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 运输二/三肽。我们的团队和其他人已经证明，PepT1 在上皮细胞中高度表达 小肠中存在，但在正常大肠的此类细胞中含量较低或检测不到 (1-8)。 我们之前表明 PepT1 的表达和转运活性有助于结肠炎和结肠炎 相关癌症 (5, 9)。最近，我们报道了这种膜转运蛋白的功能不是 仅限于其作为二三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 表达/分泌来帮助维持肠道稳态 (10, 48)。 总之，我们之前的研究表明 PepT1 可能与肠道稳态有关，并暗示 各种发病机制，包括结肠炎和结肠炎相关癌症的发病机制。我们新颖的总体假设 小肠 PepT1 表达在维持肠道稳态和 塑造肠道微生物群。该提案的最初目的是证明小肠缺乏 PepT1 表达将肠道微生物群塑造成抗炎微生物群，这与 预防结肠炎和结肠炎相关癌症。然后我们将探讨小肠 PepT1 的影响 表达以及因此肠道 miRNA 失调对肠粘膜稳态的影响。 最后，我们将研究宿主 miRNA 的表达/分泌如何调节微生物群， 取决于小肠中 PepT1 的表达，我们将定义操纵 PepT1 的方法 通过施用特定的 miRNA 来实现微生物组。我们预计计划的工作将确定所发挥的作用 小肠 PepT1 表达在维持肠道稳态和塑造肠道中发挥着关键作用 肠道微生物群。拟议的研究还将促进治疗策略的制定 针对肠道炎症状况。