Vitamin D Receptor Regulation of Microbiota in Intestinal Epithelia

维生素 D 受体对肠上皮微生物群的调节

• 批准号: 10736407
• 负责人: Jun Sun
• 金额: $ 62.58万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736407
• 关键词: Animal Model; Area; Bacterial Infections; Biochemical; Biological Factors; Biology; Biopsy; Carbohydrates; Categories; Chronic; Chronic Disease; Clinical; Colitis; Colon; Complex; Crohn' s disease; Data; Development; Digestive System Disorders; Disease; Down-Regulation; Elements; Ensure; Environmental Risk Factor; Epithelial Cells; Epithelium; Etiology; Functional disorder; Gastroenterology; Genetic Predisposition to Disease; Germ-Free; Goals; Homeostasis; Host Defense; Human; Ileitis; Immune system; Impairment; Inflammation; Inflammatory Bowel Diseases; Integration Host Factors; Intestinal Diseases; Intestines; Knowledge; Lead; Lipids; Literature; Methods; Modeling; Molecular; Mucositis; Mus; Natural Immunity; Organoids; Paneth Cells; Pathogenesis; Patients; Physiology; Play; Predisposition; Process; Proteins; Qualifying; Regulation; Relapse; Research; Role; Salmonella; Sampling; Severities; Shapes; Signal Pathway; Signal Transduction; Small Intestines; Source; Technology; Tissues; Transgenic Mice; Ulcerative Colitis; Vitamin D; Vitamin D3 Receptor; alertness; antimicrobial peptide; base; bile acid metabolism; bioinformatics tool; conditional knockout; design; dysbiosis; fecal transplantation; gut inflammation; gut microbiome; gut microbiota; host-microbe interactions; human disease; innovation; insight; intestinal epithelium; microbial; microbiome; microbiome alteration; microbiota; microbiota metabolites; mouse model; novel; novel strategies; overexpression; pathogenic bacteria; prevent; receptor; single cell technology; stem cells

Abstract Inflammatory bowel diseases (IBD) occur when there is an unfortunate combination of microbial dysbiosis and genetic susceptibility. Downregulation of Vitamin D receptor (VDR), a host factor, promotes the severity, extent, and duration of mucosal inflammation and dysbiosis. However, most studies examining gut microbiota have primarily relied on fecal or colonic luminal samples. In contrast, few studies have considered the roles of the small intestinal microbiome. Classically, Paneth cells located in the small intestine are a significant source of antimicrobial peptides (AMPs) and proteins important in host defense. Although Paneth cells are located in the small intestine, AMPs are released to the entire intestine, thus shaping the gut microbiome. VDR regulation of gut bacterial pathogenesis has become an emerging area in IBD, however, the aspect of small intestinal microbiome and metabolites has yet to be explored. Given the challenges in treating patients with Crohn’s disease and the limited studies on the small intestinal microbiome, it is critical to understand how Paneth cell VDR is involved in microbial homeostasis, balanced metabolites, and innate immunity. The objective of our current R01 proposal is to study regulatory mechanisms of Paneth cell VDR and to restore microbiome / metabolites in inflamed states. Our preliminary data showed Paneth cell VDR conditional knockout (VDRΔPC) leads to dysbiosis and susceptibility to Salmonella-induced colitis. We established a method to purify Paneth cells and study their alertness to bacterial pathogens. Furthermore, conditional VDR deletion severely changed the metabolite profile. However, the complex mechanisms in the ileitis through the Paneth cell VDR are still unknown. We hypothesize that VDR deficiency in Paneth cells alters the microbiome/metabolites and makes the host susceptible to chronic intestinal inflammation (e.g., ileitis). We have designed two Aims to rigorously examine the hypotheses at the cellular and microbiome levels: Aim 1. Define the mechanism by which VDR maintains healthy Paneth cells and impacts ileitis inflammation. Aim 2. Investigate the role of Paneth cell VDR in altering the microbiome / metabolites and define the mechanism of VDR in restoring microbial homeostasis, when administering microbiome via fecal transplantation or recolonization in originally germ-free mice. Specifically, we will use novel animal models, organoids from human IBD biopsies, and statistical and bioinformatic tools to understand the host factors and aspects of microbiome / metabolites in chronic intestinal inflammation. Our research team includes experts in the following areas: epithelial biology, animal models, clinical gastroenterology, and microbiome. Our studies are innovative because we provide a unifying hypothesis that can potentially account for defective a host factor in VDR signaling pathway, abnormal Paneth cells, and dysbiosis in IBD. Cutting edge technologies and models will be employed to gain greater mechanistic insights into the interrelationships among VDR, microbiome, and metabolites in inflammation. This study will fill the knowledge gap and provide novel treatment by targeting microbiome / metabolites in IBD and other disorders.

抽象的 当微生物失调和微生物失调不幸结合时，就会发生炎症性肠病 (IBD)。 遗传易感性。宿主因子维生素 D 受体 (VDR) 的下调会促进病情的严重程度、程度、 以及粘膜炎症和生态失调的持续时间。然而，大多数检查肠道微生物群的研究都表明 主要依靠粪便或结肠腔样本。相比之下，很少有研究考虑到 小肠微生物组。传统上，位于小肠的潘氏细胞是重要的来源 抗菌肽 (AMP) 和蛋白质对宿主防御很重要。尽管潘氏细胞位于 小肠中，AMP 被释放到整个肠道，从而塑造肠道微生物组。 VDR 监管 肠道细菌发病机制已成为 IBD 的一个新兴领域，然而，小肠方面 微生物组和代谢物仍有待探索。鉴于治疗克罗恩病患者面临的挑战 由于对小肠微生物组的研究有限，了解潘氏细胞如何 VDR 参与微生物稳态、平衡代谢物和先天免疫。我们的目标 目前的R01提案是研究潘氏细胞VDR的调节机制并恢复微生物组/ 炎症状态下的代谢物。我们的初步数据显示潘氏细胞VDR条件敲除（VDRΔPC） 导致生态失调和对沙门氏菌引起的结肠炎的易感性。我们建立了一种纯化潘氏的方法 细胞并研究它们对细菌病原体的警觉性。此外，条件性 VDR 删除严重改变了 代谢物概况。然而，潘氏细胞VDR在回肠炎中的复杂机制仍不清楚。 未知。我们假设潘氏细胞中的 VDR 缺陷会改变微生物组/代谢物， 使宿主易患慢性肠道炎症（例如回肠炎）。我们设计了两个目标 在细胞和微生物组水平上严格检验假设： 目标 1. 定义机制 VDR 维持健康的潘氏细胞并影响回肠炎炎症。目标 2. 研究潘氏细胞的作用 VDR 改变微生物组/代谢物并定义 VDR 恢复微生物的机制 通过粪便移植或在最初无菌环境中重新定植来施用微生物组时，实现稳态 老鼠。具体来说，我们将使用新型动物模型、来自人类 IBD 活检的类器官以及统计和 生物信息工具，用于了解慢性肠道中的宿主因素和微生物组/代谢物的方面 炎。我们的研究团队包括以下领域的专家：上皮生物学、动物模型、 临床胃肠病学和微生物组。我们的研究具有创新性，因为我们提供了统一的 可能解释 VDR 信号通路中宿主因子缺陷、潘氏异常的假设 IBD 中的细胞和生态失调。将采用尖端技术和模型来获得更大的机械性 深入了解炎症中 VDR、微生物组和代谢物之间的相互关系。这项研究将填补 弥补知识差距，并通过针对 IBD 和其他疾病的微生物组/代谢物提供新的治疗方法。