Hunt, Carrie Lynn (2016-08). Identification of the Microbiota Metabolite, Indole, as a Novel Immune Modulator for Antigen-Presenting Cells in the Gut. Doctoral Dissertation.
Mammals are colonized by trillions of symbiotic microbes, termed the microbiota. This collection of predominantly bacteria greatly outnumbers the host's own cells in number, genomic content, and biochemical potential. Extensive research has revealed the necessity of the microbiota for developing a fully functional intestinal and systemic immune system. While definitive crosstalk between host microbiota and immune system exists, the discrete compounds responsible for altering immune cell function remain to be fully characterized. Antigen-presenting cells (APCs) are fundamental regulators of immunity and integrate signals from their local environment to direct immune responses. Primary roles of APCs include antigen presentation to na?ve T cells, tissue integrity maintenance, and cytokine secretion to instruct activity of other immune cells. APCs residing at mucosal sites have a unique role in maintaining homeostasis by promoting peripheral tolerance to harmless commensal microorganisms. The dysregulation of this phenomenon promotes chronic inflammation in the intestinal tract, which predisposes the host to numerous cancers and metabolic disorders. Identifying and manipulating the specific microbiota components that drive tolerance in the gastrointestinal tract is a primary goal of current immunological research. Indole is a microbiota-derived metabolite produced by numerous bacterial species and present at high concentrations in the intestines. Previous work from our lab and others has demonstrated a protective role of indole in the GI tract. In this study, we show that indole is able to suppress pro-inflammatory responses and promote mucosal phenotype and function in APCs. Remarkably, indole-conditioned dendritic cells (DCs) imprinted na?ve T cells with gut-homing markers and preferentially induced regulatory T cells. Our overall findings reveal that indole conditions DCs towards a mucosal phenotype in a manner mechanistically distinct from the canonical GI signal, retinoic acid. In addition, indole-conditioned DCs are capable of promoting a regulatory phenotype in na?ve T cells. These observations reveal a novel mechanism by which an endogenous microbiota metabolite conditions APCs for optimal function in mucosal tissues, thus providing evidence for a single metabolite promoting properties associated with peripheral tolerance. This revelation paves the way for future work in manipulating the microbiota for therapeutic potential in autoimmune and inflammatory disorders of the GI tract.