Deconstructing Inflammation and Altered Microbiota in Metabolic Syndrome

解构代谢综合征中的炎症和改变的微生物群

• 批准号: 9194750
• 负责人: Andrew T Gewirtz
• 金额: $ 44.51万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9194750
• 关键词: Automobile Driving; Bacteria; Cardiovascular Diseases; Chronic; Detection; Development; Diabetes Mellitus; Diet; Disease; Epidemic; Epithelial; Epithelial Cells; Event; Fatty Liver; Fiber; Food; Food Additives; Funding; Goals; Grant; Harvest; Healthcare Systems; Hepatocyte; Human; Humanities; Hyperglycemia; Hyperlipidemia; Hypertension; Immune; Immune system; Incidence; Individual; Inflammation; Inflammatory; Insulin Receptor; Insulin Resistance; Intestines; Lead; Link; Liver; Liver Dysfunction; Liver diseases; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Modality; Modeling; Molecular; Mouse Strains; Mucous body substance; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Phenotype; Play; Public Health; Receptor Signaling; Reporting; Research; Risk; Role; Signal Transduction; TLR5 gene; Testing; Translating; Transplantation; Work; base; design; gut microbiota; human disease; improved; inflammatory marker; leptin receptor; lipid biosynthesis; microbial; microbiota; mouse model; non-alcoholic fatty liver; prevent; public health relevance; soluble fiber

Humanity is facing an epidemic of interrelated obesity-associated disorders including insulin-resistance, hyperlipidemia, hepatic steatosis and hypertension that are collectively referred to as metabolic syndrome. Pioneering work by Jeff Gordon and colleagues have demonstrated that a central component of metabolic syndrome, namely obesity, is influenced by the ability of an individual's intestinal microbiota to mediate energy harvest from ingested food. Our work, which this competitive renewal application seeks to sustain, has developed the hypothesis that gut microbiota plays a pivotal role in numerous aspects of metabolic syndrome primarily via driving low-grade inflammation. This hypothesis builds upon the "inflammatory explanation for insulin resistance" that seeks to explain the causal link between obesity and type 2 diabetes. However, our hypothesis holds that inflammation is not purely a consequence of obesity but, rather, alterations in gut microbiota drive low-grade inflammation that promote adiposity via driving lipogenesis and interfering with metabolic receptor signaling (e.g. insulin and leptin receptors). Work performed under this grant demonstrates that such alterations in microbiota composition can originate from a variety of underlying causes including an innate immune deficiency, timely presence of pathobiont bacteria, or select food additives. That altered microbiota are not merely a marker of inflammation but drive inflammation and metabolic syndrome in these mouse models is supported by our demonstration that transplanting them recapitulates the low-grade inflammation/metabolic syndrome phenotype in the recipients. While the specific microbial species whose abundance is altered differs depending upon mouse strain, vivarium, and underlying cause of low-grade inflammation, this project has revealed general functional features of microbiotas associated with models of metabolic syndrome. Specifically, we've observed that microbiotas associated with metabolic syndrome, in mice, express high levels of activators of the innate immune system and, moreover, penetrate the inner mucus layer thus encroaching upon intestinal epithelial cells. Our long-term goal is to define the molecular events that result in such alterations and develop approaches to restore a more beneficial host-microbiota relationship thus allowing design of modalities to ameliorate the metabolic syndrome epidemic in humans. Herein, we propose to advance toward this goal.

人类正面临着与肥胖相关的疾病的流行，包括胰岛素抵抗、 高脂血症、肝脂肪变性和高血压统称为代谢综合征。 杰夫·戈登（Jeff Gordon）及其同事的开创性工作表明，代谢的核心组成部分 综合症，即肥胖，受到个体肠道微生物群调节能量能力的影响 从摄入的食物中收获。我们的工作是这个有竞争力的续订申请所寻求维持的， 提出了肠道微生物群在代谢综合征的许多方面发挥关键作用的假设 主要通过驱动低度炎症。这一假设建立在“炎症性解释”的基础上 胰岛素抵抗”试图解释肥胖与 2 型糖尿病之间的因果关系。然而，我们的研究 假设认为炎症并不纯粹是肥胖的结果，而是肠道变化的结果 微生物群驱动低度炎症，通过驱动脂肪生成和干扰来促进肥胖 代谢受体信号传导（例如胰岛素和瘦素受体）。在这笔赠款下完成的工作表明 微生物群组成的这种变化可能源于多种潜在原因，包括 先天性免疫缺陷、致病菌及时存在或选择食品添加剂。那改变了 微生物群不仅是炎症的标志物，而且还驱动这些疾病的炎症和代谢综合征 小鼠模型得到了我们的演示的支持，即移植它们重现了低级 受者的炎症/代谢综合征表型。而特定的微生物物种其 丰度的改变取决于小鼠品系、饲养室和低等级的根本原因 炎症，该项目揭示了与炎症模型相关的微生物群的一般功能特征 代谢综合征。具体来说，我们观察到与代谢综合征相关的微生物群 小鼠，表达高水平的先天免疫系统激活剂，此外，还能渗透内部粘液 层从而侵入肠上皮细胞。我们的长期目标是定义分子事件 导致这种改变并开发恢复更有益的宿主-微生物群关系的方法 从而可以设计出改善人类代谢综合征流行的方法。在此，我们 建议朝着这个目标前进。