Microbiota-derived Metabolites in Mucosal Homeostasis

描述（由申请人提供）：肠道微生物群是整体哺乳动物体内平衡的关键伙伴，这一事实在无菌小鼠中得到了有效的例证，这些小鼠除了严重的代谢异常外，还具有免疫发育和宿主防御缺陷。除了在宿主生理学中的作用外，最近的研究表明，肠道微生物群也是人类胃肠道中复杂信号分子环境的贡献者。到目前为止，我们实验室和其他人的大多数研究都从细菌的角度研究了王国间的信号传导-宿主来源的线索如何调节肠道细菌的反应。最近，我们假设肠道细菌和肠上皮细胞的密切联系，将导致肠道上皮细胞（IEC）中细菌分子的界间识别和信号传导。我们发现，细菌分泌的信号吲哚，作为色氨酸代谢的结果，确实加强了上皮细胞单层的完整性和粘蛋白的生产，同时抑制炎症IL-8的生产和TNF-介导的NF-κ B的表达，并增加抗炎IL-10。我们的观察结果表明，在一个模型中，多个粘膜细胞连续暴露于微生物来源的吲哚，这导致我们的中心假设，吲哚有助于，部分，肠道粘膜免疫稳态。基于这一概念，我们推断树突状细胞（DC）可能是吲哚的主要靶点，我们提出吲哚通过其对DC的作用有助于塑造粘膜淋巴细胞应答的质量。具体来说，我们将测试的假设，吲哚暴露教育DCs对非炎症，粘膜表型和功能。我们的总体目标是确定微生物群衍生的吲哚如何影响DC功能，并有助于非炎性粘膜DC的独特性质。 公共卫生相关性：肠道微生物群的研究是一个新兴的研究领域，对人类整体健康有着深远的影响。我们的工作描述了微生物来源的L-色氨酸代谢物，在正常肠道中以高浓度存在，是一种新的模式，为王国间的通信，这些代谢物具有免疫调节特性，并可能参与肠道粘膜稳态。这项工作为治疗炎症性疾病提供了一种新的治疗选择。

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.