Prebiotics, Gut Microbiota, and Cardiometabolic Health

描述（由申请人提供）： 糖尿病前期与低级别慢性炎症相关，其不仅增加了发展2型糖尿病（T2 DM）的风险，而且还增加了患心血管疾病（CVD）相关事件的风险。与肠道微生物群的生态失调相关的脂多糖（或内毒素）浓度升高与T2 DM和CVD的发展有关。在啮齿动物模型中，用益生元选择性调节肠道微生物群可降低肠道通透性和内毒素浓度、全身和局部炎症以及代谢功能障碍。益生元补充剂对糖尿病前期人群心脏代谢功能的影响尚不清楚。该R21提案的总体目标是：1）确定补充益生元菊粉对糖尿病前期人类的心脏代谢功能的影响的可行性并建立概念验证，以便在未来进行更大、更全面的随机双盲安慰剂对照试验; 2）建立我们对肠渗透性测量和表征粪便细菌组成的熟练程度;和3）获得用于产生效应量的初步数据。为此，我们将48名糖尿病前期成人（50-75岁）随机分配至4周的益生元补充剂菊粉（10 g/天）或安慰剂（麦芽糊精）。 在研究期间，将从我们的代谢厨房为受试者提供所有食物，以避免个体间饮食摄入差异造成的潜在混淆。肠通透性的测量（糖探针），血清内毒素浓度（C因子内毒素检测试验），胰岛素敏感性（静脉葡萄糖耐量试验）、骨骼肌代谢灵活性（离体脂肪酸、葡萄糖和丙酮酸氧化），内皮功能（血流介导的扩张）、动脉僵硬将在基线和治疗4周后测量粪便细菌组成（压平眼压计和高分辨率超声）和粪便细菌组成（16 S rDNA焦磷酸测序）。这项创新的综合和翻译生理学研究将由一个既定的P. I.和研究团队，具有丰富的经验和成功进行针对心脏代谢功能障碍的干预研究的良好记录。这些研究具有重大的转化潜力，因为它们可能会将啮齿动物的基础科学发现推向人类。确定补充菊粉益生元作为降低糖尿病前期患者心脏代谢风险的简单有效的预防策略，可以通过告知饮食建议和增加科学和医学界对益生元的接受来改变临床实践。

DESCRIPTION (provided by applicant): Prediabetes is associated with a low grade chronic inflammation which increases the risk, not only for developing type 2 diabetes (T2DM), but also for suffering from cardiovascular disease (CVD)-related events. An elevated lipopolysaccharide (or endotoxin) concentrations, associated with dysbiosis of the intestinal microbiota, has been implicated in the development of both T2DM and CVD. Selective modulation of the intestinal microbiota with prebiotics reduces intestinal permeability and endotoxin concentrations, systemic and local inflammation, and metabolic dysfunction in rodent models. The effect of prebiotic supplementation on cardiometabolic function in prediabetic humans is not known. The general objectives of this R21 proposal are to: 1) determine the feasibility and establish proof-of-concept for the effects of supplementation with the prebiotic inulin on cardiometabolic function in prediabetic humans in order to conduct a larger, more comprehensive randomized double-blind placebo- controlled trial in the future; 2) establish our proficiency with measurements of intestinal permeability and characterizing fecal bacterial composition; and 3) obtain preliminary data for effect size generation. To this end, we will randomize 48 prediabetic adults (50-75 yrs) to 4 weeks of prebiotic supplementation with inulin (10 g/day) or placebo (maltodextrin). Subjects will be provided with all of their food for the duration of the study from our metabolic kitchen to avoid potential confounding through differences in dietary intake between individuals. Measurements of intestinal permeability (sugar probes), serum endotoxin concentrations (Factor C Endotoxin Detection Assay), insulin sensitivity (intravenous glucose tolerance testing), skeletal muscle metabolic flexibility (ex vivo fatty acid, glucose and pyruvate oxidation), endothelial function (flow-mediated dilatation), arterial stiffness (applanation tonometry and high resolution ultrasound), and fecal bacterial composition (16S rDNA pyrosequencing) will be measured at baseline and following 4 weeks of treatment. This innovative integrative and translational physiological study will be conducted by an established P.I. and investigative team with extensive experience and a strong record of success performing intervention studies targeting cardiometabolic dysfunction. These studies have significant translational potential as they may advance basic science findings in rodents to humans. The identification of prebiotic supplementation with inulin as a simple and efficacious adjunctive strategy for reducing cardiometabolic risk in prediabetics could change clinical practice by informing dietary recommendations and increasing acceptance of prebiotics by the scientific and medical community.