METS-Sleep: Sleep timing, gut microbiota and cardiometabolic risk across the Epidemiologic Transition

项目总结 较晚的时型与肠道生物失调和心脏代谢(CM)风险增加有关，但其原因 机制尚不清楚。现有的研究受到相互矛盾的发现、小样本量、不精确的限制 对睡眠和CM风险的测量，以及缺乏饮食摄入量和其他详细测量 环境暴露/调解人。这项研究的目的是比较睡眠模式、肠道微生物区系、 来自5个不同非洲裔人群的生活方式行为和患CM疾病的风险。第二 目标是用来自研究参与者的肠道微生物区系人源化小鼠(早期和晚期) 在5个队列中的每一个中，挑战小鼠以高脂饲料喂养，以确认 较晚的时型对肠道生物失调的影响。这项拟议的研究将调查睡眠时间与 肠道微生物区系和CM风险，包括腰围增加，空腹血糖升高， 具有显著生活方式多样性的现有队列中的高甘油三酯血症、高血压和低高密度脂蛋白 (即饮食和体力活动)，自2010年以来一直被预期跟踪。已确定的协会 将指导使用年代型确定的参与者的粪便在小鼠身上进行粪便微生物区系移植实验， 并接受为期20周的高脂肪饮食挑战，以确认睡眠时间和肠道之间的联系 微生物区系和CM危险因素。参与者目前在Mets-Microbiome(R01-DK111848)注册，并 正在进行的前瞻性队列研究利用了现有的五个不同的、定义明确的人群 流行病学转变研究的模型化(METS，R01-DK080763)。大都会队由2500人组成 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。我们的 来自Mets队列的初步数据表明，肠道微生物区系多样性与CM风险和 睡眠障碍。除了每年的健康测量，包括人体测量、血压和CM 风险测量，我们建议使用活动记录仪测量1000名参与者(每个站点200人)的睡眠时间 目前在Mets-Microbiome注册。我们将使用因果中介分析来确定直接和间接 睡眠时间对肠道微生物区系的影响。因此，我们将利用现有的、被广泛描述的队列 来自地理上分散的种群的成虫，导致环境协变量的显著差异。 这项拟议的研究将极大地促进我们对睡眠时间与肠道之间关系的理解 微生物区系和CM风险，这是至关重要的，因为现代全天候“按需”社会需要夜间和早起 早间工作时间。

PROJECT SUMMARY Late chronotype has been associated with gut dysbiosis and increased cardiometabolic (CM) risk, yet the causal mechanisms are unknown. Existing studies are limited by contradictory findings, small sample sizes, imprecise measurements of sleep and CM risk, as well as lack of detailed measures of dietary intake and other environmental exposures/mediators. The objective of this study is to compare sleep patterns, gut microbiota, lifestyle behaviors, and risk for CM disease in individuals from 5 distinct African-origin populations. The second objective is to humanize mice with gut microbiota from study participants identified by chronotype (early vs. late) in each of the 5 cohorts and challenge the mice to high fat feeding in order to confirm the transferability of the late chronotype impact on gut dysbiosis. The proposed study will investigate sleep timing associations with the gut microbiota and CM risk, including elevated waist circumference, elevated fasting glucose, hypertriglyceridemia, elevated blood pressure, and low HDL, in existing cohorts with significant lifestyle diversity (i.e., diet and physical activity), who have been followed prospectively since 2010. The associations identified will guide fecal microbiota transplant experiments in mice using stool from participants identified by chronotype, and exposed to a 20-week high fat diet challenge to confirm the associations between sleep timing, gut microbiota and CM risk factors. Participants are currently enrolled in METS-Microbiome (R01-DK111848), an ongoing prospective cohort study 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 adults, living in 5 distinctly different environments: Ghana, South Africa, Jamaica, Seychelles and the US. Our preliminary data from the METS cohorts suggest that gut microbiota diversity is negatively related to CM risk and sleep disruption. In addition to yearly health measurements, including anthropometrics, blood pressure and CM risk measures, we propose to measure sleep timing using actigraphy in 1000 participants (N=200 from each site) currently enrolled in METS-Microbiome. We will use a causal mediation analysis to identify the direct and indirect effects of sleep timing on the gut microbiota. We will thus capitalize upon existing, extensively described cohorts of adults from geographically dispersed populations, resulting in significant variation in environmental covariates. The proposed study will substantially advance our understanding of sleep timing associations with the gut microbiota and CM risk, which is critical given modern 24/7 “on-demand” societies requiring both night and early morning work hours.