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Interaction between genes, environment, the microbiome and metabolome in type 2 diabetes and metabolic syndrome

2 型糖尿病和代谢综合征中基因、环境、微生物组和代谢组之间的相互作用

基本信息

批准号：
10153768
负责人：
C RONALD KAHN
金额：
$ 54.82万
依托单位：
JOSLIN DIABETES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10153768
关键词：
Affect Antibiotics Biochemical Pathway Breeding Carbohydrates Cecum Communities Data Development Diabetes Mellitus Diet Disease Environment Epidemic Exercise Fatty acid glycerol esters Fructose Genes Genetic Genetic Risk Germ Germ-Free Glucose Intolerance Goals Grant High Fat Diet Human In Vitro Insulin Insulin Resistance Laboratories Laboratory mice Link Mediator of activation protein Metabolic Metabolic syndrome Metabolism Metagenomics Modeling Molecular Mouse Strains Mus Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Pathogenesis Phenotype Plasma Play Predisposition Process Production Resistance Rodent Role Type 2 diabetic Weight Work diabetes risk diet and exercise diet-induced obesity fecal transplantation gene environment interaction gene product gut microbiome gut microbiota in vivo insulin signaling metabolic phenotype metabolome metabolomics metagenome microbial microbiome microbiome alteration microbiota microbiota metabolites mouse model non-diabetic novel obesity development response

项目摘要

We are in the midst of a worldwide epidemic of diabetes and obesity. A central component of these disorders is insulin resistance. Insulin resistance is the product of gene-environment interactions. A recently identified major mediator of these gene-environment interactions is the gut microbiome. To begin to dissect the role of the microbiome in gene-environment interactions in the pathogenesis of type 2 diabetes and obesity, we have developed a novel model taking advantage of three strains of laboratory mice: C57Bl6/J and 129S1 mice from Jax (B6J and 129J) and 129S6 mice from Taconic (129T). When challenged with high fat diet (HFD), B6J mice are insulin resistant and obesity- and diabetes-prone, while 129J mice are insulin sensitive and obesity- and diabetes-resistant. 129T mice, which are similar genetically to 129J, on the other hand, gain almost as much weight as B6J mice on HFD, but remain insulin sensitive and non-diabetic, i.e., are a model of “metabolically healthy” obesity. While genetics plays a role in these phenotypic differences, the microbiome also contributes. Thus, some of these differences can be reduced or modified by breeding the mice in the same environment or by treating the mice with antibiotics to alter the microbiome. These differences in phenotype are paralleled by differences in insulin signaling at the molecular level. Importantly, the propensity to metabolic syndrome and abnormalities in insulin signaling can be transferred in part to germ-free mice by fecal transplant. Using non-targeted metabolomics, we have shown that these effects of the microbiome are associated with dramatic changes in the levels of multiple circulating metabolites, including both known and unknowns. The major goal of this project is to identify microbiota and metabolites which are altered by the changing microbiome and contribute to insulin resistance and metabolic dysregulation. The specific aims are: 1) Using our robust model of mice on three different genetic backgrounds, we will define how changes in gut microbiota, as assessed by metagenomic analysis, in response to high fat and high carbohydrate diets, as well as exercise, are related to alterations in insulin signaling and metabolic phenotype; we will also determine how host-genetics interacts with gut microbiota to affect the metabolome by microbiome transfer into mice with different genetic risk of diabetes and metabolic syndrome. 2) Define how changes in the community of microbiota and their metagenomic representation relate to changes in the plasma/cecal metabolome across all models, and how these contribute to the insulin resistance in these models. We will also integrate the metabolomics data to create complete metabolic networks. 3) Integrate metabolomic data across all models to prioritize the unknown metabolites linked to insulin resistance for identification; and determine how both the known and the newly-identified unknown metabolites linked to insulin resistance alter insulin signaling in vitro and in vivo. Together these data will allow us to define the role of the microbiome and its associated metabolome in insulin resistance and metabolic dysregulation and how these interact with host genetics in this process.

我们正处于糖尿病和肥胖症的全球流行之中。这些疾病的一个核心组成部分是胰岛素抵抗。胰岛素抵抗是基因与环境相互作用的产物。最近发现的这些基因-环境相互作用的主要媒介是肠道微生物组。为了开始分析微生物组在2型糖尿病和肥胖发病机制中基因-环境相互作用中的作用，我们利用三种实验室小鼠：来自Jax的C57Bl6/J和129S1小鼠（B6J和129J）和来自Taconic的129S6小鼠（129T）建立了一个新的模型。在高脂肪饮食（HFD）的刺激下，B6J小鼠表现出胰岛素抵抗、肥胖和易患糖尿病，而129J小鼠表现出胰岛素敏感、肥胖和易患糖尿病。另一方面，与129J基因相似的129T小鼠，在HFD上增加的体重几乎与B6J小鼠一样多，但仍保持胰岛素敏感和非糖尿病，即是“代谢健康”肥胖的模型。虽然基因在这些表型差异中起作用，但微生物组也起作用。因此，通过在相同的环境中饲养小鼠或用抗生素治疗小鼠以改变微生物组，可以减少或修改其中的一些差异。这些表型差异与胰岛素信号在分子水平上的差异是平行的。重要的是，代谢综合征的倾向和胰岛素信号异常可以通过粪便移植部分转移到无菌小鼠身上。使用非靶向代谢组学，我们已经表明，微生物组的这些影响与多种循环代谢物水平的急剧变化有关，包括已知的和未知的。该项目的主要目标是确定微生物群和代谢物，这些微生物群被变化的微生物群所改变，并有助于胰岛素抵抗和代谢失调。具体目标是：1)使用我们的三种不同遗传背景的小鼠模型，我们将定义通过宏基因组分析评估的肠道微生物群变化如何响应高脂肪和高碳水化合物饮食以及运动，与胰岛素信号传导和代谢表型的改变相关；我们还将确定宿主遗传学如何与肠道微生物群相互作用，通过将微生物组转移到具有不同糖尿病和代谢综合征遗传风险的小鼠中来影响代谢组。2)定义微生物群落及其宏基因组表征的变化如何与所有模型中血浆/盲肠代谢组的变化相关，以及这些变化如何促进这些模型中的胰岛素抵抗。我们还将整合代谢组学数据以创建完整的代谢网络。3)整合所有模型的代谢组学数据，优先考虑与胰岛素抵抗相关的未知代谢物进行鉴定；并确定已知和新发现的与胰岛素抵抗相关的未知代谢物如何在体外和体内改变胰岛素信号。这些数据将使我们能够确定微生物组及其相关代谢组在胰岛素中的作用