Developmental effects of intestinal microbes on metabolic and behavioral circadian rhythms

肠道微生物对代谢和行为昼夜节律的发育影响

• 批准号: 10581777
• 负责人: Vanessa Anne Leone
• 金额: $ 16.2万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-07 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581777
• 关键词: Abate; Address; Adolescent; Adult; Affect; Age; Automobile Driving; Behavior; Behavioral; Birth; Brain; Child; Circadian Dysregulation; Circadian Rhythms; Clinical Data; Consumption; Data; Development; Diet; Disease; Elements; Epidemic; Exhibits; Fatty acid glycerol esters; Feedback; Feeding behaviors; Gene Expression; Genetic Transcription; Genomics; Germ-Free; Gnotobiotic; Goals; Health; Health Resources; Healthcare; Hepatic; Individual; Intervention; Investments; Knowledge; Life; Longevity; Metabolic; Metabolic Diseases; Metabolism; Microbe; Molecular; Mus; Obese Mice; Obesity; Outcome; Output; Overweight; Pattern; Periodicity; Persons; Phenotype; Physiologic Thermoregulation; Physiology; Play; Population; Pregnancy; Prevalence; Prophylactic treatment; Public Health; Research; Ribosomal RNA; Risk; Role; Severities; Shapes; Signal Transduction; Specific qualifier value; Sterility; System; Telemetry; Testing; Thinness; Weaning; aged; care burden; circadian; circadian behavioral rhythms; circadian pacemaker; diet-induced obesity; dietary; disorder risk; effective intervention; experimental study; feeding; global health; gut microbes; gut microbiota; host-microbe interactions; innovation; insight; liver metabolism; microbial; microbial community; microbial host; microbiome; microbiota; novel; obese person; obesity development; obesity in children; obesogenic; pre-clinical; programs; sugar; transcriptome sequencing; transcriptomics; western diet; wireless

PROJECT SUMMARY Metabolic diseases are increasing worldwide in prevalence and severity. Globally, approximately 650 million people are obese or overweight, over half of whom are children. The healthcare burden of obesity is enormous and only growing. Circadian rhythms play a central role in healthy metabolism and in maintaining proper host- microbe interactions. Circadian rhythms in feeding and behavior create a feedback loop, driving rhythms in hepatic transcription, which in turn drive rhythms in host and microbial metabolism that ultimately feedback onto circadian rhythms in host behavior. This network of rhythms is severely disrupted in obese mice consuming a Western diet. Early-life diet interacts with the developing microbiome to program metabolism and disease risk, but how the early-life microbiota contribute to development of the host metabolic circadian network remains unknown. There is an urgent need to identify mechanisms by which gut microbes interact with diet early in life to shape these circadian networks that coordinate daily rhythms in metabolism. Mice devoid of all microbes (‘germ-free’) exhibit disrupted circadian rhythms in numerous aspects of host metabolism compared to mice that have had microbes since birth. Remarkably, repopulating germ-free mice later in adulthood with microbes (‘conventionalization') only partially normalizes their circadian rhythms. This indicates that the age at which gut microbes are acquired must play a critical role in the development of circadian networks that govern metabolism. But when and how healthy and obesogenic microbes first begin to normalize and disrupt, respectively, the circadian network remain unexamined. Our research will bridge this gap in knowledge by testing the hypothesis that the organismal circadian network is shaped by interactions between the type of gut microbes acquired and the developmental age of acquisition. Aim 1 tests the hypothesis that the age when mice acquire a normal, healthy microbiome determines the robustness of their circadian network in adulthood. We will conventionalize germ-free mice with microbes during gestation, at weaning, or in adulthood. Phenotypes across the entire circadian network will be examined later in life, including: hepatic clock and clock-controlled gene expression via RNA-seq, microbial community oscillations via 16S rRNA, and host behavioral circadian rhythms thermoregulation and via wireless telemetry inside sterile isolators. Aim 2 will test the hypothesis that obesogenic diets early in life disrupt normal development of the circadian network through a combination of microbe-dependent and microbe-independent mechanisms. Beginning early in life, germ-free mice will be administered an obesogenic diet alone, obesogenic microbes alone, or both obesogenic diet and microbes. Metabolic circadian networks will be examined as in Aim 1. These studies will specify how diet and microbes interact to affect the developing host-microbial circadian network. New insights into how metabolic programming impacts the circadian system will inform early-life dietary and microbial interventions that may afford prophylaxis against the development of obesity.

项目摘要 代谢性疾病在世界范围内的患病率和严重程度都在增加。全球约有6.5亿 人们肥胖或超重，其中一半以上是儿童。肥胖的医疗负担是巨大的 只会不断增长昼夜节律在健康的新陈代谢和维持适当的宿主中起着核心作用。 微生物相互作用进食和行为的昼夜节律创造了一个反馈回路， 肝脏转录，这反过来又驱动宿主和微生物代谢的节奏，最终反馈到 宿主行为的昼夜节律这种节律网络在肥胖小鼠中被严重破坏， 西式饮食。早期饮食与发育中的微生物组相互作用，以规划代谢和疾病风险， 但早期微生物群如何促进宿主代谢昼夜节律网络的发展仍是一个未知数， 未知迫切需要确定肠道微生物在生命早期与饮食相互作用的机制， 塑造这些昼夜节律网络，协调新陈代谢的日常节奏。 缺乏所有微生物（"无菌"）的小鼠在宿主的许多方面表现出破坏的昼夜节律。 与从出生起就有微生物的小鼠相比，值得注意的是，无菌小鼠的繁殖 成年后与微生物接触（"常规化"）只能部分地使他们的昼夜节律正常化。这 表明肠道微生物获得的年龄必须在发育中起关键作用。 控制新陈代谢的昼夜节律网络。但是健康和致肥微生物开始 分别正常化和破坏，昼夜节律网络仍然没有得到检查。 我们的研究将通过测试生物体昼夜节律 网络是由获得的肠道微生物类型和发育过程之间的相互作用形成的。 获取年龄。目的1测试了小鼠获得正常健康微生物组的年龄 决定了他们成年后昼夜节律网络的稳定性。我们将无菌小鼠与 微生物在妊娠期，断奶，或在成年。整个昼夜节律网络的表型将是 在以后的生活中进行检查，包括：通过RNA-seq的肝脏时钟和时钟控制的基因表达，微生物 通过16S rRNA和宿主行为昼夜节律温度调节以及通过无线电 无菌隔离器内的遥测。目标2将检验这一假设，即在生命早期的致胖饮食会破坏正常的 通过微生物依赖性和微生物非依赖性相结合来发展昼夜节律网络 机制等从生命早期开始，无菌小鼠将被单独施用致肥胖饮食，致肥胖饮食将被单独施用。 单独的微生物，或致肥饮食和微生物两者。代谢昼夜节律网络将在Aim中进行检查 1.这些研究将详细说明饮食和微生物如何相互作用，影响发育中的宿主-微生物的昼夜节律 网络关于代谢程序如何影响昼夜节律系统的新见解将为早期生活饮食提供信息 和微生物干预，可以提供预防肥胖症的发展。