Microbiota-dependent Epigenetic Regulation of Circadian Rhythms in Nutrient Uptake and Energy Homeostasis

项目摘要 代谢综合征已成为现代社会面临的重大公共挑战。一个主要原因是失衡 能量摄取和消耗之间的关系，这是积极调节的环境因素，如饮食 营养成分、进食和睡眠的昼夜节律以及肠道微生物群。肠道微生物群是一种 肠道内有大量的微生物群落，在哺乳动物的代谢中起着至关重要的作用。 禁忌症通过从复杂的饮食中释放可吸收的营养素供宿主吸收。有趣的是，最近的研究 已经表明，微生物群还可以通过调节生物钟来影响宿主的代谢活动， 干扰这种串扰会导致代谢紊乱。尽管有这种普遍的理解， 机制仍然难以捉摸。我的初步研究表明，组蛋白乙酰基的昼夜节律振荡 肠上皮细胞的功能取决于微生物群。另外，我发现了一个潜在的机甲- 涉及组蛋白去乙酰化酶3（HDAC 3）表达的微生物活化的疾病。我发现很多基因- 编码营养摄取和代谢功能是循环组蛋白乙酰化信号的目标。上皮细胞 al细胞特异性HDAC 3缺陷小鼠表现出组蛋白乙酰化振荡的完全丧失， 血糖水平的节律。突变小鼠摄取较少的脂质，并抵抗高脂饮食诱导的高脂血症。 肥胖解剖微生物-上皮细胞信号通路揭示了肠道微生物的特定成分， 生物群和免疫系统激活上皮HDAC 3。出于这些原因，我假设肠道微生物群 通过激活肠上皮HDAC 3驱动转录和营养摄取的昼夜节律， 这反过来又有助于维持能量稳态和代谢健康。在目标1中，我将研究机甲- 微生物群通过其调节肠道基因表达和营养吸收的节律。在 目的2，我将确定肠道微生物群如何通过上皮细胞调节脂质摄取和能量稳态， HDAC 3及其下游靶点。在目标3中，我将联合收割机结合免疫学、蛋白质组学和计算应用 研究确定微生物群激活上皮HDAC 3的机制，确定 HDAC 3，并确定其代谢功能。这些研究将提供新的见解，如何微观， 生物群调节宿主的昼夜节律和代谢状态，将有助于开发新的策略， 通过针对HDAC或微生物群来治疗代谢疾病。

Project Summary Metabolic syndrome has become a major public challenge in modern society. One main cause is an imbalance between energy uptake and expenditure, which is actively modulated by environmental factors such as diet composition, circadian rhythms of feeding and sleeping, and the intestinal microbiota. The gut microbiota is a vast community of microorganisms that colonize the intestine, and it plays an essential role in mammalian me- tabolism by liberating absorbable nutrients from complex diets for host uptake. Interestingly, recent studies have shown that the microbiota can also impact host metabolic activities by regulating the circadian clock, and disrupting this crosstalk can cause metabolic disorders. Despite this general understanding, the underlying mechanisms remain elusive. My preliminary studies have revealed that circadian oscillation of histone acetyla- tion in intestinal epithelial cells depends on the microbiota. Furthermore, I have identified a potential mecha- nism involving microbial activation of histone deacetylase 3 (HDAC3) expression. I found that many genes en- coding nutrient uptake and metabolic functions are targeted by the cycling histone acetylation signals. Epitheli- al cell-specific HDAC3-deficient mice exhibit a complete loss of histone acetylation oscillation and disrupted rhythms of blood glucose levels. The mutant mice take up less lipid and are resistant to high fat diet-induced obesity. Dissecting the microbial-epithelial signaling circuits reveals that specific components of the gut micro- biota and immune system activate epithelial HDAC3. For these reasons, I hypothesize that the gut microbiota drives the circadian rhythms of transcription and nutrient uptake by activating intestinal epithelial HDAC3, which in turn helps to maintain energy homeostasis and metabolic health. In Aim 1, I will study the mecha- nisms by which the microbiota regulates the rhythms of intestinal gene expression and nutrient absorption. In Aim 2, I will determine how the gut microbiota regulates lipid uptake and energy homeostasis through epithelial HDAC3 and its downstream targets. In Aim 3, I will combine immunological, proteomic and computational ap- proaches to identify the mechanisms by which the microbiota activates epithelial HDAC3, identify co-factors of HDAC3, and determine their metabolic functions. These studies will provide novel insights into how the micro- biota regulates host circadian and metabolic states and will help develop new strategies to protect against metabolic diseases by targeting HDACs or the microbiota.