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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).

摘要