A Novel Relationship Between the Gut Microbiota and Pancreatic Beta Cells contributes to Gestational Glucose Homeostasis

肠道微生物群和胰腺β细胞之间的新关系有助于妊娠血糖稳态

• 批准号: 9898235
• 负责人: Brian Thomas Layden
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898235
• 关键词: Ablation; Affect; B Cell Proliferation; Beta Cell; Blood; Cells; Child; Coupled; Data; Diabetes Mellitus; Disease; Exhibits; FFAR2 gene; Failure; Female; Fermentation; GTP-Binding Proteins; General Population; Genes; Germ-Free; Gestational Diabetes; Glucose; Goals; Hormonal; Human; In Vitro; Insulin; Insulin Resistance; Knock-out; Knockout Mice; Life; Ligands; Mediating; Metabolic; Metabolic Diseases; Metabolism; Metagenomics; Mothers; Mus; Names; Newborn Infant; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Pathway interactions; Population; Pre-Eclampsia; Pregnancy; Production; Risk; Rodent; Role; Signal Transduction; Structure of beta Cell of islet; Testing; Therapeutic; Translating; Veterans; Volatile Fatty Acids; Woman; Women' s Health; blood glucose regulation; data modeling; germ free condition; glucose metabolism; gut microbiota; health administration; high risk; impaired glucose tolerance; in vivo; innovation; insight; insulin secretion; islet; meetings; microbiota transplantation; mouse model; non-diabetic; novel; null mutation; receptor; response

The human gut microbiota undergoes compositional changes during pregnancy, and these bacterial changes have been shown to influence maternal metabolic responses; however, how this occurs is unclear. Part of these maternal metabolic changes include enhanced glucose stimulated insulin secretion (GSIS) and an expansion of pancreatic β cell mass (BCM). Providing a potential understanding of how the gut microbiota mediates this maternal response, we have new data suggesting a relationship may exist during pregnancy through the β cell-expressed free fatty acid receptor-2 (Ffar2), where this receptor is activated by nutrients derived from the gut microbiota, short chain fatty acids (SCFAs). Exploring this potential relationship, we have observed the following; 1) Ffar2 expression is altered in mouse islets by gestational insulin resistance, which suggests FFA2 may help in β cell adaption during pregnancy, 2) mice with a null mutation of FFA2 (Ffar2-/-) exhibit impaired glucose tolerance, lower insulin levels and diminished BCM expansion during pregnancy, 3) SCFAs, the primary ligands for FFAR2, are altered during pregnancy within the gut and blood of mice, and finally 4) the bacterial species in the mouse gut microbiota are influenced during pregnancy, as observed for humans. Because of these compelling data, our goal in this proposal is to dissect and test how the gut microbiota, SCFAs, and Ffar2 on β-cells are contributing to gestational glucose homeostasis during pregnancy. First, through a novel mouse model created by our group, a β cell specific knockout of Ffar2, we will explore how β cell expressed Ffar2 mediates GSIS and BCM changes during pregnancy. Next, we will identify the key fermentative gut bacterial taxa and the metagenomic profiles of these taxa that contribute to SCFA level changes during pregnancy. And finally, we will test the collective relationship between gut microbiota, SCFAs, and β cell expressed Ffar2 by modulating the gut microbiota through germ-free conditions, testing the influence of the gut microbiota on glucose homeostasis in our β cell specific knockout of Ffar2. If this novel relationship exists during pregnancy, we will reveal a new paradigm in gestational glucose metabolism, and provide new insight into how the gut microbiota influences host metabolism. !

人类肠道微生物群在怀孕期间经历了组成变化，这些细菌变化 已被证明会影响母体代谢反应;然而，这是如何发生的尚不清楚。的一部分 这些母体代谢变化包括葡萄糖刺激的胰岛素分泌（GSIS）增强和 胰腺β细胞团（pancreatic β cell mass，PSCs）的扩增。提供了一个潜在的了解如何肠道微生物群 介导这种母体反应，我们有新的数据表明，在怀孕期间可能存在的关系， 通过β细胞表达的游离脂肪酸受体2（Ffar 2），该受体被营养素激活 来源于肠道微生物群的短链脂肪酸（SCFA）。探索这种潜在的关系，我们有 观察到以下情况：1）妊娠期胰岛素抵抗改变了小鼠胰岛中Ffar 2的表达， 提示FFA 2可能有助于妊娠期间的β细胞适应，2）具有FFA 2无效突变（Ffar 2-/-）的小鼠 在怀孕期间表现出葡萄糖耐量受损、胰岛素水平降低和胰岛素扩张减少，3） SCFA是FFAR 2的主要配体，在妊娠期间在小鼠的肠道和血液中发生变化， 最后，4）小鼠肠道微生物群中的细菌种类在妊娠期间受到影响，如对 人类由于这些令人信服的数据，我们在这项提案中的目标是解剖和测试肠道如何 β-细胞上的微生物群、SCFA和Ffar 2有助于妊娠期间的妊娠葡萄糖稳态。 首先，通过我们小组创建的一种新的小鼠模型，即Ffar 2的β细胞特异性敲除，我们将探索 妊娠期β细胞表达Ffar 2介导GSIS和TNM的变化。接下来，我们将识别关键 发酵肠道细菌分类群和这些分类群的宏基因组谱，有助于SCFA水平 怀孕期间的变化。最后，我们将测试肠道微生物群，SCFAs， 和β细胞通过无菌条件调节肠道微生物群来表达Ffar 2， 在我们的Ffar 2的β细胞特异性敲除中，肠道微生物群对葡萄糖稳态的影响。如果这段新奇的恋情 存在于怀孕期间，我们将揭示妊娠期葡萄糖代谢的新范式，并提供新的 深入了解肠道微生物群如何影响宿主代谢。 !