Gut microbiota, short chain fatty acids, and adiposity across the epidemiologic transition

流行病学转变过程中的肠道微生物群、短链脂肪酸和肥胖

• 批准号: 9903285
• 负责人: Lara Ruth Dugas
• 金额: $ 58.04万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 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/9903285
• 关键词: Acetates; Address; Adult; African; Biological Markers; Body Composition; Butyrates; Carbohydrates; Complex; Data; Diet; Economic Development; Environment; Environmental Exposure; Epidemiology; Etiology; Feces; Geographic Distribution; Geography; Ghana; Goals; Health; Human; Individual; Jamaica; Lead; Measurement; Measures; Mediating; Mediation; Mediator of activation protein; Metabolic; Metabolic Diseases; Modeling; Nutrient; Obesity; Obesity Epidemic; Participant; Pathway interactions; Pattern; Physical activity; Play; Population; Population Heterogeneity; Population Study; Populations at Risk; Prevalence; Production; Propionates; Research; Research Design; Risk; Risk Factors; Role; Sample Size; Seychelles; Site; Social Development; South Africa; Testing; Validation; Variant; Volatile Fatty Acids; Weight; Work; cohort; design; epidemiological model; gut microbiota; improved; insight; longitudinal design; microbial; microbiota; microorganism; multidisciplinary; new therapeutic target; novel; novel therapeutics; obesity development; obesity risk; obesity treatment; obesogenic; prospective; public health relevance; therapeutic target

Project summary The objective of this study is to define associations between gut microbiota, short chain fatty acids (SCFAs) and obesity in populations spanning the epidemiologic transition, and explore mechanisms by which these factors may independently and collectively influence the development of obesity. The gut microbiota and SCFAs have been associated with obesity, yet the causal mechanisms are unknown, as are the individual obesogenic effects of the individual SCFAs (butyrate, acetate and propionate). Existing studies are, limited by contradictory findings, small sample sizes, limited and imprecise measurements of obesity, and lack of detailed dietary and other environmental exposures/mediators. We propose to overcome these challenges by leveraging an existing cohort of five diverse, well-defined populations from the Modeling the Epidemiologic Transition Study (METS, R01-DK080763). METS is comprised of a cohort of 2,500 African-origin adults, living in 5 distinctly different environments; Ghana, South Africa, Jamaica, the Seychelles and the US, and who have been prospectively followed since 2010. Our preliminary data suggest that while gut microbiota and SCFAs differences exist across sites, similar relationships exist across the sites for gut microbiota/SCFAs adiposity effects. In addition to yearly health measurements; we propose to measure gut microbiota and stool SCFAs in all participants (2500) during the first year of the current study, thus providing one of the largest gut microbiota population-based studies to date. We will divide our cohort of 2500 individuals into 2 sets: (1) a test set of 1000 individuals to explore which gut microorganisms and stool SCFAs are associated with adiposity; (2) a validation set of 1500 individuals to independently verify the biomarkers identified in the test set, thus minimizing spurious correlations due to large number of features (e.g., bacterial taxa). We will follow all 2500 individuals for 3 years to assess weight and adiposity changes, using Bayesian Kernel Machine Regression modeling to explore whether changes can be predicted by gut microbiota and SCFAs factors. Finally, using a causal mediation analysis, we will identify the direct and indirect effect of single and/or cumulative gut microbiota on adiposity as mediated by SCFA. We will thus capitalize upon an existing, extensively well described cohort of adults of African-origin, with significant variability as a result of the widespread geographic distributions, and therefore variation in the environmental covariate exposures. The proposed study will substantially advance the understanding of the role gut microbiota and SCFAs play in the development of obesity and provide novel obesity therapeutic targets targeting SCFAs producing features of the gut microbiota.

项目总结 这项研究的目的是确定肠道微生物区系、短链脂肪酸 (单链脂肪酸)和肥胖在跨越流行病学过渡的人群中，并探索 这些因素可能独立地和共同地影响 肥胖的发展。肠道微生物区系和单链脂肪酸一直与肥胖有关，但 原因机制是未知的，个人的肥胖效应也是未知的。 单链脂肪酸(丁酸盐、醋酸盐和丙酸)。现有的研究受到相互矛盾的发现的限制， 样本量小，对肥胖的测量有限且不准确，缺乏详细的饮食 和其他环境暴露/调解人。我们建议通过以下方式克服这些挑战 利用现有的由五个不同的、定义明确的群体组成的队列 流行病学转变研究(METS，R01-DK080763)。大都会队由2500人组成 非洲裔成年人，生活在5个截然不同的环境中；加纳、南非、牙买加、 塞舌尔和美国，这些国家自2010年以来一直受到预期的跟踪。我们的 初步数据表明，虽然肠道微生物区系和短链脂肪酸在不同地点存在差异， 肠道微生物区系/单链脂肪酸肥胖效应的不同部位之间也存在类似的关系。此外 到每年的健康测量；我们建议测量所有肠道微生物区系和粪便中的SCFA 在当前研究的第一年期间，参与者(2500人)，从而提供了最大的胆量之一 迄今为止，以微生物种群为基础的研究。我们将把2500人分成2组 集合：(1)1000人的测试集合，以探索肠道微生物和粪便中的SCFA是什么 与肥胖有关；(2)1500人的验证集，以独立验证 在测试集中识别的生物标记，从而最大限度地减少由于大量的 特征(例如，细菌分类群)。我们将对所有2500人进行为期3年的跟踪调查，以评估体重和 肥胖的变化，用贝叶斯核机回归模型来探索 变化可以通过肠道微生物区系和单链脂肪酸因子来预测。最后，使用因果调解 分析，我们将确定单个和/或累积肠道微生物区系的直接和间接影响 关于SCFA介导的肥胖症。因此，我们将利用现有的一口广泛的油井 描述了非洲裔成年人的队列，由于普遍存在的 地理分布，因此环境协变量暴露的变化。这个 拟议的研究将极大地促进对肠道微生物区系和单链脂肪酸作用的理解 在肥胖的发展中发挥作用并提供针对SCFAs的新的肥胖治疗靶点 产生肠道微生物区系的特征。