Organotin influences on assembly and obesogenic activity of the gut microbiota

描述(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。肠道微生物区系也是已知的促进肥胖的因素，但目前尚不清楚TBT是否通过影响肠道微生物区系的组成而在体内促进肥胖。此外，目前尚不清楚TBT诱导的肠道微生物区系组成的改变是否足以改变宿主的肥胖症。这些知识上的差距很重要，因为如果没有这些信息，就不太可能开发出通过减轻TBT和其他致肥物对肠道微生物区系的影响来预防肥胖症和相关疾病的方法。这项应用的总体目标是利用斑马鱼模型系统的优势来确定TBT对肠道微生物区系组装和有氧活动的影响。这项拟议的研究将检验中心假设，即TBT暴露会导致肠道微生物区系的成分改变，从而足以增加其 肥胖活动。这项拟议研究的基本原理是，定义TBT对肠道微生物区系的组装和肥胖活动的影响将导致通过减少TBT对肠道微生物区系的修改来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，需要检验的工作假设是 暴露于TBT会导致肠道微生物区系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TBT，然后将使用高通量16S 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区系组成和肥胖症的影响。在具体目标2中，需要检验的工作假设是，TBT诱导的肠道微生物区系组成的变化增加了肥胖活动。肠道微生物将从暴露于TBT和未暴露于TBT的常规饲养的斑马鱼捐赠者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重大的，因为它将在我们理解TBT-微生物区系相互作用以及这些相互作用如何影响宿主肥胖症方面提供亟需的纵向进展。这项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区系组成的影响，以及TBT引起的肠道微生物区系组成变化对其肥胖潜力的后果。这项研究的创新通过使用脊椎动物模型进一步加强，该模型允许对脂肪组织进行高分辨率的活体分析，并使用灵知菌宿主和微生物区系移植来直接测试 TBT暴露对肠道微生物区系致肥胖潜力的影响。

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.