Deconstructing Inflammation and Altered Microbiota In Metabolic Syndrome

描述(申请人提供)：肠道中有一大片不同的细菌群落，统称为肠道微生物区系。肠道微生物区系的变化 成分与多种疾病状态有关，包括肥胖、糖尿病和炎症性肠病(IBD)。抗生素改变了宿主的代谢，将微生物区系从患病者(或小鼠)移植到无菌小鼠身上，转移了疾病表型的某些方面，提示改变的微生物区系可能在疾病表现中发挥作用。肠道微生物区系的改变可能通过多种潜在机制促进疾病，包括增加能量获取、有毒代谢物的产生和宿主蛋白的分子模仿。我们对患有离散先天性免疫缺陷的小鼠的研究，即鞭毛受体Toll样受体5(TLR5)的丢失，导致我们假设异常微生物群对健康产生负面影响的主要机制是通过推动慢性炎症。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-微生物区系关系改变的严重但相对罕见的结果，而这种紊乱的更常见的后果是“低级别”炎症，其特征是与代谢综合征相关的促炎基因表达升高，并可能促进代谢综合征。然而，微生物区系改变在多大程度上是炎症的原因和/或结果，以及调节这种相互关系的机制仍然不清楚。因此，这项建议的总体目标是破译微生物区系组成、炎症信号和代谢综合征之间的相互关系。我们利用WT和TLR5缺陷(T5KO)小鼠作为一个高度易处理的模型，在其中我们可以控制和测量微生物区系组成和促炎信号。具体地说，我们将：1)确定炎症小体激活在T5KO小鼠低度炎症、代谢综合征和肠道微生物区系改变中的作用。2)确定TLR5的缺失如何影响肠道微生物区系的促炎潜力。3)研究T5KO代谢综合征的最低要求。TLR5缺乏的人类可能容易患上代谢综合征，这支持了这些机械性研究的相关性。然而，这项工作的更广泛的重要性是，它将促进对维持稳定微生物区系的正常手段的理解，并阐明微生物区系的变化如何，无论潜在原因如何，都可以促进低度炎症和代谢综合征。

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.