Microbial regulation of mammalian circadian rhythms and the sexual dimorphism: from metabolism to immunity

哺乳动物昼夜节律和性二态性的微生物调节：从新陈代谢到免疫

• 批准号: 10473122
• 负责人: Zheng Kuang
• 金额: $ 135.27万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10473122
• 关键词: Affect; Bacteria; Biological Assay; Cells; Circadian Rhythms; Communities; Cues; Diet; Digestive System Disorders; Disease; Diurnal Rhythm; Eating; Environmental Risk Factor; Epigenetic Process; Epithelial Cells; Exposure to; Genetic; Genomics; Gnotobiotic; Health; Hour; Immune; Immune System Diseases; Immunity; Infection; Intestines; Light; Metabolic; Metabolic Control; Metabolic Diseases; Metabolism; Modification; Molecular; Mus; Nutrient; Pathway interactions; Physiology; Play; Process; Regulation; Role; Schedule; Signal Transduction; Sleep; System; Techniques; Time; absorption; base; chromatin modification; circadian; environmental intervention; fighting; gut microbes; gut microbiota; immune activation; immune function; insight; intestinal epithelium; male; microbial; microbiota; microorganism; mouse genetics; multidisciplinary; novel; nutrient absorption; pathogen; programs; response; screening; sexual dimorphism; uptake

Project Summary The intestine plays essential roles in health and disease based on its two main functions: nutrient absorption and immune defense. These two processes are highly intertwined with each other and are influenced by a variety of genetic and environmental factors. Abnormal absorption causes nutrient deficiency or excess, which leads to various metabolic diseases. Compromised immune defense increases the exposure to pathogens and other noxious agents, and promotes systemic immune activation, infections and metabolic disorders. Therefore, understanding how the two processes are regulated in the intestine is critical for fighting these digestive system diseases. Intriguingly, many of the metabolic and immune functions are integrated in the same group of cells, the intestinal epithelial cells. However, how these cells coordinate the two distinct processes, especially in the face of environmental challenges, remains a puzzle. We recently identified that the gut microbiota, a community of microorganisms in the gut, controls a 24-hour diurnal rhythm in the intestinal epithelium through an epigenetic mechanism. This leads to a hypothesis that the microbiota may temporally orchestrate metabolic and immune functions in the intestine to maintain just-in-time capacities of nutrient uptake and immune defense in response to the diurnal oscillations of nutrient availability and microbial burden. In this proposal, we will examine how metabolic and immune activities are temporally coordinated in the intestine and how these rhythms are affected by environmental interventions. We will scrutinize the components and activities of the microbiota to understand how gut microbes regulate the circadian system to influence host metabolic health and immune integrity. We will identify and characterize other epigenetic programs that integrate microbial and circadian cues to regulate intestinal physiology. From a preliminary screen, we found that the microbiota drives the rhythm of another chromatin modification that is only present in male mice but not females. This finding provides a new avenue for understanding how microbial, circadian and sexual dimorphic signals converge in the intestine to control metabolic and immune functions. We will exploit multidisciplinary techniques including bacteria and mouse genetics, genomics, gnotobiotics, and more importantly we will develop new computational approaches and screening assays to understand the crosstalk between the gut microbiota and host circadian rhythms. These studies will provide novel mechanistic insights into the microbial regulation of host circadian programs and shed light on unexpected roles of the microbiota and epigenetic modification in regulating sexual dimorphisms of mammalian metabolism and immunity. Ultimately, the findings will help develop new strategies to protect against metabolic and immune diseases by targeting the microbiota or epigenetic pathways.

项目摘要 肠道基于其两个主要功能在健康和疾病中起着至关重要的作用：营养吸收， 免疫防御这两个过程相互交织，并受到各种因素的影响。 遗传和环境因素。不正常的吸收会导致营养缺乏或过剩，从而导致 各种代谢性疾病。受损的免疫防御增加了对病原体和其他病原体的暴露。 有毒物质，并促进全身免疫激活，感染和代谢紊乱。因此，我们认为， 了解这两个过程在肠道中是如何调节的， 疾病有趣的是，许多代谢和免疫功能都整合在同一组细胞中， 肠上皮细胞。然而，这些细胞如何协调这两个不同的过程，特别是在 面对环境挑战，仍然是一个谜。我们最近发现，肠道微生物群，一个社区， 肠道中的微生物，通过表观遗传控制肠上皮细胞的24小时昼夜节律。 机制这导致了一种假设，即微生物群可能在时间上协调代谢和免疫调节。 在肠道中起作用，以维持及时的营养吸收和免疫防御能力， 养分有效性和微生物负荷的昼夜振荡。在本建议中，我们将研究如何 代谢和免疫活动在肠道中的时间协调以及这些节律如何受到影响 通过环境干预。我们将仔细检查微生物群的组成和活动， 肠道微生物如何调节昼夜节律系统以影响宿主的代谢健康和免疫完整性。我们将 识别和表征整合微生物和昼夜节律线索以调节的其他表观遗传程序 肠道生理学从初步的筛选中，我们发现微生物群驱动着另一个微生物群的节奏， 染色质修饰只存在于雄性小鼠中，而不存在于雌性小鼠中。这一发现提供了一个新的途径， 了解微生物，昼夜节律和性二态信号如何在肠道中会聚，以控制 代谢和免疫功能。我们将利用多学科技术，包括细菌和小鼠 遗传学，基因组学，gnotobiotics，更重要的是，我们将开发新的计算方法， 筛选分析以了解肠道微生物群和宿主昼夜节律之间的串扰。这些 研究将为宿主昼夜节律程序和脱落的微生物调节提供新的机制见解。 微生物群和表观遗传修饰在调节性二型性方面的意想不到的作用 哺乳动物的新陈代谢和免疫力。最终，这些发现将有助于开发新的策略，以防止 通过靶向微生物群或表观遗传途径来治疗代谢和免疫疾病。