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

基本信息

批准号：
10542824
负责人：
Andrew T Gewirtz
金额：
$ 49.61万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10542824
关键词：
16S ribosomal RNA sequencing Ablation Adipocytes Adipose tissue American Antibiotics Antibodies Antigens Applications Grants Automobile Driving Bacteria Biopsy Cardiovascular Diseases Chronic Colon Cost of Illness Coupled Diabetes Mellitus Diet Disease Epidemic Event Exhibits Fatty Liver Flagellin Food Supply Gene Expression Genetic Engineering Germ-Free Gnotobiotic Human Humanities 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 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 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

项目摘要

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).

抽象的人类正面临着一系列相互关联的肥胖相关疾病的流行，这些疾病统称为代谢性疾病。 Met Syn 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，所有这些都可能发展为高发病率和昂贵的疾病，例如糖尿病，心血管疾病和肝功能衰竭与全身慢性低度炎症有关。 (LGI)。LGI 不仅仅是 Met Syn 的标志物，而且 LGI 还会干扰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 更好。了解 LGI 的根本原因与管理 Met Syn 流行病密切相关。 LGI 的原因包括肥胖本身会导致脂质超载，从而导致内质网然而，应激会诱导促炎基因表达，从而定义了 LGI。寻求更新的结果表明，LGI 以及随后的 Met Syn 也可能源于管理不善肠道微生物群，实际上是 Met Syn 的许多方面所必需的，而我们的假设是 Met Syn 的改变。微生物群促进 LGI/Met Syn 源自对具有基因工程先天免疫的小鼠的研究缺陷，即缺乏鞭毛蛋白受体 Toll 样受体 5 (TLR5)，此后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群宿主事实上，我们发现一个中心 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部粘液中这种微生物群的侵入可以激活肠道中的促炎信号和/或导致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。相比之下，缺乏微生物群侵蚀的肥胖人类也缺乏 Met Syn 。此外，在小鼠中，Met Syn 的消除。通过抗生素、无菌状态或维持无菌小鼠不含病原体来维持微生物群微生物组，导致看似类似的“健康肥胖”状态，以响应西式饮食（WSD），这些结果强调了我们的中心假设，即微生物群的入侵是一个关键。该假设认为，可以预防或逆转微生物群。侵蚀将改善 Met Syn。因此，我们将建议识别侵蚀细菌（目标 1）和定义它们如何驱动 LGI 并影响新陈代谢（目标 2）。免疫系统，以减少微生物群的侵入并改善 Met Syn（目标 3）。