Developmental PBDE exposure, gut microbiome, and diabetes

发育性 PBDE 暴露、肠道微生物组和糖尿病

基本信息

批准号：
10541164
负责人：
Yue Cui
金额：
$ 59.66万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2024-04-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10541164
关键词：
Abbreviations Acceleration Acute Adipose tissue Adult Age Agonist Animal Experiments Animal Model Bacteria Behavioral Body Composition ChIP-seq Complex Conceptions Development Diabetes Mellitus Diet Dietary Intervention Disease Dose Economic Burden Environment Environmental Risk Factor Equilibrium Experimental Models Exposure to Flame Retardants Gene Expression Genetic Germ-Free Growth Health Histopathology Human Human Milk Indoles Inflammation Inflammatory Intestinal Diseases Intestinal permeability Intestines Investigation Islets of Langerhans Lactation Life Ligands Link Literature Liver Mediating Metabolic Metabolic Diseases Metabolic syndrome Metabolism Metagenomics Mus Nature Neonatal Non-Insulin-Dependent Diabetes Mellitus Nuclear Receptors Obesity Oral Outcome Pancreas Pathway interactions Performance Phenotype Pregnancy Prevalence Propionic Acids Receptor Activation Receptor Signaling Regimen Research Risk Factors Rodent Sampling Serum Testing Thyroid Gland Tissues Toxic Environmental Substances Toxicology Transgenic Mice Transgenic Organisms Tryptophan Tryptophan Metabolism Pathway United States Weaning Xenobiotics cell injury chemokine cytokine diabetic diabetogenic dietary control dietary supplements dysbiosis energy balance environmental chemical epidemiology study fecal transplantation food consumption gene environment interaction glucose tolerance gut dysbiosis gut microbiome human model humanized mouse insulin secretion insulin sensitivity insulin tolerance lipophilicity metabolic phenotype metabolomics microbial microbiome mouse model neurotoxicity new therapeutic target novel pandemic disease persistent organic pollutants polybrominated diphenyl ether pregnane X receptor pup receptor social

项目摘要

PROJECT SUMMARY Diabetes is a pandemic, causing grave social and economic burdens. This complex disease is caused by an interaction among genetic, metabolic, behavioral, and environmental factors. Epidemiology studies and animal experiments demonstrate that developmental exposure to the persistent environmental toxicants polybrominated diphenyl ethers (PBDEs) is associated with increased diabetes prevalence and persistent diabetic phenotype in adulthood. However, mechanisms governing early life PDBE exposure and the diabetogenic phenotype remain unknown. Current literature supports the mechanistic link between gut microbiome and metabolic syndrome in humans and animal models. We showed that oral exposure to PBDEs in adult mice results in dysbiosis with profound changes in bacteria known to be associated with inflammation and obesity, as well as reduced tryptophan microbial metabolites including indoles, which are novel activators of the host pregane X receptor (PXR) which is known to contribute to obesity and diabetes. Building on our findings that there is a gene-environment interaction between PXR and PBDEs through gut microbiome and indole metabolites, we seek to establish a causal relationship between developmental PBDE exposure, a change in the gut microbiome, and diabetes later in life using humanized PXR transgenic (hPXR-TG) mice in conventional (CV) and germ-free (GF) background. We hypothesize that developmental PBDE exposure causes acute and persistent dysbiosis, which contributes to diabetes through suppression of microbial tryptophan metabolism and selective PXR modulation (sPXRm) in early life and beyond. To test our hypothesis, in Aim 1 we will determine if developmental PBDE exposure perturbs the gut microbiome and microbial metabolism of tryptophan, leading to sPXRm in early life and beyond. In Aim 2 we will determine whether microbial metabolites, mainly including indoles and indole-derivatives, can reduce inflammation and rescue the diabetic phenotype following developmental PBDE exposure. In Aim 3 we will determine that reprogramming the gut microbiome using fecal transplant mechanistically contributes to developmental PBDE exposure mediated disruption of PXR signaling and delayed onset of diabetes. The expected outcome of the proposed research is a new research paradigm demonstrating that dysbiosis of the gut microbiome mechanistically contributes to early life PBDE exposure-induced diabetes and metabolic syndrome later in life, and more importantly, enables a toxico-metagenomics approach targeting metabolic disorders resulted from exposure to PBDEs and potentially other persistent organic pollutants.

项目摘要糖尿病是一个大流行，导致严重的社会和经济伯恩根。这种复杂疾病是由遗传，代谢，行为和环境因素之间的相互作用。流行病学研究和动物实验表明，发育暴露于持续的环境有毒物质多溴二苯基醚（PBDES）与糖尿病患病率增加和持续性有关成年后的糖尿病表型。但是，管理早期生命的机制PDBE暴露和糖尿病发作表型仍然未知。当前文献支持肠道之间的机械联系人类和动物模型中的微生物组和代谢综合征。我们表明口头暴露于PBDES 在成年小鼠中导致营养不良，细菌的深刻变化与炎症有关和肥胖，以及减少色氨酸微生物代谢物，包括吲哚，它们是新型激活剂宿主Pregane X接收器（PXR），已知有助于肥胖和糖尿病。建立在我们的基础上调查结果表明，PXR和PBDE之间存在基因 - 环境的相互作用，并通过肠道微生物组和吲哚代谢物，我们寻求建立发育性PBDE暴露之间的因果关系肠道微生物组的变化和糖尿病在生命后期使用人源化PXR转基因（HPXR-TG）小鼠在生活中的变化常规（CV）和无菌（GF）背景。我们假设发育性PBDE暴露引起急性和持续性营养不良，这通过抑制微生物会导致糖尿病早期及以后的色氨酸代谢和选择性PXR调制（SPXRM）。测试我们的假设，在AIM 1中，我们将确定发育性PBDE暴露是否存在肠道微生物组和色氨酸的微生物代谢，导致早期及以后的SPXRM。在AIM 2中，我们将确定微生物代谢产物（主要包括吲哚和吲哚衍生物）是否可以减少炎症和发育性PBDE暴露后，营救糖尿病表型。在AIM 3中，我们将确定使用粪便移植机械地重新编程肠道微生物组，有助于发育PBDE 暴露介导的PXR信号传导的破坏和糖尿病发作延迟。预期的结果拟议的研究是一项新的研究范式，表明肠道微生物组的营养不良机械上有助于早期PBDE暴露引起的糖尿病和代谢综合征，以后更重要的是，启用一种靶向代谢性疾病的毒性 - 金属元素学方法是由暴露于PBDE，并可能其他持久的组织污染物。