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 当微生物营养不良和 遗传敏感性。维生素D受体（VDR）的下调是一种宿主因素，促进了严重程度，程度， 粘膜注射和营养不良的持续时间。但是，大多数检查肠道菌群的研究具有 相反，很少有研究认为 小肠道微生物组。从经典上讲，位于小肠中的Paneth细胞是重要的来源 抗菌胡椒（AMP）和蛋白质对宿主防御很重要。尽管Paneth细胞位于 小肠，放大器被释放到整个肠，从而塑造肠道微生物组。 VDR调节 肠道细菌发病机理已成为IBD的新兴区域，但是小肠的方面 微生物组和代谢产物尚未探索。鉴于治疗克罗恩的患者面临的挑战 疾病和对小肠道微生物组的有限研究，了解如何泛池细胞至关重要 VDR参与微生物稳态，平衡的代谢产物和先天免疫组织化学物质。我们的目标 当前的R01建议是研究Paneth Cell VDR的调节机制，并恢复微生物组 / 发炎状态的代谢产物。我们的初步数据显示了Paneth Cell VDR条件敲除（VDRΔPC） 导致营养不良和对沙门氏菌诱发的结肠炎的敏感性。我们建立了一种净化paneth的方法 细胞并研究其对细菌病原体的警觉性。此外，有条件的VDR缺失严重更改 代谢物剖面。然而，通过paneth细胞VDR的腹膜炎中的复杂机制仍然是 未知。我们假设Paneth细胞中的VDR缺乏改变了微生物组/代谢物和 使宿主容易受到慢性肠炎的影响（例如，肠炎）。我们设计了两个目标 严格检查细胞和微生物组水平的假设：目标1。定义该机制 VDR维持健康的泛细胞并影响回肠炎保险。 AIM 2。研究Paneth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 稳态，当通过粪便移植或重新殖民施用微生物组时 小鼠。特别是，我们将使用新颖的动物模型，人类IBD活检的器官以及统计和 了解慢性肠中微生物组 /代谢物的宿主因素和方面的生物信息学工具 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，因为我们提供了一个统一的 假设可能说明VDR信号通路中的宿主因子有缺陷，异常paneth IBD中的细胞和失调。尖端技术和模型将被雇用以获得更大的机械性 炎症中VDR，微生物组和代谢产物之间的相互关系的见解。这项研究将填补 知识差距并通过靶向IBD和其他疾病中的微生物组 /代谢产物来提供新的治疗方法。