Deconstructing Inflammation and Altered Microbiota in Metabolic Syndrome

人类正面临着一种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·戈登及其同事的开创性工作表明，代谢的一个核心组成部分， 综合征，即肥胖，受个体肠道微生物群介导能量的能力的影响 从摄入的食物中收获。我们的工作，这一竞争性的更新申请寻求维持， 提出了一个假设，即肠道微生物群在代谢综合征的许多方面起着关键作用 主要是通过驱动低度炎症。这一假设建立在“对 胰岛素抵抗”，旨在解释肥胖和2型糖尿病之间的因果关系。但我们的 一种假说认为，炎症不纯粹是肥胖的结果，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 代谢受体信号传导（例如胰岛素和瘦素受体）。在这项赠款下开展的工作表明， 微生物群组成的这种改变可能源于各种潜在原因，包括 先天性免疫缺陷、致病菌的及时存在或选择食品添加剂。改变的 微生物群不仅仅是炎症的标志物，而且在这些疾病中驱动炎症和代谢综合征。 小鼠模型是支持我们的示范，移植它们重演了低级别的 炎症/代谢综合征表型。虽然特定的微生物物种， 丰度的改变取决于小鼠品系、饲养场和低级别的潜在原因。 该项目揭示了与炎症模型相关的微生物群落的一般功能特征， 代谢综合征具体来说，我们已经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性免疫系统激活剂，此外， 层，从而侵入肠上皮细胞。我们的长期目标是确定 并开发出恢复更有益宿主-微生物群关系的方法 从而允许设计改善人类代谢综合征流行的模式。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.