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

项目 4：肠道微生物组 - 宿主对 TCDD 暴露的反应

• 批准号: 8695354
• 负责人: SYED A. HASHSHAM
• 金额: $ 26.34万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8695354
• 关键词: Appearance; Arthritis; Aryl Hydrocarbon Receptor; Autoimmune Diseases; Bacteria; Bacteroides fragilis; C57BL/6 Mouse; CD4 Positive T Lymphocytes; Carbazoles; Cell Differentiation process; Cells; Chemicals; Choline; Clostridium; Colitis; Collaborations; Communities; Competence; Complement; Crohn' s disease; Development; Dietary Component; Dioxins; Disease; Disease Outcome; Environmental Exposure; Environmental Pollution; Equilibrium; Evaluation; Excretory function; Exposure to; Fatty Liver; Fatty acid glycerol esters; Gene Expression Profile; Generations; Genes; Germ-Free; Health; Helicobacter; Hepatic; Hepatotoxicity; Homeostasis; Immune; Immune response; Immune system; Inflammatory Bowel Diseases; Inflammatory Response; Instruction; Interleukin-10; Interleukin-17; Interleukin-6; Lead; Ligands; Link; Liver diseases; Measures; Metabolism; Mono-S; Mus; Odors; Pathway interactions; Play; Polysaccharides; Population; Production; Regulation; Regulatory T-Lymphocyte; Relative (related person); Research Personnel; Research Support; Rivers; Role; Sampling; Site; Skin Cancer; Students; Syndrome; System; Testing; Tetrachlorodibenzodioxin; Training; Transforming Growth Factors; Translational Research; Up-Regulation; aryl hydrocarbon receptor ligand; base; carbazole; choline deficient diet; design; fatty acid transport; genome sequencing; interest; interleukin-22; member; microbial; microbiome; mouse model; non-alcoholic fatty liver; pathogen; prevent; promoter; research study; response; transcriptomics; trimethylamine; trimethyloxamine; urinary

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.

项目随附资料（见说明）： 肠道微生物组的关键微生物种群在暴露于2，3，7，8-四氯二苯并对二恶英（TCDD）后形成宿主反应中的作用才刚刚开始研究。有证据表明，肠道微生物组与宿主反应密切相关，并且还直接和间接地受到环境污染物的影响。在这个项目中，提出了两个这样的相互作用进行研究，使用C57 BL/6无菌，单相关，鸡尾酒相关和传统提出的小鼠模型。第一个与Treg/Th 17免疫调节系统及其对二恶英暴露的反应失调有关，第二个与胆碱-三甲胺（TMA）途径及其调节有关。Treg/Th 17系统的失调由于其在免疫调节系统中的核心作用而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。近日，具体 肠道群落的成员，例如分节丝状细菌（SFB，其全基因组序列现在是可获得的）和簇IV和XIVa梭菌，以及脆弱拟杆菌（Bacteroides fragilis）已经涉及调节Treg/Th 17系统。Treg/Th 17平衡也受到二恶英的影响，因为AhR促进Foxp 3 + Treg的产生并抑制分化为产生IL-17的ROR-yt Th 17。 因此，肠道微生物组的特定群体，Treg/Th 17平衡和TCDD通过其AhR系统相互关联。其错误调节可能导致疾病结果。项目4建立了这些具体的和相反的“机制”的规定，在无菌小鼠使用SFB，6。fragilis和clusterIV和XIVa梭菌，并研究了这些肠道微生物种群在使宿主更少或更易受感染方面的作用 二恶英对健康的影响。还提出了评估簇IV和XlVa梭菌和SFB对TCDD、2，3，4，7，9-PeCDF和2，3，7，8-TCDF暴露的转录组响应。项目4还检查了TCDD和相关化合物对宿主和肠道微生物组胆碱代谢的影响，以及在脂肪肝和改变尿液中的潜在作用。 三甲基胺/三甲基胺-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）以及研究支持核心A和B合作研究这些影响。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。学生的项目被设计为纳入培训核心。