Environmental Ah Receptor Ligand Impact on the Host-Microbiome Metabolic Axis

环境 Ah 受体配体对宿主微生物组代谢轴的影响

基本信息

批准号：
9419367
负责人：
Andrew Patterson
金额：
$ 15.72万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9419367
关键词：
Address Adult Albumins Aroclor 1254 Aryl Hydrocarbon Receptor Automobile Driving Biology Ceramides Communities Consult Data Dependence Development Diet Dioxins Discipline of Nursing Disease Outcome Dose Electrophoretic Mobility Shift Assay Environmental Pollutants Environmental Pollution Experimental Designs Exposure to Fatty Liver Future Genes Genomics Germ-Free Gnotobiotic Hepatic Human Inflammation Inflammatory Intestines Knock-out LCN2 gene Ligands Link Liver Measurement Mediating Metabolic Metabolic Diseases Metagenomics Molecular Toxicology Mus Nurses Obesity Pathogenesis Pathway interactions Play Polychlorinated Biphenyls Population Predisposition Production Publishing Receptor Activation Repression Research Research Personnel Role Sequence Analysis Specificity Techniques Tetrachlorodibenzodioxin Time Tissues Toxicology Weaning aryl hydrocarbon receptor ligand chromatin immunoprecipitation cytokine experimental study flexibility gut microbiome gut microbiota innovation insight interest lipid biosynthesis liver development metabolic phenotype metabolomics microbiome mid-career faculty mouse model non-alcoholic fatty liver novel programs rRNA Genes response villin

项目摘要

PROJECT SUMMARY/ABSTRACT The scientific community is increasingly appreciative of the important role the aryl hydrocarbon receptor (AHR) plays in modulating the host-microbiome metabolic axis. Interestingly, there are strong links between the gut microbiota and the development and/or exacerbation of nonalcoholic fatty liver disease (NAFLD), all of which are modulated by activation or repression of the AHR. At present, however, a direct connection between AHR activation, changes in gut microbiota composition, ceramide synthesis, and NAFLD development has not been established. Further the concept that environmental pollutant-mediated disruption and/or modulation of the AHR-gut microbiota metabolic axis leads to the development of NAFLD has not been addressed. Our published and preliminary data with 2,3,7,8-tetrachlorodibenzofuran (TCDF) indicates AHR activation profoundly alters the gut microbiota in a qualitative and quantitative manner, increases hepatic lipogenesis, and significantly alters hepatic ceramide synthesis through direct AHR activity (a proposed driver of NAFLD). These results have led us to the novel central hypothesis: Dietary exposure to potent environmental AHR ligands leads to functionally significant changes in the gut microbiota that exacerbate NAFLD in a time- and Ahr-dependent manner. Through the innovative use of cutting-edge techniques (metagenomics and metabolomics) and unique mouse models (tissue specific knockouts of Ahr, gnotobiotic mice, and fecal transfer experiments), we plan to identify the functional changes imparted to the gut microbiota following dietary exposure to potent AHR ligands such as TCDF and to evaluate the Ahr-dependent role of ceramides in driving NAFLD pathogenesis and progression. This combination of approaches will allow us to accurately assess bacterial phyla dynamics and its interaction with and impact on the host, and whether these changes result in increased susceptibility to NAFLD. We are particularly interested in how the timing (weaning and adulthood) of the exposure influences disease outcome. This study will provide invaluable insight into the effects of exposure on a number of environmentally relevant persistent AHR ligands, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and co-planar PCBs and provide valuable endpoints for future studies in human populations.

项目概要/摘要科学界越来越认识到芳烃受体（AHR）的重要作用调节宿主-微生物组代谢轴。有趣的是，肠道之间存在着密切的联系。微生物群和非酒精性脂肪肝病 (NAFLD) 的发展和/或恶化，所有这些通过 AHR 的激活或抑制来调节。然而，目前 AHR 之间的直接连接激活、肠道微生物群组成的变化、神经酰胺合成和 NAFLD 的发展尚未得到证实已确立的。进一步的概念是环境污染物介导的破坏和/或调节 AHR-肠道微生物群代谢轴导致 NAFLD 的发展尚未得到解决。我们的已发表的 2,3,7,8-四氯二苯并呋喃 (TCDF) 初步数据表明 AHR 激活以定性和定量的方式深刻改变肠道微生物群，增加肝脏脂肪生成，并通过直接 AHR 活性显着改变肝神经酰胺合成（NAFLD 的拟议驱动因素）。这些结果使我们得出了新的中心假设：饮食中暴露于有效的环境 AHR 配体导致肠道微生物群功能发生显着变化，从而加剧 NAFLD 时间和 Ahr 相关的方式。通过创新地使用尖端技术（宏基因组学和代谢组学）和独特的小鼠模型（Ahr 的组织特异性敲除、无菌小鼠和粪便转移实验），我们计划确定饮食中暴露于强效 AHR 配体（例如 TCDF 并评估神经酰胺在驱动 NAFLD 发病机制和进展中的 Ahr 依赖性作用。这种方法的组合将使我们能够准确评估细菌门动态及其相互作用对宿主的影响，以及这些变化是否导致 NAFLD 易感性增加。我们是特别感兴趣的是暴露时间（断奶和成年）如何影响疾病结果。这项研究将为了解暴露对许多环境相关的影响提供宝贵的见解。持久性 AHR 配体，例如 2,3,7,8-四氯二苯并-对二恶英 (TCDD) 和共面 PCB，并提供为未来人群研究提供有价值的终点。