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

小肠 PepT1 表达在维持肠道稳态和塑造肠道微生物群中发挥着关键作用

• 批准号: 10266018
• 负责人: DIDIER MERLIN
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266018
• 关键词: Acute; Adult; Affect; Americas; Anti-Inflammatory Agents; Cells; Chronic; Colitis; Colorectal Cancer; Data; Diagnosis; Encapsulated; Epigenetic Process; Epithelial Cells; Etiology; Feces; Foundations; Future; Gastrointestinal tract structure; General Population; Germ-Free; Healthcare; Homeostasis; Inflammatory; Intestinal Mucosa; Intestinal permeability; Intestines; Large Intestine; Lead; Mediating; Membrane Transport Proteins; MicroRNAs; Mucous Membrane; Mus; Nanotechnology; Oligopeptides; Pathologic; Patients; Phenotype; Play; Population; Proteins; Protons; Reporting; Research; Role; Shapes; Small Intestines; United States National Center for Health Statistics; Veterans; Work; colitis associated cancer; dextran sulfate sodium induced colitis; exosome; experimental study; gut microbiota; inflammatory disease of the intestine; intestinal epithelium; intestinal homeostasis; large bowel Crohn' s disease; member; microbiome; microbiota; military veteran; mouse model; novel; prevent; therapeutic development

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.

Pept1是质子寡肽转运蛋白（POT）超家族的成员，众所周知 运输DI/三肽。我们的小组和其他人表明，Pept1在 小肠，但在正常大肠（1-8）的此类细胞中以低或无法检测到的水平存在。 我们先前表明，PEPT1的表达和运输活性有助于结肠炎和结肠炎 相关癌症（5，9）。最近，我们报道了该膜转运蛋白的功能不是 仅限于其作为二肽转运蛋白的经典功能。例如，我们证明了Pept1 表达通过介导肠道miRNA的表达/分泌有助于维持肠道稳态（10，48）。 总之，我们先前的研究表明，Pept1可能与肠内稳态有关，并牵涉 在各种病原体中，包括结肠炎和结肠炎相关的癌症。我们新颖的总体假设 小肠PEPT1表达在维持肠内稳态和在 塑造肠道菌群。该提议的最初目的是证明缺乏小肠 PEPT1表达将肠道微生物群塑造成抗炎的微生物群 预防结肠炎和结肠炎相关的癌症。然后，我们将探索小肠PEPT1的影响 因此，肠粘膜稳态上的肠道miRNA失调。 最后，我们将研究微生物群如何通过宿主miRNA的表达/分泌来调节 取决于pept1在小肠中的表达，我们将定义操纵方法 微生物组通过管理特定的miRNA。我们设想计划的工作将确定起作用的作用 通过小肠pept1表达在维持肠内稳态和塑造方面起着至关重要的作用 肠道菌群。拟议的研究还将促进治疗策略的发展 靶向肠道炎症条件。