Prebiotics, Gut Microbiota, and Cardiometabolic Health

描述(由申请人提供)： 糖尿病前期与低度慢性炎症有关，这不仅增加了发生2型糖尿病(T2 DM)的风险，还增加了发生心血管疾病(CVD)相关事件的风险。与肠道微生物区系失调相关的脂多糖(或内毒素)浓度升高与T2 DM和CVD的发生有关。在啮齿动物模型中，用益生素选择性调节肠道微生物区系可以减少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。益生素补充剂对糖尿病前期患者心脏代谢功能的影响尚不清楚。这项R21建议的总体目标是：1)确定补充益生元菊粉对糖尿病前期人类心脏代谢功能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)建立我们对肠道通透性测量和粪便细菌组成特征的熟练程度；以及3)获得产生效果大小的初步数据。为此，我们将48名糖尿病前期成人(50-75岁)随机分为4周，分别补充菊粉(每天10g)或安慰剂(麦芽糊精)。在研究期间，受试者将从我们的新陈代谢厨房获得他们所有的食物，以避免由于个体之间饮食摄入的差异而可能产生的混淆。在基线和治疗4周后，将测量肠道通透性(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)、骨骼肌代谢弹性(体外脂肪酸、葡萄糖和丙酮酸氧化)、内皮功能(血流介导的扩张)、动脉僵硬(压平血压计和高分辨率超声)和粪便细菌组成(16S rDNA焦磷酸测序)。这项创新性、综合性和转化性的生理学研究将由一支成熟的P.I.和研究团队进行，他们拥有丰富的经验和成功执行针对心脏代谢功能障碍的干预研究的良好记录。这些研究具有巨大的翻译潜力，因为它们可能会将啮齿动物的基础科学发现推广到人类身上。将菊粉作为降低糖尿病前期患者心脏代谢风险的一种简单而有效的辅助策略来确定益生素补充剂，可以通过告知饮食建议和增加科学界和医学界对益生素的接受度来改变临床实践。

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.