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

人类肠道微生物区系在怀孕期间经历了成分变化，这些细菌变化 已经被证明会影响母体的代谢反应；然而，这是如何发生的还不清楚。部分 这些母体代谢变化包括葡萄糖刺激的胰岛素分泌增加(GSIS)和 胰腺β细胞团扩张。提供了一个潜在的了解肠道微生物区系如何 调节这种母性反应，我们有新的数据表明在怀孕期间可能存在这种关系 通过β细胞表达的游离脂肪酸受体-2(FARA2)，该受体被营养物质激活 来源于肠道微生物区系的短链脂肪酸(SCFA)。探索这种潜在的关系，我们有 观察到：1)妊娠期胰岛素抵抗改变了小鼠胰岛Ffar2的表达。 提示FFA2可能有助于妊娠期间β细胞的适应，2)FFA2零突变(Ffar2-/-)小鼠 在怀孕期间表现出糖耐量受损、胰岛素水平降低和BCM扩张减少，3) FFAR2的主要配体SCFA在怀孕期间在小鼠的肠道和血液中发生变化，并且 最后，小鼠肠道微生物区系中的细菌种类在怀孕期间会受到影响，正如观察到的 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 β细胞上的微生物区系、单链脂肪酸和FFAR2有助于妊娠期间的葡萄糖稳态。 首先，通过我们团队创建的一种新的小鼠模型，即β细胞特异性的Ffar2基因敲除，我们将探索 β细胞如何表达FFAR2介导妊娠期GSIS和BCM的变化。接下来，我们将确定密钥 发酵肠道细菌分类群及其对SCFA水平的影响 怀孕期间的变化。最后，我们将测试肠道微生物区系、SCFA和 β细胞在无菌条件下通过调节肠道微生物区系表达FFAR2，检测其对FFAR2的影响 在我们的β细胞中，肠道微生物群对葡萄糖动态平衡的影响是特异的Ffar2基因敲除。如果这种新奇的关系 ，我们将揭示妊娠糖代谢的新范式，并提供新的 深入了解肠道微生物区系如何影响宿主新陈代谢。 好了！

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. !