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Organotin influences on assembly and obesogenic activity of the gut microbiota

有机锡对肠道微生物群的组装和致肥活性的影响

基本信息

批准号：
8605677
负责人：
John F Rawls
金额：
$ 31.4万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-21 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8605677
关键词：
Adipocytes Adipose tissue Animals Bacterial Physiology Biological Biological Models Cell Culture Techniques Chemicals Communities Complex Development Diet Dose Ecology Environmental Pollution Environmental Risk Factor Exposure to Fatty acid glycerol esters Genetic Germ-Free Gnotobiotic Goals Habitats Harvest Health Human Immune response Immunity Incidence Intestines Knowledge Lead Mammals Metabolism Methods Microbe Mission Modeling Modification Molecular Monitor Morbidity - disease rate Mus Nutrient Obesity Outcome Physiological Physiology Public Health Research Resolution Shapes Staging System Testing Time Toxic Environmental Substances Transplantation Vertebrates Work Zebrafish base burden of illness cell type energy balance gut microbiota in vivo in vivo imaging innovation insight method development microbial microorganism novel novel strategies obesity risk obesogen pressure prevent programs public health relevance rRNA Genes tributyltin

项目摘要

DESCRIPTION (provided by applicant): The organotin tributyltin (TBT) is a prominent environmental toxin that promotes obesity in vertebrates. The gut microbiota is also known to promote obesity, but it is unknown whether TBT promotes obesity in vivo by influencing the composition of the gut microbiota. Moreover, it remains unknown if TBT-induced alterations of gut microbiota composition are sufficient to alter host adiposity. These gaps in knowledge are important, because without this information, the development of methods to prevent obesity and associated morbidities by mitigating effects of TBT and other obesogens on gut microbiota, is highly unlikely. The overall objective of this application is to exploit the advantages of the zebrafish model system to define the impact of TBT on the assembly and on the obesogenic activity of the gut microbiota. The proposed research will test the central hypothesis that TBT exposures cause compositional alterations to the gut microbiota that are sufficient to increase its obesogenic activity. The rationale for this proposed research is that defining TBT's impact on the assembly and obesogenic activity of the gut microbiota will lead to new approaches for preventing and treating obesity and associated morbidities in humans by reducing TBT-induced modifications to the gut microbiota. In Specific Aim 1, the working hypothesis to be tested is that exposure to TBT causes alterations in gut microbiota composition and host adiposity. Conventionally raised zebrafish will be chronically exposed to different doses of TBT and then high-throughput 16S rRNA gene sequencing and high-resolution in vivo imaging will be used to evaluate the effects of exposure on gut microbiota composition and adiposity, respectively. In Specific Aim 2, the working hypothesis to be examined is that TBT-induced alterations in gut microbiota composition confer increased obesogenic activity. Gut microbiotas will be transplanted from TBT-exposed and unexposed conventionally-raised zebrafish donors into unexposed germ-free zebrafish recipients, and then monitor the ability of the transplanted microbiota to promote adiposity in the recipient hosts. The contribution of this work will be significant because it will provide a much-needed vertical advance in our understanding of TBT-microbiota interactions and how those interactions impact host adiposity. The proposed research is innovative because it constitutes the first analysis of the impact of TBT exposures on gut microbiota composition in any animal and the consequences of TBT-induced alterations in gut microbiota composition on its obesogenic potential. The innovation of this research is further enhanced by our use of a vertebrate model that permits high-resolution in vivo analysis of adipose tissue, and the use of gnotobiotic hosts and microbiota transplants to directly test the impact of TBT exposure on the obesogenic potential of the gut microbiota.

描述（由申请人提供）：有机锡三丁基锡（TBT）是一种主要的环境毒素，可促进脊椎动物肥胖。众所周知，肠道微生物群也会导致肥胖，但尚不清楚三丁基锡化合物是否通过影响肠道微生物群的组成而在体内导致肥胖。此外，TBT诱导的肠道微生物群组成的改变是否足以改变宿主的肥胖仍然是未知的。这些知识差距很重要，因为如果没有这些信息，就不可能开发出通过减轻三丁基锡化合物和其他致肥剂对肠道微生物群的影响来预防肥胖和相关疾病的方法。本申请的总体目标是利用斑马鱼模型系统的优势，确定三丁基锡化合物对肠道微生物群的组装和致肥活性的影响。这项拟议的研究将检验核心假设，即TBT暴露会导致肠道微生物群的组成改变，足以增加其致肥活性这项拟议研究的基本原理是，确定三丁基锡化合物对肠道微生物群的组装和致肥活性的影响，将导致通过减少三丁基锡化合物对肠道微生物群的诱导改变来预防和治疗人类肥胖症和相关疾病的新方法。在具体目标1中，有待检验的工作假设是，接触三丁基锡化合物会导致肠道微生物群组成和宿主肥胖的改变。常规饲养的斑马鱼将长期暴露于不同剂量的三丁基锡化合物，然后将使用高通量16 S rRNA基因测序和高分辨率体内成像分别评估暴露对肠道微生物群组成和肥胖的影响。在具体目标2中，待检验的工作假设是TBT诱导的肠道微生物群组成的改变赋予增加的致肥胖活性。肠道微生物群将从TBT暴露和未暴露的常规饲养的斑马鱼供体移植到未暴露的无菌斑马鱼受体中，然后监测移植的微生物群促进受体宿主肥胖的能力。这项工作的贡献将是显著的，因为它将为我们理解TBT-微生物群相互作用以及这些相互作用如何影响宿主肥胖提供急需的纵向进展。拟议的研究具有创新性，因为它首次分析了三丁基锡化合物暴露对任何动物肠道微生物群组成的影响，以及三丁基锡化合物诱导的肠道微生物群组成改变对其致肥胖潜力的影响。这项研究的创新进一步加强了我们使用的脊椎动物模型，允许高分辨率的体内分析脂肪组织，并使用gnotobiotic宿主和微生物群移植直接测试，三丁基锡化合物暴露对肠道微生物群致肥潜力的影响。