Vitamin A metabolizing activity of the gut microbiome.

项目总结： 人和小鼠的结肠微生物区系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)的集合估计约有300万个基因~150倍 比人类基因组还大。这个庞大而多样的微生物群落具有同样的 广泛的代谢谱，补充肝脏中哺乳动物酶的活性 然而，它在肠道维生素A代谢中的作用还没有得到研究 探索过了。维生素A，一种来自饮食的营养素，是调节免疫力和多方面的关键 对感染的敏感性。维生素A的作用是通过其代谢物维甲酸(RA)来协调的， 是细胞转录程序的有力调节器。淋巴细胞中的RA信号是必需的 启动转录程序，引导它们归巢到粘膜组织以及它们的 肠粘膜中细胞命运的转变。此外，RA信令对于维护 肠上皮的可塑性，允许它们去分化和补充自行车池 受损后丢失的细胞。我们发现常规小鼠的肠腔要高得多。 RA水平处于无菌状态时，在管腔中检测不到RA水平。此外，我们发现 肠道细菌对乙醛脱氢酶表现出很强的活性，乙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，我们在小鼠体内鉴定了乳杆菌。 肠道微生物群是具有维生素A代谢活性的细菌类群。我们假设 肠道微生物群是维生素A代谢活动的一种新的有效来源，它发挥着 在肠道中调节代谢活性维甲酸水平的关键作用和调节 肠道和肠道以外的依赖维生素A的宿主生理学。在本提案中，我们将 探讨肠道微生物群将膳食维生素A代谢成RA的潜力及其对RA的影响 哺乳动物的宿主。

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.