Deconstructing Inflammation and Altered Microbiota In Metabolic Syndrome

解构代谢综合征中的炎症和改变的微生物群

• 批准号: 8891414
• 负责人: Andrew T Gewirtz
• 金额: $ 34.1万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8891414
• 关键词: Antibiotics; Automobile Driving; Bacteria; Bacterial Genes; Cardiovascular Diseases; Cells; Chronic; Communities; Complex; Data; Diabetes Mellitus; Disease; Epidemic; Fatty Liver; Flagellin; Future; Gene Expression; Germ-Free; Goals; Harvest; Health; Healthcare Systems; Human; Humanities; Hyperglycemia; Hyperlipidemia; Immune; Incidence; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Insulin Resistance; Intestines; Knowledge; Liver Dysfunction; Maintenance; Mastigophora; Measures; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Modeling; Molecular Mimicry; Mus; Natural Immunity; Obesity; Outcome; Persons; Play; Production; Proteins; Proteobacteria; Public Health; Relative (related person); Reporter; Risk; Role; Signal Transduction; System; Toll-Like Receptor 5; Transplantation; Work; disease phenotype; germ free isolator; gut microbiota; in vivo; mouse model; prevent; receptor

DESCRIPTION (provided by applicant): The intestinal tract is inhabited by a large diverse community of bacteria collectively referred to as the gut microbiota. Alterations in gut microbiota composition are associated with a variety of disease states including obesity, diabetes, and inflammatory bowel disease (IBD). Antibiotics alter host metabolism and transplant of microbiota from diseased persons (or mice) to germfree mice transfers some aspects of disease phenotype, suggesting that altered microbiota may play a role in disease manifestation. There are myriad potential mechanisms by which alterations in gut microbiota might promote disease including increasing energy harvest, production of toxic metabolites, and molecular mimicry of host proteins. Our study of mice with a discrete innate immune deficiency, namely loss of the flagellin receptor toll-like receptor 5 (TLR5), led us to hypothesize that an overarching mechanism by which an aberrant microbiota negatively impacts health is by driving chronic inflammation. More specifically, we hypothesize that the histopathologically-evident gut inflammation that defines IBD is a severe but relatively rare outcome of an altered host-microbiota relationship while a much more common consequence of such disturbances is "low-grade" inflammation, characterized by elevated proinflammatory gene expression that associates with, and may promote, metabolic syndrome. However, the extent to which altered microbiota are a cause and/or consequence of inflammation, and the mechanisms that mediate this interrelationship remains ill defined. Thus, the overall goal of this proposal is to decipher he interrelationship between microbiota composition, inflammatory signaling, and metabolic syndrome. We utilize WT and TLR5-deficient (T5KO) mice as a highly tractable model in which we can both control and measure microbiota composition and pro-inflammatory signaling. Specifically, we will: 1) Define the role of inflammasome activation in the low-grade inflammation, metabolic syndrome, and gut microbiota alterations in T5KO mice. 2) Determine how loss of TLR5 influences the pro-inflammatory potential of the gut microbiota. 3) Investigate the minimal requirements for T5KO metabolic syndrome. That TLR5- deficient humans may be prone to metabolic syndrome supports the relevance of these mechanistic studies. However, the broader importance of this work is that it will advance understanding of the normal means by which a stable microbiota is maintained and elucidate how alterations in microbiota, irrespective of underlying cause, can promote low-grade inflammation and metabolic syndrome.

描述（由申请人提供）：肠道中居住着大量不同的细菌群落，统称为肠道微生物群。肠道微生物群的改变 在某些实施方案中，组合物与多种疾病状态相关，包括肥胖症、糖尿病和炎性肠病（IBD）。抗生素改变宿主代谢，并且将微生物群从患病的人（或小鼠）移植到无菌小鼠转移疾病表型的某些方面，这表明改变的微生物群可能在疾病表现中起作用。肠道微生物群的改变可能会促进疾病，包括增加能量收获，产生有毒代谢物和宿主蛋白质的分子模拟。我们对患有离散先天性免疫缺陷的小鼠的研究，即鞭毛蛋白受体toll样受体5（TLR 5）的缺失，使我们假设异常微生物群对健康产生负面影响的总体机制是通过驱动慢性炎症。更具体地说，我们假设，定义IBD的组织病理学明显的肠道炎症是宿主-微生物群关系改变的严重但相对罕见的结果，而这种紊乱的更常见后果是“低度”炎症，其特征在于与代谢综合征相关并可能促进代谢综合征的促炎基因表达升高。然而，改变的微生物群是炎症的原因和/或后果的程度，以及介导这种相互关系的机制仍然不清楚。因此，该提案的总体目标是破译微生物群组成，炎症信号和代谢综合征之间的相互关系。我们利用WT和TLR 5缺陷（T5 KO）小鼠作为高度易处理的模型，其中我们可以控制和测量微生物群组成和促炎信号传导。具体而言，我们将：1）定义炎性小体活化在T5 KO小鼠中的低度炎症、代谢综合征和肠道微生物群改变中的作用。2)确定TLR 5的损失如何影响肠道微生物群的促炎潜力。3)调查T5 KO代谢综合征的最低要求。缺乏TLR 5的人可能容易患代谢综合征，这支持了这些机制研究的相关性。然而，这项工作更广泛的重要性在于，它将促进对维持稳定微生物群的正常手段的理解，并阐明微生物群的改变如何促进低度炎症和代谢综合征，无论其根本原因如何。