Project 3 - Ming Song

项目3-鸣歌

• 批准号: 10377898
• 负责人: Ming Song
• 金额: $ 21.56万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-10 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10377898
• 关键词: 6-Phosphofructo-2-kinase; Acute; Anaerobic Bacteria; Antibiotics; Butyrates; Centers of Research Excellence; Chronic; Clinical; Consumption; Development; Economic Burden; Energy Supply; Epithelial Cells; FDA approved; Feedback; Female; Fructose; Fructose-2,6-bisphosphatase; Gastrointestinal tract structure; Genetic; Glucose; Glycolysis; Growth; HIF1A gene; Health; Hyperglycemia; Hypoxia; Insulin Resistance; Intestines; Ketohexokinase; Liver; Liver diseases; Luciferases; Maintenance; Malignant Neoplasms; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Mitochondria; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Organ; Oxygen; Oxygen Consumption; Pathogenesis; Pathway interactions; Perfusion; Pharmacotherapy; Physiological; Play; Prevalence; Proteobacteria; Rattus; Reporter; Risk Factors; Rodent; Role; Site; Solid; Stress; Testing; Tight Junctions; Toxicology; United States; Upper digestive tract structure; cardiovascular disorder risk; cross-species transmission; dietary; drinking water; dysbiosis; fecal transplantation; feeding; gut microbiome; gut microbiota; intestinal epithelium; male; mortality; non-alcoholic fatty liver disease; obesity development; oxidation; pathogenic bacteria; polyol; preservation

Project Title: Metabolic effect of fructose in intestine induces gut microbiota dysbiosis Abstract. Emerging evidence has demonstrated that gut microbiota dysbiosis plays a causative role in the development of obesity, type 2 diabetes and NAFLD. Gut “physiologic hypoxia” is key to maintaining a balanced gut microbiota and gut barrier function. Disturbance of gut “physiologic hypoxia”, namely oxygenation, results in gut microbiota dysbiosis. Our preliminary studies have shown that chronic feeding with either fructose or glucose induces gut microbiota dysbiosis in a similar manner in rats and mice. Moreover, both daily gavage and chronic feeding with fructose or glucose results in intestinal oxygenation as shown by HIF-1 alpha reporter (ODD-luc) mice, and this effect is more robust with glucose. Given that fructose is preferentially metabolized under hypoxia, and glucose can be rapidly converted to fructose via the polyol pathway, the proposed studies will test the hypothesis that fructose metabolism in the intestine results in metabolic reprogramming which switches the host metabolic pathway from mitochondrial β-oxidation to glycolysis and consumes less oxygen. This, in turn, leads to intestinal oxygenation, subsequent inhibiting the growth of obligate anaerobic bacteria and facilitating the expansion of pathogenic bacteria. The hypothesis will be tested in three specific aims: Aim 1. Determine whether fructose induces metabolic reprogramming in intestinal epithelial cells and determine if this results in gut microbiota dysbiosis. We will test the hypothesis that fructose metabolism in the intestine results in metabolic reprogramming and leads to intestinal oxygenation, which in turn, results in gut microbiota dysbiosis. Aim 2. Determine whether modulation of glycolytic activity in intestinal epithelial cells alters gut microbiota composition. We hypothesize that genetic modulation of glycolytic activity via 6-phosphofructo-2-kinase/fructose-2,6- bisphosphatase (PFK2) in intestinal epithelial cells results in altered oxygen consumption rate which in turn leads to the alteration of gut microbiota. Aim 3. Determine whether the metabolic effect of fructose in intestine contributes to the development of NAFLD. We will test the hypothesis that the metabolic effects of fructose in intestine on the development of NAFLD is mediated by gut microbiota dysbiosis.

项目标题：果糖在肠道中的代谢作用导致肠道微生物区系失调 抽象的。越来越多的证据表明，肠道微生物区系失调在 肥胖、2型糖尿病和非酒精性脂肪肝的发展。肠道“生理性缺氧”是维持平衡的关键 肠道微生物区系和肠道屏障功能。肠道“生理性缺氧”的紊乱，即氧合，导致 肠道微生物区系失调。我们的初步研究表明，长期喂食果糖或葡萄糖 以类似的方式诱导大鼠和小鼠的肠道微生物区系失调。此外，无论是每日灌胃还是慢性灌胃 HIF-1α报告(ODD-LUC)显示，喂食果糖或葡萄糖会导致肠道氧合 小鼠，而且这种作用在葡萄糖的作用下更加强烈。鉴于果糖在低氧条件下优先代谢， 葡萄糖可以通过多元醇途径快速转化为果糖，拟议的研究将测试 假设肠道中的果糖代谢导致代谢重新编程，从而改变宿主 从线粒体β氧化到糖酵解的代谢途径，消耗更少的氧气。这反过来又导致了 促进肠道氧合，继而抑制专性厌氧菌的生长，促进 病原菌的扩张。这一假设将在三个具体目标中进行检验：目标1.确定 果糖是否诱导肠上皮细胞代谢重编程，并确定这是否会导致 肠道微生物区系失调。我们将检验这样一个假设，即肠道中的果糖代谢导致代谢 重新编程并导致肠道氧合，进而导致肠道微生物区系失调。目标2. 确定肠道上皮细胞糖酵解活性的调节是否改变肠道微生物区系组成。 我们推测，糖酵解活性的遗传调控是通过6-磷酸果糖-2-激酶/果糖-2，6-磷酸-2，6-磷酸。 肠上皮细胞中的二磷酸酶(PFK2)导致氧耗率改变，进而导致 肠道微生物区系的改变。目的3.测定果糖在肠道中的代谢作用 为NAFLD的发展做出了贡献。我们将检验这一假设，即果糖在人体内的代谢作用 肠道对NAFLD的发生发展是由肠道微生物区系失调介导的。