Investigating Metabolically Protective Members of the Microbiota that Modulate Ceramides

项目摘要 患有肥胖和2型糖尿病等代谢性疾病的人数正在以压倒性的速度增长， 在全球范围内，越来越多地影响到年轻人口， 社区.新兴的临床、流行病学和实验室研究表明， 肠道细菌在调节新陈代谢中的作用。另一个关键因素的发病机制，这些代谢 神经酰胺是神经鞘脂。神经酰胺的产生是对脂肪摄入量增加的反应， 介导许多导致脂质摄取增加、胰岛素抵抗和脂肪肝的分子途径 疾病一些研究已经开始调查肠道微生物群、神经酰胺和 代谢疾病，并已表明微生物群可以调节神经酰胺的产生。尽管有这些 目前还不清楚哪些细菌以及这些细菌如何影响神经酰胺的产生， 宿主代谢我们的实验室已经确定了一个社区的梭菌类细菌，提供代谢 保护免受高脂肪饮食的形式减少体重增加，改善精益，并减少空腹 葡萄糖此外，我们已经发现梭菌降低神经酰胺的产生速率。 本提案的目的是了解哪些细菌对提供代谢保护至关重要， 确定这些细菌如何影响神经酰胺合成和整体宿主代谢。我们假设 选择梭菌可以通过减少神经酰胺来保护代谢疾病的特征， 减少肠上皮中的脂质吸收。我们将从两个方面来检验这一假设：1）定义社区 保护免受高脂肪饮食诱导的代谢疾病特征的梭菌，以及2）确定 梭菌减少肠上皮细胞中的神经酰胺和脂质吸收。Aim 1将继续培养， 表征和定义提供代谢保护的最有限的梭菌群落。目标2将 使用无菌（GF）和无菌小鼠模型的体外和体内方法来评估 梭菌和神经酰胺在脂质吸收方面的关系。这项工作将具有重大意义。 对代谢性疾病和微生物群研究的影响，通过提供微生物群驱动的新见解， 这些机制可以用于治疗益处。

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.