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: 10539433
• 负责人: Shipra Vaishnava
• 金额: $ 21.25万
• 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/10539433
• 关键词: Bacteria; Body Patterning; Cell Cycle; Cell Death; Cell Differentiation process; Cell Maturation; Cells; Cessation of life; 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; Receptor Signaling; Regenerative capacity; Retinoic Acid Receptor; Retinoids; Role; Signal Transduction; Source; Symbiosis; Time; 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 一组肠道微生物群（肠道微生物组）估计约为300万个基因~150倍 比人类的基因组还要大。这个庞大而多样的微生物群落具有同样的 广泛的代谢库，补充了哺乳动物肝脏中酶的活性 然而，其在代谢肠维生素A中的作用还没有被证实。 探讨了维生素A是一种饮食来源的营养素，是调节免疫力多个方面的关键， 易受感染。维生素A的作用通过其代谢产物维甲酸（RA）协调， 细胞转录程序的有效调节器。需要淋巴细胞中的RA信号传导 用于启动引导它们归巢到粘膜组织的转录程序， 肠粘膜中的细胞命运转变。此外，RA信号传导对于维持 肠上皮的可塑性，使他们去分化和补充池的循环 这些细胞在受损时会丢失。我们发现，常规小鼠的肠腔具有高得多的 RA水平，而在无菌状态RA水平是不可检测的管腔。此外，我们发现， 肠道细菌对醛脱氢酶显示出强活性，醛脱氢酶是一种关键限速酶， 负责将维生素A转化为RA。最后，我们在小鼠中鉴定了乳杆菌属， 肠道微生物组作为具有维生素A代谢活性的细菌分类群。我们假设 肠道微生物组是维生素A代谢活性的一种新的有效来源， 在调节肠道中代谢活性类维生素A水平方面起着至关重要的作用， 维生素A依赖的宿主生理学在肠道和超越。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