Microbiota-derived Metabolites in Mucosal Homeostasis

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DESCRIPTION (provided by applicant): Intestinal microbiota are critical partners in overall mammalian homeostasis and this fact is effectively exemplified in germ-free mice that have deficient immune development and host defenses, in addition to profound metabolic abnormalities. Beyond a role in host physiology, recent studies suggest that intestinal microbiota are also contributors to the complex signal molecule milieu in the human gastrointestinal track. To date, a majority of these studies from our lab and others have investigated inter-kingdom signaling from the bacteria's perspective - how host-derived cues modulate intestinal bacterial responses. More recently, we hypothesized that the close association of commensal bacteria and intestinal epithelial cells, will lead to inter-kingdom recognition and signaling of bacterial molecules in intestinal epithelial cells (IEC). We identified that the bacterial secreted signal indole, produced as a result of tryptophan metabolism, indeed strengthens epithelial cell monolayer integrity and mucin production, while suppressing inflammatory IL-8 production and TNF¿-mediated NF¿B expression and increasing anti-inflammatory IL-10. Our observations suggest a model in which multiple mucosal cells are continuously exposed to microbiota-derived indole and this leads to our central hypothesis that indole contributes, in part, to gut mucosal immune homeostasis. Based on this notion, we reasoned that dendritic cells (DCs) are likely major targets of indole and we propose that indole contributes to shaping the quality of mucosal lymphocyte responses through its effect on DCs. Specifically, we will test the hypothesis that indole exposure educates DCs towards a non-inflammatory, mucosal phenotype and function. Our overall objectives are to determine how microbiota-derived indole affect DC function and contribute to the unique properties of non-inflammatory, mucosal DCs. PUBLIC HEALTH RELEVANCE: Investigation of the intestinal microbiota is a burgeoning are of research that has profound impact on overall human health. Our work describes how microbiota-derived L-tryptophan metabolites, present at high concentrations in the normal gut, are a new paradigm for inter-kingdom communication, and that these metabolites have immunomodulatory properties and may participate in gut mucosal homeostasis. This work offers a novel therapeutic option for treating inflammatory disorders.