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: 9323386
• 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/9323386
• 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; Hyperglycemia; Hyperlipidemia; Hypertension; Immune; Immune signaling; Incidence; Individual; Inflammation; Inflammatory; Innate Immune System; Insulin Receptor; Insulin Resistance; Intestines; Lead; Link; Liver; Liver Dysfunction; 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; TLR5 gene; Testing; Time; Translating; Transplantation; Work; base; cost; 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.

人类面临着相互关联的肥胖相关疾病的流行，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证明了代谢的中心部分 综合征，即肥胖，受个人肠道菌群介导能量的能力的影响 从摄入的食物中收获。我们的竞争性更新申请旨在维持的工作已有 提出了一个假设，即肠道菌群在代谢综合征的许多方面起着关键作用 主要是通过驱动低级炎症。该假设以“炎症解释为基础 胰岛素抵抗”试图解释肥胖与2型糖尿病之间的因果关系。但是，我们 假设认为炎症不仅是肥胖的结果，而是肠道的改变 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）。根据这笔赠款进行的工作证明了 微生物群组成的这种改变可以源自多种基本原因 先天免疫缺陷，病原细菌的及时存在或选择食物添加剂。发生了变化 微生物群不仅是炎症的标志，而且在这些炎症中驱动炎症和代谢综合征 我们的演示支持了鼠标模型，该演示将其移植概括了低级 受体中的炎症/代谢综合征表型。而特定的微生物物种 由于小鼠的应变，小体和低度的根本原因，丰度有所不同 炎症，该项目揭示了与模型相关的微生物群的一般功能特征 代谢综合征。具体而言，我们观察到与代谢综合征相关的微生物群在 小鼠，表达先天免疫系统的高水平激活剂，此外，可以穿透内部粘液 层因此侵占了肠上皮细胞。我们的长期目标是定义分子事件 这导致这种改变并开发方法以恢复更有益的宿主 - 微生物关系 因此，设计方式可以改善人类代谢综合征的流行。这里，我们 建议朝着这一目标迈进。