Vitamin A metabolizing activity of the gut microbiome.

肠道微生物组的维生素 A 代谢活性。

• 批准号: 10628029
• 负责人: Shipra Vaishnava
• 金额: $ 23.96万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-25 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10628029
• 关键词: Bacteria; Body Patterning; Cell Cycle; Cell Death; Cell Differentiation process; Cell Maturation; Cells; Cessation of life; Communication; Complement; Complex; Diet; Disease; Embryo; Enterocytes; Enzymes; Epithelial Cell Proliferation; Epithelial Cells; Equilibrium; Generations; Genes; Genetic Transcription; Germ-Free; Gut Mucosa; Homeostasis; Homing; Human; Human Genome; Immunity; Infection; Inflammation; Intestinal Mucosa; Intestines; Lactobacillus; Length; Liver; Lymphocyte; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Microbe; Micronutrients; Modeling; Mucous Membrane; Mus; Natural regeneration; Nutrient; Organoids; Physiology; Play; Predisposition; Proliferating; Receptor Signaling; Regenerative capacity; Retinoic Acid Receptor; Retinoids; Role; Signal Transduction; Source; Symbiosis; Transcription Initiation; Tretinoin; Villus; Vitamin A; Vitamin B Complex; Work; aldehyde dehydrogenases; bacterial community; base; colon microbiota; commensal bacteria; crypt cell; dietary; gut bacteria; gut microbiome; gut microbiota; host microbiome; immune function; intestinal crypt; intestinal epithelium; microbial; microbial community; microbiota; novel; programs; regenerative; stem cell niche; stem cell proliferation

Project Summary: The human and mouse colonic microbiota is a large and complex microbial community. The gene set of the gut microbiota (the gut microbiome) is estimated to be about 3 million genes ~150 times larger than that of the human genome. This large and diverse microbial community has an equally extensive metabolic repertoire that complements the activity of mammalian enzymes in the liver and gut mucosa however its role in metabolizing intestinal vitamin A has not been explored. Vitamin A, a diet derived nutrient, is key for regulating multiple aspects of immunity and susceptibility to infections. Effect of vitamin A are coordinated via its metabolite retinoic acid (RA), a potent regulator of cellular transcriptional program. RA signaling in the lymphocytes is required for initiating transcriptional programs that guide their homing to the mucosal tissue as well their cell-fate transitions in the intestinal mucosa. Additionally, RA signaling is critical for maintaining plasticity of intestinal epithelium, allowing them to dedifferentiate and replenish the pool of cycling cells that are lost upon damage. We find that gut lumen of conventional mice has much higher RA levels while in germ-free state RA levels are undetectable in the lumen. Moreover, we find that gut bacteria show strong activity for aldehyde dehydrogenase, a key rate limiting enzyme that is responsible for conversion of vitamin A to RA. Finally, we identify Lactobacillus spp in the mouse gut microbiome as bacterial taxa possessing vitamin A metabolic activity. We hypothesize that gut microbiome is a novel and potent source of vitamin A metabolic activity that plays a crucial role in regulating levels of metabolically active retinoids in the gut and regulates vitamin A dependent host physiology in the intestine and beyond. In this proposal we will explore the potential of gut microbiome to metabolize dietary vitamin A into RA and its effect on the mammalian host.

项目概要： 人类和小鼠结肠微生物群是一个庞大而复杂的微生物群落。基因 肠道微生物群（肠道微生物组）的集合估计约为 300 万个基因 ~150 倍 比人类基因组还要大。这个庞大而多样化的微生物群落具有同样的 广泛的代谢功能，可补充哺乳动物肝脏酶的活性 和肠粘膜，但其在肠道维生素 A 代谢中的作用尚未得到证实。 探索过。维生素 A 是一种饮食来源的营养素，对于调节免疫力和免疫力等多个方面至关重要。 易受感染。维生素 A 的作用通过其代谢物视黄酸 (RA) 协调， 细胞转录程序的有效调节剂。淋巴细胞中的 RA 信号传导是必需的 用于启动转录程序，引导它们归巢到粘膜组织以及它们的 肠粘膜中的细胞命运转变。此外，RA 信号对于维持 肠上皮的可塑性，使它们能够去分化并补充循环池 因损伤而丢失的细胞。我们发现传统小鼠的肠腔具有更高的 无菌状态下的 RA 水平在管腔中是检测不到的。此外，我们发现 肠道细菌对醛脱氢酶表现出很强的活性，醛脱氢酶是一种关键的限速酶， 负责将维生素 A 转化为 RA。最后，我们鉴定了小鼠体内的乳酸菌 肠道微生物组是具有维生素 A 代谢活性的细菌类群。我们假设 肠道微生物组是维生素 A 代谢活动的新型有效来源，在 在调节肠道中代谢活性类视黄醇的水平方面发挥着至关重要的作用，并调节 肠道内外的维生素 A 依赖宿主生理学。在本提案中，我们将 探索肠道微生物组将膳食维生素 A 代谢为 RA 的潜力及其对 哺乳动物宿主。