Bacterial Regulation of Intestinal Lipid Metabolism

项目摘要 世界范围内的肥胖症流行呈现出严重的公共卫生危机，并且正在逐步恶化。这 已经导致了密集的努力，以确定宿主和环境因素，调节人体代谢， 能量平衡肠道微生物群已被确定为调节脂质的环境因素 在肠道中的代谢和吸收，从而促进高脂肪饮食诱导的肥胖。然而一个主要 关于调节肠道脂质吸收的特定细菌和宿主因素的知识缺口仍然存在， 新陈代谢.因此，本建议的总体目标是确定肠道细菌和宿主免疫 识别途径，调节肠道脂质代谢。我们小组先前的工作确定了 转录因子NFIL3作为肠道微生物群在高脂肪、高脂饮食小鼠中驱动肥胖的作用所必需。 糖西式饮食。NFIL3的表达受微生物群的调节，并促进NFIL3的转录。 肠上皮细胞基因调节脂质吸收和代谢。单菌落的初步研究 小鼠显示，有鞭毛的革兰氏阴性细菌诱导NFIL3表达。因此，我的中央 假设是革兰氏阴性鞭毛细菌物种，如大肠杆菌，选择性地促进脂质 肠上皮吸收。我将通过使用知菌鼠和基因操作来验证这一假设 老鼠和细菌。我的第一个目标是确定调节肠道脂质摄取的肠道细菌， 通过NFIL3代谢。单定殖小鼠将喂食西式饮食并分析脂质含量， 小肠中的基因表达变化和代谢综合征。然后我会用转基因的 细菌，以确定促进肠道脂质吸收所需的特定细菌因子。我的第二 目的是鉴定NFIL3调节的代谢产物的细菌活化所需的宿主免疫途径， 途径。将使用具有特定模式识别受体缺失的遗传改变小鼠来鉴定 脂质摄取和代谢所需的宿主因子。这些研究将提供新的见解， 微生物群调节宿主的脂质代谢，并应确定治疗干预的新途径 变成肥胖症。

Project Summary The worldwide obesity epidemic presents a significant public health crisis that is progressively worsening. This has led to intensive efforts to identify the host and environmental factors that regulate human metabolism and energy homeostasis. The gut microbiota has been identified as an environmental factor that regulates lipid metabolism and absorption in the intestine, and thus promotes high fat diet-induced obesity. However, a major knowledge gap remains about the specific bacterial and host factors that regulate intestinal lipid absorption and metabolism. The overall goal of this proposal is therefore to identify the intestinal bacteria and host immune recognition pathways that regulate intestinal lipid metabolism. Prior work by our group identified the circadian transcription factor NFIL3 as essential for the gut microbiota’s role in driving obesity in mice fed a high-fat, high sugar Western-style diet. NFIL3 expression is regulated by the microbiota, and promotes the transcription of intestinal epithelial genes that regulate lipid absorption and metabolism. Preliminary studies of monocolonized mice revealed that flagellated Gram-negative bacteria induced NFIL3 expression. Therefore, my central hypothesis is that Gram-negative flagellated bacterial species, such as Escherichia coli, selectively promote lipid absorption in intestinal epithelium. I will test this hypothesis by using gnotobiotic mice and genetic manipulation of both mice and bacteria. My first aim is to identify intestinal bacteria that regulate intestinal lipid uptake and metabolism through NFIL3. Monocolonized mice will be fed a Western style diet and analyzed for lipid content, gene expression changes in the small intestine, and metabolic syndrome. I will then use genetically-altered bacteria to identify specific bacterial factors that are required to promote intestinal lipid absorption. My second aim is to identify the host immune pathways that are required for bacterial activation of NFIL3-regulated metabolic pathways. Genetically altered mice with deletions of specific pattern recognition receptors will be used to identify host factors required for lipid uptake and metabolism. These studies will provide new insight into how the microbiota regulates lipid metabolism of the host and should identify new avenues for therapeutic interventions into obesity.