权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
9753729
负责人：
Andrew Patterson
金额：
$ 34.63万
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：
2017-09-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9753729
关键词：
16S ribosomal RNA sequencing Address Adult Albumins Aroclor 1254 Aryl Hydrocarbon Receptor Automobile Driving Bioinformatics Biology Ceramides Consult Data Dependence Development Diet Dioxins 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 Obesity Pathogenesis Pathway interactions Polychlorinated Biphenyls Population Predisposition Production Publications Receptor Activation Repression Research Research Personnel Role Sequence Analysis Specificity Structure Techniques Tetrachlorodibenzodioxin Time Tissues Toxicology Weaning aryl hydrocarbon receptor ligand bacterial community chromatin immunoprecipitation cytokine experimental study flexibility gut microbiome gut microbiota host microbiome innovation insight interest lipid biosynthesis liver development metabolic phenotype metabolomics microbiome mid-career faculty mouse model non-alcoholic fatty liver disease novel programs rRNA Genes response villin

项目摘要

ABSTRACT The aryl hydrocarbon receptor (AHR) modulates the host-microbiome metabolic axis. 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. A mechanistic connection between AHR activation, changes in gut microbiota composition/function, 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 published4-7 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, significantly alters hepatic ceramide synthesis through direct AHR activity (a proposed driver of NAFLD), and increases systemic inflammation. These results have led 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 (16S rRNA gene sequencing, 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 community 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, adulthood) of the exposure influences disease outcome. This study will provide new 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 (PCB-126) and provide valuable endpoints for future studies in human populations.

摘要