DECONSTRUCTING INFLAMMATION AND ALTERED MICROBIOTA IN METABOLIC SYNDROME

摘要 人类正面临着一种流行病的相互关联的肥胖相关的疾病统称为代谢 Met Syn综合征。Met Syn的主要特征包括胰岛素抵抗、高脂血症、肝脂肪变性 和高血压，所有这些都可以发展成高度病态和昂贵的疾病，如糖尿病， 心血管疾病和肝功能衰竭Met Syn与系统性慢性低度炎症相关 （LGI）。LGI不仅是Met Syn的标志物，而且LGI干扰了一系列代谢信号传导 途径，包括胰岛素和瘦素信号传导，使得慢性LGI促进Met Syn。因此， 了解LGI的根本原因与管理Met Syn流行病密切相关。提出 LGI的原因包括肥胖本身导致脂质过载，导致内质网 应激诱导定义LGI的促炎基因表达。然而，批准这项申请 寻求更新表明，LGI，以及随后的Met Syn，也可能源于对 肠道微生物群，事实上，这是Met Syn的许多方面所需的。虽然我们的假设是改变 微生物群促进LGI/Met Syn起源于基因工程先天免疫小鼠的研究 缺乏，即缺乏鞭毛蛋白受体toll样受体5（TLR 5），它已经被证明适用于 了解饮食，特别是食品供应的工业化，可能会改变微生物宿主 以促进LGI和随后的Met Syn的方式建立关系。事实上，我们发现， 在小鼠和人类中，Met Syn的特征是细菌渗透到通常接近无菌的内部粘液中 层.这样的微生物群侵入可以激活肠中的促炎信号传导和/或导致肠道炎症。 细菌及其产物易位到肝脏和脂肪组织中，从而驱动这些器官中的LGI。在 相反，缺乏微生物群侵入的肥胖人也缺乏Met Syn。此外，在小鼠中， 通过抗生素，无菌状态，或维持无致病菌的gnotobiotic小鼠 微生物组，导致一种看似类似的“健康肥胖”状态，以应对西式饮食 （水务署）。总之，这些结果强调了我们的核心假设，即微生物群的侵入是一个关键因素。 事件驱动LGI，随后Met Syn。这一假说认为，预防或逆转微生物群 侵蚀将改善Met Syn。因此，我们将提出识别入侵细菌（目标1）， 定义它们如何驱动LGI和影响新陈代谢（目标2）。此外，我们将开发培训 免疫系统以减少微生物群侵入并改善Met Syn（目的3）。

Abstract Humanity is facing an epidemic of interrelated obesity-associated disorders collectively referred to as metabolic syndrome (Met Syn). Central features of Met Syn include insulin-resistance, hyperlipidemia, hepatic steatosis and hypertension, all of which can progress to highly morbid and costly diseases such as diabetes, cardiovascular disease, and liver failure. Met Syn is associated with systemic chronic low-grade inflammation (LGI). LGI is not merely a marker of Met Syn but, rather, LGI interferes with a panoply of metabolic signaling pathways, including insulin and leptin signaling, such that chronic LGI promotes Met Syn. Thus, better understanding of the underlying causes of LGI is germane to managing the Met Syn epidemic. Proposed causes of LGI include the notion that obesity itself leads to lipid overload, resulting in endoplasmic reticulum stress that induces the pro-inflammatory gene expression that defines LGI. However, the grant this application seeks to renew has shown that LGI, and subsequently Met Syn, can also originate from poor management of gut microbiota, which is, in fact, required for many aspects of Met Syn. While our hypothesis that alterations in microbiota promote LGI/Met Syn originated from study of mice with a genetically engineered innate immune deficiency, namely lack of the flagellin receptor toll-like receptor 5 (TLR5) it has since proven applicable to understanding how diet, particularly industrialization of the food supply, might be altering the microbiota-host relationship in a manner that promotes LGI and, subsequently, Met Syn. Indeed, we’ve found that a central feature of Met Syn in both mice and humans, is infiltration of bacteria into the normally near-sterile inner mucus layer. Such microbiota encroachment can activate pro-inflammatory signaling in the intestine and/or result in translocation of bacteria, and their products, into liver and adipose tissue thus driving LGI in these organs. In contrast, obese humans lacking microbiota encroachment also lacked Met Syn . Moreover, in mice, ablation of microbiota via antibiotics, germfree status, or maintaining gnotobiotic mice with the pathobiont-free microbiome, results in a seemingly analogous state of “healthy obesity” in response to a western-style diet (WSD). Together, these results underscore our central hypothesis that microbiota encroachment is a pivotal event in driving LGI and, subsequently Met Syn. This hypothesis holds that preventing or reversing microbiota encroachment will ameliorate Met Syn. Hence, we will propose to identify encroaching bacteria (Aim 1) and define how they drive LGI and impact metabolism (Aim 2). Furthermore, we will develop means to train the immune system to reduce microbiota encroachment and ameliorate Met Syn (Aim 3).