DECONSTRUCTING INFLAMMATION AND ALTERED MICROBIOTA IN METABOLIC SYNDROME

摘要 人类正面临一种相互关联的肥胖相关疾病的流行，统称为代谢性疾病 综合征(Met Syn)。Met Syn的主要特征包括胰岛素抵抗、高脂血症、肝脏脂肪变性 和高血压，所有这些都可能发展为高度病态和代价高昂的疾病，如糖尿病， 心血管疾病和肝功能衰竭。MET-Syn与全身性慢性低度炎症相关 (LGI)。LGI不仅是Met Syn的标志，而且还干扰代谢信号的整个过程 途径，包括胰岛素和瘦素信号，如慢性LGI促进Met Syn。因此，更好地 了解LGI的根本原因对控制Met Syn疫情是至关重要的。建议 导致LGI的原因包括肥胖本身会导致脂质过载，从而导致内质网 诱导定义LGI的促炎基因表达的压力。然而，批准这一申请 Seek to Renew表明，LGI以及随后的Met Syn也可能源于管理不善 肠道微生物区系，这实际上是Met Syn的许多方面所必需的。虽然我们的假设是 微生物区系促进LGI/Met Syn起源于对具有基因工程先天免疫的小鼠的研究 缺乏，即缺乏鞭毛受体Toll样受体5(TLR5)，这已被证明适用于 了解饮食，特别是食品供应的工业化，可能如何改变微生物区系宿主 以一种促进LGI和随后Met Syn的方式建立关系。事实上，我们发现了一个中央 Met Syn在小鼠和人类中的特征是细菌渗透到通常接近无菌的内粘液中 一层。这种微生物群侵袭可以激活肠道中的促炎信号和/或导致 细菌及其产物移位到肝脏和脂肪组织，从而在这些器官中驱动LGI。在……里面 相比之下，缺乏微生物区系侵袭的肥胖者也缺乏Met Syn。此外，在小鼠身上，消融 微生物区系通过抗生素、无菌状态，或维持灵知生菌的小鼠无病原体 微生物组，导致一种似乎类似于西式饮食的“健康肥胖症”状态 (水务署)。总之，这些结果强调了我们的中心假设，即微生物区系入侵是一个关键因素 在驾驶LGI和随后的Met Syn时发生的事件。这一假说认为，阻止或逆转微生物区系 侵占将改善大都会歌剧院。因此，我们将建议确定入侵细菌(目标1)和 确定它们如何驱动LGI并影响新陈代谢(目标2)。此外，我们将开发方法来培训 免疫系统，以减少微生物群的侵袭和改善Met Syn(目标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).