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.

项目摘要 未能增加胰岛素分泌并减少胰岛素清除以克服组织胰岛素耐药性导致 2型糖尿病（T2D）的发展。胰岛素轴的成分（胰岛素敏感性，胰岛素分泌， 胰岛素清除率）对于T2D的起源至关重要，但是解释其功能障碍及其的因素 与其他因素的相互作用尚不清楚。饮食的营养成分通过 与肠道微生物群（微生物组）复杂相互作用的肠屏障以撞击葡萄糖 稳态。我们的假设是，三个胰岛素轴性状的变化与肠道微生物有关 组成和功能，这种关联是通过饮食成分（例如全谷物，红肉）来改变的 包括肠道菌群产生的全身短链脂肪酸。这项研究将评估胰岛素 轴，肠道菌群和饮食中的500名非糖尿病成年人（一半非裔美国人，一半非糖尿病成年人 西班牙裔白色）超过2。5年（在三个时间点进行采样）。特定的目标1将在每个诊所进行管理 访问，具有0、30、60、120分钟测量（胰岛素，葡萄糖和C肽）的75-G口腔葡萄糖挑战 确定胰岛素敏感性，分泌和清除；习惯饮食将通过使用经过验证的 食品频率问卷。特定的目标2将通过 在收集的粪便样品上进行16S rDNA测序和低通的宏基因组测序 三次访问。这些数据将共同检验以下假设，即胰岛素抵抗增加，胰岛素受损 随着时间的流逝，分泌和胰岛素清除率降低（所有糖尿病发生） 在减少（基线）或随着时间的推移（随着时间的流逝）中的丰度下降（随着时间的推移）脂肪酸酸产生的细菌 肠道，部分归因于不健康的饮食模式。特定目标3将利用在 三个时间点通过进行深宏基因组来探测肠道微生物组的功能曲线 在180个患者的子集中循环短链脂肪酸水平的测序和评估 与没有变化的胰岛素轴特征变化的极端变化（增加和减少），从而识别 胰岛素轴性状中改变与稳定性的微生物功能。这项研究的影响很高， 产生可能导致新型基于微生物组的诊断，预防和/或治疗的知识 措施（例如特定饮食；抗生素或益生菌治疗）减轻T2D的公共卫生负担。