DECONSTRUCTING INFLAMMATION AND ALTERED MICROBIOTA IN METABOLIC SYNDROME

解构代谢综合征中的炎症和微生物群改变

• 批准号: 10323678
• 负责人: Andrew T Gewirtz
• 金额: $ 49.64万
• 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 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323678
• 关键词: 16S ribosomal RNA sequencing; Ablation; Adipocytes; Adipose tissue; American; Antibiotics; Antibodies; Antigens; Applications Grants; Automobile Driving; Bacteria; Biopsy; Cardiovascular Diseases; Chronic; Cost of Illness; Coupled; Diabetes Mellitus; Diet; Disease; Epidemic; Event; Exhibits; Fatty Liver; Flagellin; Food Supply; Gene Expression; Genetic Engineering; Gnotobiotic; Human; Hyperglycemia; Hyperlipidemia; Hypertension; Immune; Immune system; Immunization; Immunoglobulin A; Incidence; Industrialization; Infiltration; Inflammation; Inflammatory; Insulin; Insulin Resistance; Intestines; Leptin; Lipids; Liver; Liver Failure; Metabolic; Metabolic Diseases; Metabolic Marker; Metabolic syndrome; Metabolism; Mucosal Immunity; Mucous Membrane; Mucous body substance; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oral; Organ; Phagocytes; Role; Signal Pathway; Signal Transduction; Sterility; TLR5 gene; Toll-like receptors; Training; Vaccinated; Work; base; combat; diet-induced obesity; endoplasmic reticulum stress; gastrointestinal epithelium; gut microbiota; host microbiota; laser capture microdissection; microbiome; microbiota; nanoparticle; novel; pathobiont; prevent; public health emergency; public health relevance; response; western diet

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).

抽象的 人类面临着相互关联的肥胖相关疾病的流行 综合征（Met Syn）。 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为高度病态和昂贵的疾病，例如糖尿病， 心血管疾病和肝衰竭。 MET SYN与全身性慢性低级炎症有关 （LGI）。 LGI不仅是Met Syn的标记，而且LGI会干扰代谢信号 途径，包括胰岛素和瘦素信号传导，使得慢性LGI促进MET SYN。那更好 了解LGI的基本原因是管理MET Syn流行的特有的。建议的 LGI的原因包括肥胖本身导致脂质超负荷的概念，导致内质网 引起定义LGI的促炎基因表达的压力。但是，赠款此申请 寻求更新 肠道微生物群，实际上是Met Syn的许多方面所需的。而我们的变化的假设 微生物群促进LGI/MET SYN源自具有一般工程的先天免疫的小鼠的研究 不足，即缺乏鞭毛蛋白受体收费受体5（TLR5），此后已证明适用于 了解饮食，尤其是粮食供应的工业化，可能正在改变微生物群岛宿主 以促进LGI并随后遇到Syn的方式的关系。确实，我们发现了一个中央 在小鼠和人类中，MET SYN的特征是细菌浸润通常近感染内部粘液 层。这种菌群侵占可以激活肠道中的促炎信号传导和/或导致 细菌及其产物的易位进入肝脏和脂肪组织，从而在这些器官中驱动LGI。 对比，缺乏编码微生物群的肥胖人也缺乏SYN。而且，在老鼠中的消融 通过抗生素，免疫状态或维持无病病的小鼠的菌群 微生物组，导致对西方饮食的看似类似的“健康肥胖”状态 （WSD）。总之，这些结果强调了我们的核心假设，即微生物群是一个关键 驾驶LGI的事件，随后遇到SYN。该假设认为预防或逆转微生物群 侵占将改善MET SYN。因此，我们将建议识别细菌（AIM 1）和 定义它们如何驱动LGI并影响代谢（AIM 2）。此外，我们将发展手段来训练 免疫系统减少菌群侵占和改善MET SYN（AIM 3）。