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

• 批准号: 10348756
• 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
• 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/10348756
• 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

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.

我们正处于全球糖尿病和肥胖症流行之中。这些疾病的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与环境相互作用的主要调节者是肠道微生物组。为了开始剖析微生物组在 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品系开发了一种新模型：来自 Jax 的 C57Bl6/J 和 129S1 小鼠（B6J 和 129J）以及来自 Taconic 的 129S6 小鼠（129T）。当受到高脂肪饮食 (HFD) 挑战时，B6J 小鼠会出现胰岛素抵抗，并且容易出现肥胖和糖尿病，而 129J 小鼠则对胰岛素敏感，并且容易出现肥胖和糖尿病。另一方面，129T 小鼠在基因上与 129J 相似，在吃 HFD 时体重增加几乎与 B6J 小鼠一样多，但仍保持胰岛素敏感且非糖尿病，即是“代谢健康”肥胖的模型。虽然遗传学在这些表型差异中发挥着作用，但微生物组也有所贡献。因此，通过在相同环境中饲养小鼠或用抗生素治疗小鼠以改变微生物组，可以减少或改变其中一些差异。这些表型差异与分子水平上胰岛素信号传导的差异是平行的。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，我们发现微生物组的这些影响与多种循环代谢物（包括已知和未知的代谢物）水平的巨大变化有关。该项目的主要目标是确定微生物群和代谢物，这些微生物群和代谢物会因微生物群的变化而改变，并导致胰岛素抵抗和代谢失调。具体目标是：1）使用我们在三种不同遗传背景下的稳健小鼠模型，我们将通过宏基因组分析评估肠道微生物群的变化，以响应高脂肪和高碳水化合物饮食以及运动，从而确定肠道微生物群的变化如何与胰岛素信号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体内来影响代谢组。 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，以及这些变化如何导致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数据，优先识别与胰岛素抵抗相关的未知代谢物；并确定与胰岛素抵抗相关的已知和新发现的未知代谢物如何改变体外和体内的胰岛素信号传导。这些数据将使我们能够定义微生物组及其相关代谢组在胰岛素中的作用 抵抗力和代谢失调以及它们在此过程中如何与宿主遗传学相互作用。