the parent project. The primary goal of this supplemental project, which is within the scope of the research that is already supported by the parent award is to determine the structural and functional changes in SLE patient fecal microbiota during BG degradation in vitro and in vivo, and how these changes can impact autoimmune progression and lupus susceptibility. These studies will, for the first time, demonstrate the true prebiotic properties of BGs on human gut microbiota and its therapeutic value, if any, in preventing autoimmunity in lupus-prone subjects.

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