Bacteria-associated VB12 regulates neonatal ileal epithelium homeostasis

细菌相关的 VB12 调节新生儿回肠上皮稳态

基本信息

批准号：
10455546
负责人：
Mansour M Zadeh
金额：
$ 34.88万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10455546
关键词：
5&apos Untranslated Regions Adolescent Adult Aerobic Affect Bacteria Binding Biochemical Pathway Birth Cell Differentiation process Cell Proliferation Cell physiology Cells Child Childhood Communities Coupled Cytoplasm DNA DNA Methylation Dependence Diet Diet therapy Disease Epithelial Epithelial Cells Event Functional disorder Future Genome Stability Genomics Growth Helper-Inducer T-Lymphocyte Homeostasis Hypoxia Immunomodulators Immunosuppressive Agents Impairment Incidence Infection Inflammation Inflammatory Bowel Diseases Intestinal Diseases Intestines Intrinsic factor LDL-Receptor Related Protein 2 Malnutrition Metabolic Metabolic Pathway Micronutrients Mitochondria Modification Molecular Morbidity - disease rate Mus Neonatal Newborn Infant Nutritional Operon Oxygen Pathogenesis Pathogenicity Phagocytes Pharmaceutical Preparations Pregnancy Premature Infant Propionibacterium Regimen Regulation Reporting Research Proposals Respiration Risk Factors Role Salmonella Source T cell response Testing Therapeutic Tissues Transcobalamins United States Vitamin B 12 Vitamin B 12 Deficiency Vitamins cofactor dietary enteric infection enteric pathogen epigenome epigenomics genome integrity gut bacteria gut homeostasis improved insight intrinsic factor-cobalamin receptor macrophage metabolome metabolomics microbial neonatal health neonate novel novel therapeutic intervention pathogen postnatal period programs receptor research study response synergism transcriptome transcriptomics vitamin biosynthesis

项目摘要

Project Summary/Abstract Incidence of pediatric inflammatory bowel disease (IBD) is increasing worldwide. The causative mechanisms involved in the disease pathogenesis are currently elusive. However, induced pathogenic inflammation due to malnutrition, impacting the ileal epithelium homeostasis, may contribute to disease manifestation. Thus, understanding the dietary risk factors involved in pediatric IBD is urgent. Diet containing micronutrients (e.g., vitamins) functionally controls the genomic mechanisms of the neonatal intestinal cells. Deficiency in host nutritional circuitry, notably during the pre and postnatal periods of pregnancy may not only impair the host- bacteria interaction controlling the gut homeostasis but also deteriorate the metabolic networks required for bacterial syntrophic growth. Vitamin B12 (VB12) is synthesized by some intestinal bacteria. VB12 deficiency may dysfunction ileal epithelial cells (iECs) expressing VB12 receptors (e.g., cubilin, megalin) with severe intestinal disorders post-birth. We recently reported that the newly discovered Propionibacterium strain, P. UF1, regulates phagocytic and protective T cell responses to intestinal pathogen infection in newborn and adult mice. Further, P. UF1 produces VB12 and crucially controls the biosynthesis of this vitamin through a novel putative riboswitch, cbiMCbl. We now demonstrate that VB12 critically controls ileal epithelial cell (iEC) molecular and metabolic homeostasis, particularly the mitochondrial respiration, to potentially limit aerobic Salmonella (STm) infection in newborn mice. The objectives of this research proposal are to further elucidate that (a) VB12 functionally sustains iEC function during STm infection, (b) VB12 regulates oxygen levels in iECs resulting in luminal hypoxia that controls aerobic STm infection and (c) VB12 fortifies ileal epithelium integrity and supports effector T helper (Th) cell response to STm challenge. The overarching hypotheses are: (1) VB12 reprograms the molecular machinery of iECs during STm infection, (2) regulation of ileal oxygenation by VB12 induces the luminal hypoxia that limits the aerobic STm infection and (3) controlling iEC-function by VB12 contributes to epithelial integrity and protective Th cell response to aerobic STm infection. The following Specific Aims will test these hypotheses: 1. Elucidate the molecular mechanisms sustaining iEC function by VB12 during STm infection. 2. Elaborate on the mitochondrial oxygen regulation in iECs by VB12 controlling aerobic STm infection. And 3. Investigate barrier integrity regulation by VB12 and protective Th cell response to STm infection. Results obtained from the proposed mechanistic studies will be the first in-depth report underscoring VB12 potency in regulating iEC function for a sustainable therapeutic strategy that could potentially improve neonatal health.

项目概要/摘要全球范围内小儿炎症性肠病 (IBD) 的发病率正在增加。发病机制目前对该疾病发病机制的参与尚不清楚。然而，诱发致病性炎症营养不良影响回肠上皮稳态，可能导致疾病表现。因此，了解儿科 IBD 涉及的饮食危险因素刻不容缓。含有微量营养素的饮食（例如维生素）在功能上控制新生儿肠道细胞的基因组机制。宿主缺乏营养循环，特别是在怀孕的产前和产后期间，可能不仅损害宿主细菌相互作用控制肠道稳态，但也会恶化肠道所需的代谢网络细菌互养生长。维生素 B12 (VB12) 由一些肠道细菌合成。 VB12 缺乏症可能表达VB12受体（例如cubilin、megalin）的回肠上皮细胞（iEC）功能障碍，伴有严重的肠道产后疾病。我们最近报道了新发现的丙酸杆菌菌株 P. UF1，调节新生和成年小鼠肠道病原体感染的吞噬和保护性 T 细胞反应。更远， P. UF1 产生 VB12 并通过一种新型的推定核糖开关至关重要地控制这种维生素的生物合成， cbiMCbl。我们现在证明 VB12 关键控制回肠上皮细胞 (iEC) 分子和代谢体内平衡，特别是线粒体呼吸，有可能限制需氧沙门氏菌（STm）感染新生小鼠。本研究计划的目标是进一步阐明 (a) VB12 在功能上维持 STm 感染期间 iEC 的功能，(b) VB12 调节 iEC 中的氧水平，导致管腔缺氧，控制需氧 STm 感染，并且 (c) VB12 增强回肠上皮完整性并支持效应 T 辅助细胞 (Th) 细胞对 STm 挑战的反应。总体假设是：(1) VB12 重新编程分子机器 STm 感染期间 iEC 的变化，(2) VB12 对回肠氧合的调节引起管腔缺氧，从而限制有氧 STm 感染和 (3) 通过 VB12 控制 iEC 功能有助于上皮完整性和 Th 细胞对有氧 STm 感染的保护性反应。以下具体目标将检验这些假设： 1. 阐明 STm 感染期间 VB12 维持 iEC 功能的分子机制。 2. 详细说明 VB12 控制有氧 STm 感染，对 iEC 中的线粒体氧进行调节。 3. 调查障碍 VB12 的完整性调节和保护性 Th 细胞对 STm 感染的反应。获得的结果拟议的机制研究将是第一份强调 VB12 在调节 iEC 方面的效力的深入报告发挥可持续治疗策略的作用，有可能改善新生儿健康。