Project 3 - Ming Song

项目3-鸣歌

• 批准号: 10026257
• 负责人: Ming Song
• 金额: $ 21.84万
• 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/10026257
• 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.

项目名称：果糖在肠道中的代谢作用导致肠道微生物群失调 抽象。新出现的证据表明，肠道微生物群生态失调在肠道疾病中起着致病作用。 肥胖、2型糖尿病和NAFLD的发展。肠道“生理性缺氧”是维持平衡的关键。 肠道微生物群和肠道屏障功能。肠道“生理性缺氧”（即氧合）的紊乱导致 肠道微生物群失调我们的初步研究表明，长期喂食果糖或葡萄糖 在大鼠和小鼠中以类似的方式诱导肠道微生物群失调。此外，每日灌胃和长期灌胃 用果糖或葡萄糖喂养导致肠氧合，如HIF-1 α报告基因（ODD-luc）所示 小鼠，并且这种效果在使用葡萄糖的情况下更加强烈。考虑到果糖在缺氧条件下优先代谢， 葡萄糖可以通过多元醇途径迅速转化为果糖，拟议的研究将测试 假设肠道中的果糖代谢导致代谢重编程， 代谢途径从线粒体β-氧化到糖酵解，消耗较少的氧气。这反过来又导致 肠氧合，随后抑制专性厌氧菌的生长，并促进 病原菌的扩张。该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的代谢重编程，并确定这是否导致 肠道微生物群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性 这会导致肠道重新编程并导致肠道氧合，这反过来又导致肠道微生物群失调。目标二。 确定肠上皮细胞糖酵解活性的调节是否会改变肠道微生物群的组成。 我们假设通过6-磷酸果糖-2-激酶/果糖-2，6- 肠上皮细胞中的双磷酸酶（PFK 2）导致氧消耗率改变， 肠道菌群的改变。目标3.确定果糖在肠道中的代谢作用 有助于NAFLD的发展。我们将测试的假设，果糖的代谢作用， 肠道对NAFLD发展的影响是由肠道微生物群生态失调介导的。