Impact of the gut microbiome and diet on change in insulin homeostasis and cardiometabolic risk

肠道微生物组和饮食对胰岛素稳态变化和心脏代谢风险的影响

• 批准号: 9924526
• 负责人: Mark Goodarzi
• 金额: $ 58.34万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9924526
• 关键词: Adult; Affect; African American; Antibiotics; Antiinflammatory Effect; Bacteria; Beverages; Biological Assay; Blood Circulation; Butyrates; C-Peptide; Clinic Visits; Collection; Communities; Complex; Data; Deterioration; Development; Diabetes Mellitus; Diagnostic; Diet; Dietary Component; Dietary Fiber; Dietary Practices; Elements; Endocrinology; Equilibrium; Ethnic group; Evaluation; Excision; Failure; Fasting; Feces; Fishes; Food; Frequencies; Functional disorder; Gastrointestinal tract structure; Glucose; Harvest; Homeostasis; Hour; Human; Impairment; Individual; Insulin; Insulin Resistance; Intake; Knowledge; Lead; Measurement; Measures; Meat; Mediating; Metabolic; Metabolism; Metagenomics; Microbiology; Mission; Modeling; Modification; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Not Hispanic or Latino; Nutritional; Nuts; Oral; Organism; Participant; Phenotype; Population; Potato; Prediabetes syndrome; Prevention; Preventive treatment; Probiotics; Processed Meats; Prospective Studies; Prospective cohort study; Protocols documentation; Public Health; Questionnaires; Race; Recombinant DNA; Research; Research Personnel; Ribosomal DNA; Risk; Risk Factors; Role; Sampling; Seeds; Standardization; Testing; Time; Tissues; Variant; Visit; Volatile Fatty Acids; base; blood glucose regulation; cardiometabolic risk; cohort; diabetes risk; diabetogenic; experience; fruits and vegetables; glucose tolerance; good diet; gut bacteria; gut microbiome; gut microbiota; individual variation; innovation; insight; insulin secretion; insulin sensitivity; intestinal barrier; metagenomic sequencing; microbial; microbiome; microbiota; microorganism; non-diabetic; novel; nutrition; obesity risk; oral glucose tolerance; recruit; stool sample; sugar; trait

PROJECT SUMMARY Failure to increase insulin secretion and reduce insulin clearance to overcome tissue insulin resistance leads to the development of type 2 diabetes (T2D). Components of the insulin axis (insulin sensitivity, insulin secretion, insulin clearance) are critical to the genesis of T2D, yet the factors that account for their dysfunction and their interactions with other factors are not understood. The nutritional components of diet pass through the intestinal barrier in a complex interaction with the gut microbiota (the microbiome) to impact glucose homeostasis. Our hypothesis is that change in three insulin axis traits is associated with gut microbial composition and function, and this association is modified by dietary components (e.g., whole grains, red meat) including systemic short chain fatty acids produced by the gut microbiota. This study will assess the insulin axis, the gut microbiota and diet in a cohort of 500 non-diabetic adults (half African American, half non- Hispanic White) over 2.5 years (sampled at three time points). Specific Aim 1 will administer, at each clinic visit, a 75-g oral glucose challenge with 0, 30, 60, 120 min measurements (of insulin, glucose, and C-peptide) to determine insulin sensitivity, secretion, and clearance; habitual diet will be determined by use of a validated Food Frequency Questionnaire. Specific Aim 2 will characterize the gut microbiome for each participant by performing 16S rDNA sequencing and low-pass metagenomic sequencing on stool samples collected at all three visits. Together, these data will test the hypothesis that increased insulin resistance, impaired insulin secretion, and decreased insulin clearance (all diabetogenic changes) developing over time are associated with a reduced (at baseline) or declining (over time) abundance of short chain fatty acid-producing bacteria in the gut, in part attributable to unhealthy dietary patterns. Specific Aim 3 will utilize samples collected at the three time points to probe the functional profile of the gut microbiome by conducting deep metagenomic sequencing and assessment of circulating short chain fatty acid levels in a subset of 180 individuals with extreme changes (increase and decrease) versus those with no change in insulin axis traits, thereby identifying microbial functions that underlie change versus stability in insulin axis traits. This study has high impact, yielding knowledge that can lead to novel microbiome-based diagnostics, prevention, and/or treatment measures (e.g., specific diets; antibiotic or probiotic treatment) to reduce the public health burden of T2D.

项目总结 未能增加胰岛素分泌和减少胰岛素清除以克服组织胰岛素抵抗会导致 2型糖尿病(T2D)的发展。胰岛素轴的组成部分(胰岛素敏感性、胰岛素分泌、 胰岛素清除)对T2D的发生至关重要，然而导致它们功能障碍的因素和它们的 与其他因素的相互作用尚不清楚。饮食的营养成分通过 肠道屏障与肠道微生物区系(微生物组)复杂的相互作用影响血糖 动态平衡。我们的假设是，三个胰岛素轴特征的变化与肠道微生物有关 组成和功能，这种联系被饮食成分(例如，全谷物、红肉)改变 包括肠道微生物区系产生的全身性短链脂肪酸。这项研究将评估胰岛素 Axis在500名非糖尿病成年人(一半是非洲裔美国人，一半是非糖尿病人)的队列中的肠道微生物区系和饮食 西班牙裔白人)超过2.5年(在三个时间点抽样)。具体目标1将在每个诊所实施 访问，75克口服葡萄糖挑战，0，30，60,120分钟测量(胰岛素，葡萄糖和C-肽) 确定胰岛素敏感性、分泌量和清除量；习惯饮食将通过使用有效的 食物频率调查问卷。具体目标2将通过以下方式描述每个参与者的肠道微生物群 对采集的粪便样本进行16S rDNA测序和低通元基因组测序 三次拜访。总而言之，这些数据将检验这样一个假设，即胰岛素抵抗增加，胰岛素受损 随着时间的推移，胰岛素分泌和胰岛素清除量下降(都是糖尿病引起的变化)是相关的。 随着生产短链脂肪酸的细菌的数量减少(在基线上)或下降(随着时间的推移)， 肠道，部分归因于不健康的饮食模式。具体目标3将利用在 三个时间点通过进行深层元基因组研究肠道微生物组的功能图谱 180例慢性支气管炎患者循环短链脂肪酸水平的测序和评估 胰岛素轴特征的极端变化(增加和减少)与没有变化的相比，从而识别 胰岛素轴特性变化与稳定的基础微生物功能。这项研究影响很大， 产生可导致新的基于微生物组的诊断、预防和/或治疗的知识 采取措施(例如，特定的饮食；抗生素或益生菌治疗)，以减少T2D的公共卫生负担。