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的一大公共挑战。一个主要原因是不平衡。 能量摄取和消耗之间的关系，这受到饮食等环境因素的积极调节 组成、摄食和睡眠的昼夜节律，以及肠道微生物区系。肠道微生物区系是一种 寄生在肠道的巨大微生物群落，在哺乳动物的肠道中起着至关重要的作用-- 通过从复合饲料中释放可吸收的营养物质以供宿主吸收的代谢作用。有趣的是，最近的研究 已经表明，微生物区系也可以通过调节生物钟来影响宿主的代谢活动，以及 干扰这种串扰会导致新陈代谢紊乱。尽管有这种普遍的理解，但潜在的 机制仍然难以捉摸。我的初步研究表明，组蛋白乙酰的昼夜振荡- 肠上皮细胞中的TION依赖于微生物区系。此外，我还发现了一种潜在的机械装置- NISM涉及微生物激活组蛋白脱乙酰酶3(HDAC3)的表达。我发现很多基因都在- 编码营养吸收和代谢功能是循环组蛋白乙酰化信号的靶点。埃皮塞利- AL细胞特异性HDAC3缺陷小鼠表现出组蛋白乙酰化振荡的完全丧失和干扰 血糖水平的节律。突变小鼠摄入较少的脂肪，并对高脂肪饮食诱导的耐受 肥胖。解剖微生物-上皮信号通路发现，肠道微-上皮信号通路的特定成分 生物群和免疫系统激活上皮性HDAC3。出于这些原因，我假设肠道微生物区系 通过激活肠上皮细胞HDAC3来驱动转录和营养吸收的昼夜节律， 这反过来又有助于维持能量平衡和新陈代谢健康。在目标1中，我将研究机械- 微生物区系调节肠道基因表达和养分吸收的节律。在……里面 目标2，我将确定肠道微生物区系如何通过上皮细胞调节脂质摄取和能量平衡。 HDAC3及其下游目标。在目标3中，我将结合免疫学、蛋白质组学和计算AP- 确定微生物区系激活上皮性HDAC3的机制，确定与 HDAC3，并测定其代谢功能。这些研究将提供新的见解，让人们了解微型生物是如何 生物群调节宿主的昼夜节律和代谢状态，并将有助于开发新的策略来预防 以HDAC或微生物区系为靶点的代谢性疾病。

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.