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）：肠道居住着大量多样化的细菌群落，统称为肠道微生物群。肠道微生物群的改变 成分与多种疾病状态相关，包括肥胖、糖尿病和炎症性肠病（IBD）。抗生素改变宿主代谢，将患病者（或小鼠）的微生物群移植到无菌小鼠体内会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发挥作用。肠道微生物群的改变可能通过多种潜在机制促进疾病，包括增加能量收获、有毒代谢物的产生以及宿主蛋白质的分子模拟。我们对患有离散先天免疫缺陷（即鞭毛蛋白受体 Toll 样受体 5 (TLR5) 缺失）的小鼠进行的研究使我们推测，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 的组织病理学上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，而这种干扰的更常见后果是“低度”炎症，其特征是促炎基因表达升高，与代谢综合征相关，并可能促进代谢综合征。然而，微生物群改变在多大程度上是炎症的原因和/或结果，以及介导这种相互关系的机制仍然不明确。因此，该提案的总体目标是破译微生物群组成、炎症信号传导和代谢综合征之间的相互关系。我们利用 WT 和 TLR5 缺陷 (T5KO) 小鼠作为高度易处理的模型，在其中我们可以控制和测量微生物群组成和促炎信号传导。具体来说，我们将： 1) 定义炎症小体激活在 T5KO 小鼠低度炎症、代谢综合征和肠道微生物群改变中的作用。 2) 确定 TLR5 的缺失如何影响肠道微生物群的促炎潜力。 3) 研究T5KO代谢综合征的最低要求。 TLR5 缺陷的人类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，它将增进对维持稳定微生物群的正常方式的理解，并阐明微生物群的改变（无论根本原因如何）如何促进低度炎症和代谢综合征。