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

项目摘要 本研究的目的是确定肠道微生物群、短链脂肪酸 （SCFAs）和肥胖的人群跨越流行病学转变，并探讨 这些因素可能独立和共同影响的机制 肥胖症的发展。肠道微生物群和SCFAs与肥胖有关，但 因果机制尚不清楚，个体的个体致肥胖效应也是如此。 SCFA（丁酸盐、乙酸盐和丙酸盐）。现有的研究受到相互矛盾的发现的限制， 小样本量，有限和不精确的肥胖测量，以及缺乏详细的饮食 和其他环境暴露/介质。我们建议克服这些挑战， 利用现有的五个不同的队列，从建模定义明确的人群， 流行病学过渡研究（METS，R 01-DK 080763）。METS由2，500人组成 非洲裔成年人，生活在5个明显不同的环境中;加纳，南非，牙买加， 塞舌尔和美国，自2010年以来一直在进行前瞻性跟踪。我们 初步数据表明虽然不同地点存在肠道微生物群和SCFAs差异， 在肠道微生物群/SCFAs肥胖效应的各个部位之间存在类似的关系。此外 每年的健康测量;我们建议测量所有人的肠道微生物群和粪便SCFA 参与者（2500）在目前的研究的第一年，从而提供了一个最大的肠道 迄今为止，微生物群研究。我们将我们的2500人的队列分为2 组：（1）1000人的测试组，以探索哪些肠道微生物和粪便SCFA是 （2）1500名个体的验证集，以独立验证 在测试集中识别的生物标志物，从而最大限度地减少由于大量的 特征（例如，细菌分类群）。我们将跟踪所有2500人3年，以评估体重， 肥胖的变化，使用贝叶斯核机器回归建模，探讨是否 这些变化可以通过肠道微生物群和SCFAs因子来预测。最后，使用因果调解 分析，我们将确定单一和/或累积肠道微生物群的直接和间接影响， 通过SCFA介导的肥胖。因此，我们将利用现有的，广泛的 描述了非洲裔成年人的队列，由于广泛的 地理分布，以及环境协变量暴露的变化。的 拟议的研究将大大推进对肠道微生物群和SCFAs作用的理解， 在肥胖的发展中发挥作用，并提供了靶向SCFAs的新型肥胖治疗靶点 产生肠道微生物群的特征。

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.