PROJECT DESCRIPTION / ABSTRACT Unhealthy changes in the gut microbiota might trigger the pathogenesis of many diseases. We have reported that priming the gut by -glucan-shaped microbiota, prior to clinical disease onset, can profoundly suppress autoimmune and colitis severity. Accumulating evidence suggests that microbes and their metabolites critically modulate the pathophysiology of various diseases. However, vast majority of microbial metabolites including those resulting from microbiota-diet interaction remain unknown and/or uncharacterized. Non-digestible, microbiota-accessible carbohydrates (MACs) including -glucans are thought to have major impact on microbiota composition and function. Our findings show that high-pure -glucans (BGs) from yeast (yeast -1,3/1,6-glucan; YBG) and microalgae (algal -1,3-glucan; paramylon, PM): a) have prebiotic properties, b) can increase the intestinal production of SCFA, c) can enhance gut integrity, and d) can suppress autoimmune progression and gut inflammation. However, to fully explain the mechanisms associated with the host-benefits of BG-shaped microbiota and to develop nutraceutical approaches, it is important to identify metabolites generated from BG- like CDP degradation and characterize their functional impacts. In this regard, our observations from in vitro and in vivo studies suggest that “BG-degradation” by gut microbes produces a distinct metabolite profile that includes the higher abundance of immune regulatory SCFAs. Therefore, we hypothesize that “identification and functional characterization of unique microbial metabolites of BG-degradation could lead to the development of precision- nutrition and -medicine approaches to enhance gut and systemic immune regulation”. Here, in response to PAR-21-253, we have proposed to, first identify BG degradation- and autoimmunity- associated novel microbial metabolites. Our studies will focus on i) determining if BG degradation, by human fecal microbiota, produces a distinct metabolite profile and ii) identifying the novel microbial metabolites of this process. We will also examine if fecal microbes from autoimmune type 1 diabetes and systemic lupus erythematosus patients produce pro-inflammatory metabolites and determine if BG-degradation process skews this pro-inflammatory metabolite profile to immune regulatory type. The pro- and anti- inflammatory properties of BG degradation- and autoimmunity-associated microbial metabolites will be studied in a series of in vitro and in vivo studies. The functional impacts of candidate metabolites on T-, B- and dendritic- cell responses will also be studied. We will then examine if in vivo immune function and autoimmune disease outcomes can be modulated by select microbial metabolites. Overall, these studies will demonstrate if fermentation of BG-like MACs generates microbial metabolites with therapeutic value, in terms of preventing and/or treating immune mediated disorders. We will work closely with the Knowledgebase Management Center (KMC) for different aspects of the project and share data and experimental details freely with KMC and other grantees.

PROJECT NARRATIVE Fermentation of non-digestible, complex dietary polysaccharides by distal gut microbes can enhance and maintain beneficial microbes in the distal gut and generate immune regulatory metabolites. Therefore, identification and functional characterization of microbial metabolites from complex dietary polysaccharide degradation could lead to the development of precision -nutrition and -medicine approaches to prevent and treat immune-mediated disorders. Our proposed studies are expected to identify novel microbial metabolites of candidate complex dietary polysaccharide degradation and functionally characterize them for the ability to enhance gut and systemic immune regulation.