Investigating Metabolically Protective Members of the Microbiota that Modulate Ceramides

项目摘要 患有肥胖症和2型糖尿病等代谢性疾病的人数正在以惊人的速度增长 全球发病率，越来越多地影响到年轻人口，并不成比例地影响到服务不足 社区。新出现的临床、流行病学和实验室研究表明， 肠道细菌在新陈代谢中的调节。这些代谢的另一个重要致病因素 疾病是鞘磷脂神经酰胺。神经酰胺的产生是对脂肪摄入量增加和 介导导致脂肪摄取增加、胰岛素抵抗和脂肪肝的许多分子途径 疾病。一些研究已经开始调查肠道微生物区系、神经酰胺和 代谢性疾病，并表明微生物区系可以调节神经酰胺的产生。尽管如此 研究表明，目前尚不清楚哪些细菌以及这些细菌如何影响神经酰胺的生产，并最终 寄主新陈代谢。我们的实验室已经鉴定出一种梭状芽胞杆菌类细菌群落，它为 通过减少体重增加、改善苗条和降低禁食来预防高脂肪饮食 葡萄糖。此外，我们还发现梭状芽胞杆菌降低了神经酰胺的产量。 这项建议的目标是了解哪些细菌对提供代谢保护和 确定这些细菌是如何影响神经酰胺合成和整个宿主代谢的。我们假设 筛选出的梭状芽胞杆菌可通过减少神经酰胺和 减少肠道上皮细胞对脂肪的吸收。我们将在两个目标上检验这一假设：1)定义社区 保护梭状芽胞杆菌免受高脂肪饮食引起的代谢性疾病的影响，以及2)确定 梭状芽胞杆菌可减少肠道上皮细胞对神经酰胺和脂肪的吸收。目标1号将继续进行遗传培养 描述并定义提供新陈代谢保护的最有限的梭状芽胞杆菌群落。目标2将 使用体外和活体方法对无菌(GF)和诺生菌小鼠模型进行评估 在脂质吸收的背景下，梭状芽胞杆菌和神经酰胺之间的关系。这项拟议的工作将具有重要的 通过对微生物区系驱动的新见解，对代谢性疾病和微生物区系的研究产生影响 可用于治疗效益的机制。

Project Summary The number of individuals with metabolic diseases like obesity and type 2 diabetes is growing at overwhelming rates globally, increasingly affecting younger populations, and disproportionally affect under-served communities. Emerging clinical, epidemiological, and laboratory research has demonstrated an essential role for gut bacteria in the regulation of metabolism. Another key contributor to the pathogenesis of these metabolic diseases are the sphingolipids ceramides. Ceramides are produced in response to increased fat intake and mediate many of the molecular pathways that cause increased lipid uptake, insulin resistance, and fatty liver disease. A few studies have begun to investigate the relationship between the gut microbiota, ceramides, and metabolic diseases, and have shown that the microbiota can regulate ceramide production. Despite these studies, it remains unclear which bacteria and how these bacteria impact ceramide production and ultimately host metabolism. Our lab has identified a community of Clostridia Class bacteria that provide metabolic protection from a high-fat diet in the form of decreased weight gain, improved leanness, and lower fasting glucose. Furthermore, we have found that Clostridia reduce the rate of ceramide production. The objective of this proposal is to understand which bacteria are essential to providing metabolic protection and determine how these bacteria are impacting ceramide synthesis and overall host metabolism. We hypothesize that select Clostridia bacteria can protect from features of metabolic disease through decreasing ceramides and reducing lipid absorption in the gut epithelium. We will test this hypothesis in two aims: 1) defining the community of Clostridia that protect from features of metabolic disease induced by a high-fat diet, and 2) determining if Clostridia decrease ceramides and lipid absorption in the gut epithelium. Aim 1 will continue to culture, genetically characterize, and define the most limited community of Clostridia that provides metabolic protection. Aim 2 will use in vitro and in vivo approaches with germ-free (GF) and gnotobiotic mouse models to assess the relationship between Clostridia and ceramides in the context of lipid absorption. This proposed work will have a significant impact on the study of the metabolic disease and the microbiota by providing novel insight into microbiota-driven mechanisms that can be leveraged for therapeutic benefit.