Small intestinal PepT1 expression plays a critical role in maintaining intestinal homeostasis and in shaping the gut microbiota

PepT1是质子寡肽转运体(POT)超家族的成员之一，是众所周知的 转运二/三肽。我们的团队和其他人已经证明PepT1在血管内皮细胞中高表达。 小肠，但在正常大肠(1-8)的这种细胞中存在低水平或检测不到的水平。 我们以前发现PepT1的表达和转运活动与结肠炎和结肠炎有关 相关癌(5、9)。最近，我们报道了这种膜转运蛋白的功能不是 仅限于其作为二三肽转运体的经典功能。例如，我们演示了PepT1 通过调节肠道miRNA的表达/分泌，表达有助于维持肠道内环境的稳定(10，48)。 综上所述，我们先前的研究表明PepT1可能与肠道内稳态有关，并与 在各种病因中，包括结肠炎和结肠炎相关癌症。我们新的总体假设 小肠PepT1的表达在维持肠道内环境平衡方面起着关键作用 塑造肠道微生物区系。这项提议的最初目的是证明缺乏小肠 PepT1的表达将肠道微生物区系塑造成抗炎微生物区系，这与 预防结肠炎和结肠炎相关癌症。然后我们将探索小肠PepT1的作用 表达，从而导致肠道miRNA对肠粘膜动态平衡的失调。 最后，我们将研究微生物区系如何受到宿主miRNAs的表达/分泌的调节 依赖于PepT1在小肠中的表达，我们将定义如何操纵 通过给予特定的miRNAs来控制微生物群。我们设想，计划的工作将确定所发挥的作用 通过小肠，PepT1的表达在维持肠道内环境稳定和塑造方面起着关键作用 肠道微生物区系。拟议的研究还将促进治疗策略的发展。 针对肠道炎症情况。

PepT1, which is a member of the proton oligopeptide transporter (POT) superfamily, is well known to transport di/tripeptides. Our group and others have shown that PepT1 is highly expressed in epithelial cells of the small intestine, but present at low or undetectable levels in such cells of the normal large intestine (1-8). We previously showed that the expression and transport activities of PepT1 contribute to colitis and colitis associated cancer (5, 9). More recently, we reported that the function of this membrane transporter is not restricted to its classical function as transporter of di-tripeptides. For example, we demonstrated that PepT1 expression helps maintain intestinal homeostasis by mediating intestinal miRNA expression/secretion (10, 48). Together, our prior studies revealed that PepT1 may be associated with intestinal homeostasis and implicated in various pathogeneses, including those of colitis and colitis associated cancer. Our novel overall hypothesis is that small intestinal PepT1 expression plays a critical role in maintaining intestinal homeostasis and in shaping the gut microbiota. The initial aim of this proposal is to demonstrate that a lack of small intestinal PepT1 expression shapes the gut microbiota into an anti-inflammatory microbiota that is implicated in preventing colitis and colitis associated cancer. We will then explore the effects of small intestinal PepT1 expression and consequently the intestinal miRNA dysregulation on the intestinal mucosal homeostasis. Finally, we will investigate how the microbiota is regulated by the expression/secretion of host miRNAs that depend on the expression of PepT1 in the small intestine, and we will define ways to manipulate the microbiome by administering specific miRNAs. We envisage that the planned work will identify the role played by small intestinal PepT1 expression plays a critical role in maintaining intestinal homeostasis and in shaping the gut microbiota. The proposed research will also facilitate the development of therapeutic strategies targeting intestinal inflammatory conditions.