Deconstructing Inflammation and Altered Microbiota in Metabolic Syndrome

人类正面临着包括胰岛素抵抗在内的相互关联的肥胖相关疾病的流行， 高脂血症、肝脏脂肪变性和高血压统称为代谢综合征。 杰夫·戈登和他的同事们的开创性工作证明，新陈代谢的一个核心组成部分 综合症，即肥胖，受个人肠道微生物区系调节能量的能力的影响 从摄入的食物中收获。我们的工作，这项竞争性续签申请寻求支持的工作， 提出了肠道微生物区系在代谢综合征的许多方面起关键作用的假说 主要是通过推动低度炎症。这一假说建立在“炎症解释”的基础上 “胰岛素抵抗”试图解释肥胖和2型糖尿病之间的因果联系。 假说认为，炎症不仅仅是肥胖的结果，而是肠道的改变。 微生物区系驱动低度炎症，通过推动脂肪生成和干扰 代谢受体信号(如胰岛素和瘦素受体)。在这笔赠款下完成的工作展示了 微生物区系组成的这种变化可以由各种潜在原因引起，包括 先天免疫缺陷，及时出现致病菌，或精选食品添加剂。这一点改变了 微生物区系不仅是炎症的标志，而且还会导致炎症和代谢综合征 小鼠模型得到了我们的实验支持，即移植它们可以重现低级 受者的炎症/代谢综合征表型。而其特定的微生物种类 丰度的变化取决于小鼠的品系、和低级别的潜在原因。 炎症，这个项目揭示了与模型相关的微生物的一般功能特征 代谢综合征。具体地说，我们观察到微生物与代谢综合征有关，在 小鼠，表达高水平的天然免疫系统的激活物，而且，穿透内部粘液。 因此，这一层侵占了肠道上皮细胞。我们的长期目标是定义分子事件 这导致了这样的改变，并开发了恢复更有利的宿主-微生物区系关系的方法 从而允许设计模式来改善人类中的代谢综合征流行。在此，我们 建议朝着这个目标前进。

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.