Project 4: Gut Microbiome - Host Interactions in Response to TCDD Exposure

项目SuIVIMARY(请参阅说明)： 肠道微生物组的关键微生物群在2，3，7，8-四氯二苯并-对二恶英(TCDD)暴露引起的宿主反应中的作用才刚刚开始研究。有证据表明，肠道微生物群与宿主的反应有着千丝万缕的联系，也直接或间接地受到环境污染物的影响。在这个项目中，建议使用无菌、单相关、鸡尾酒相关和传统饲养的小鼠模型来研究两种这样的相互作用。第一个与Treg/Th17免疫调节系统及其对二恶英暴露的生物失调有关，第二个与胆碱-三甲胺(TMA)途径及其调节有关。由于其在免疫调节系统中的核心作用，Treg/Th17系统的生物失调具有广泛的健康影响。它可能导致自身免疫性疾病，如关节炎、炎症性肠病和皮肤癌。最近，具体 肠道群落的成员，如节段性丝状细菌(现已获得其全基因组序列的SFB)、簇IV和XlVa梭状杆菌，以及脆弱类杆菌，都参与了Treg/Th17系统的调节。二恶英也影响Treg/Th17的平衡，因为AhR促进Foxp3 Treg的产生，并抑制向IL-17的分化，产生ROR-yt Thi7。 因此，肠道微生物组的特定种群、Treg/Th17平衡和TCDD通过其AhR系统相互关联。它的错误调控可能会导致疾病后果。项目4使用SFBS、6.脆弱菌、第IV簇和XlVa梭状芽胞杆菌在无菌小鼠中建立了这些特定的和相反的“调节机制”，并研究了这些肠道微生物种群在使宿主更少或更容易受到感染方面的作用 二恶英对健康的影响。此外，还提出了对簇IV和XlVa梭状芽孢杆菌和SFB对TCDD、2，3，4，7，9-PeCDF和2，3，7，8-TCDF暴露的转录组反应的评估。项目4还检查了TCDD和相关化合物对宿主和肠道微生物群胆碱代谢的影响，以及在脂肪肝和尿液改变中的潜在作用。 三甲胺/三甲胺-N-氧化物(TMA/TMAO)比率。正在与项目1(Kaminski/Kaplan)、项目3(Zacharewski)、项目5(Zylstra)和项目6(Boyd)以及研究支助核心A和B合作研究影响。结果通过社区参与核心和研究翻译核心传播给社区和研究人员。学生项目的设计是为了纳入培训核心。

PROJECT SUIVIMARY (See instructions): Role of key microbial populations of the gut microbiome in formulating host response as a result of 2,3,7,8- tetrahlorodibenzo-p-dioxin (TCDD) exposure is only beginning to be studied. Evidence suggests that gut microbiome is intricately linked to the host response and is also impacted directly and indirectly by exposure to environmental contaminants. In this project two such interactions are proposed to be studied using C57BL/6 germ free, mono-associated, cocktail associated and traditionally raised mouse models. The first is related to Treg/Th17 immune regulatory system and its dysbiosis in response to dioxin exposure and the second is related to choline-trimethylamine (TMA) pathway and its modulation. Dysbiosis of Treg/Th17 system has a broad range of health effects due to its central role in the immune regulatory system. It may lead to autoimmune diseases such as arthritis, inflammatory bowel disease, and skin cancer. Recently, specific members of the gut community, such as segmented filamentous bacteria (SFBs for which whole genome sequences are now available) and cluster IV and XlVa Clostridia, and Bacteroides fragilis have been implicated in regulating the Treg/Th17 system. The Treg/Th17 balance is also impacted by dioxin because AhR promotes the generation of Foxp3+ Treg and suppresses the differentiation to IL-17 producing ROR-yt Thi7. Thus specific populations of the gut microbiome, the Treg/Th17 balance, and TCDD via its AhR system are interconnected. Its mis-regulation may lead to disease outcomes. Project 4 establishes these specific and opposing "mechanisms" of regulation in germ-free mice using SFBs, 6. fragilis, and cluster IV and XlVa Clostridia and studies the role of these gut microbial populations in making the host less or more susceptible to health effects of dioxins. Evaluation of the transcriptome response of cluster IV and XlVa Clostridia and SFBs in response to TCDD, 2,3,4,7,9-PeCDF, and 2,3,7,8-TCDF exposure is also proposed. Project 4 also examines the effects of TCDD and related compounds on the metabolism of choline by the host and the gut microbiome, and the potential roles in the development of fatty liver and altering urinary trimethylamine/trimethylamine-N-oxide (TMA/TMAO) ratios. The effects are being studied in collaboration with Projects 1 (Kaminski/Kaplan), 3 (Zacharewski), 5 (Zylstra), and 6 (Boyd) and Research Support Cores A and B. The results are disseminated to communities and researchers through the Community Engagement Core and Research Translation Core. Student projects are designed to be incorporated in the Training Core.