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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）是一种重要的环境毒素，可促进脊椎动物肥胖。肠道微生物群也已知会促进肥胖，但尚不清楚TBT是否通过影响肠道微生物群的组成而在体内促进肥胖。此外，目前尚不清楚 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。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 TBT 和其他致肥胖因素对肠道微生物群的影响来预防肥胖和相关疾病的方法。该应用的总体目标是利用斑马鱼模型系统的优势来确定 TBT 对肠道微生物群组装和致肥活性的影响。拟议的研究将检验一个中心假设，即 TBT 暴露会导致肠道微生物群的组成发生改变，从而足以增加其肠道微生物群的数量。致肥胖活动。这项拟议研究的基本原理是，确定 TBT 对肠道微生物群组装和致肥活性的影响，将通过减少 TBT 引起的肠道微生物群改变，找到预防和治疗人类肥胖及相关疾病的新方法。在具体目标 1 中，要检验的工作假设是接触 TBT 会导致肠道微生物群组成和宿主肥胖的改变。传统饲养的斑马鱼将长期暴露于不同剂量的 TBT，然后使用高通量 16S rRNA 基因测序和高分辨率体内成像来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，要检验的工作假设是 TBT 诱导的肠道微生物群组成的改变导致肥胖活性增加。肠道微生物群将从暴露于TBT和未暴露的常规饲养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巨大的，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 TBT 暴露对任何动物肠道微生物群组成的影响，以及 TBT 引起的肠道微生物群组成变化对其致肥潜力的影响。我们使用脊椎动物模型进一步增强了这项研究的创新性，该模型允许对脂肪组织进行高分辨率体内分析，并使用无菌宿主和微生物移植来直接测试 TBT 暴露对肠道微生物群致肥潜力的影响。