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

项目摘要 晚期生理时钟型与肠道生态失调和心脏代谢（CM）风险增加有关， 机制不明。现有的研究受到相互矛盾的发现，小样本量，不精确性， 睡眠和CM风险的测量，以及缺乏饮食摄入和其他 环境暴露/介质。这项研究的目的是比较睡眠模式，肠道微生物群， 生活方式行为和CM疾病的风险在5个不同的非洲裔人群的个人。第二 目的是用来自研究参与者的肠道微生物群对小鼠进行人源化，这些研究参与者通过时间型（早期与晚期）进行鉴定。 在5个组群的每一个中，并激发小鼠进行高脂肪喂养，以确认 晚期生理时钟型对肠道生态失调的影响。这项拟议中的研究将调查睡眠时间与 肠道微生物群和CM风险，包括腰围增加，空腹血糖升高， 高脂血症、高血压和低HDL，在现有的具有显著生活方式多样性的队列中 (i.e.,饮食和身体活动），自2010年以来一直进行前瞻性随访。确定的协会 将指导小鼠的粪便微生物群移植实验，这些实验使用的粪便来自通过时间型识别的参与者， 并接受了20周的高脂肪饮食挑战，以证实睡眠时间、肠道 微生物群和CM风险因素。受试者目前已入组METS-微生物组（R 01-DK 111848）， 正在进行的前瞻性队列研究，利用现有的五个不同的，明确定义的人群队列， 流行病学过渡研究建模（METS，R 01-DK 080763）。METS由2，500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 来自METS队列的初步数据表明，肠道微生物群多样性与CM风险呈负相关， 睡眠中断除了每年的健康测量，包括人体测量，血压和CM 风险测量，我们建议在1000名参与者中使用体动计测量睡眠时间（每个研究中心N=200） 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的 睡眠时间对肠道菌群的影响。因此，我们将利用现有的，广泛描述的队列 成年人从地理上分散的人群，导致环境协变量的显着变化。 这项拟议中的研究将大大推进我们对睡眠时间与肠道关系的理解 微生物群和CM风险，这对于现代24/7“按需”社会来说至关重要，需要夜间和清晨 上午工作时间

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.