Bacteria-associated VB12 regulates neonatal ileal epithelium homeostasis

项目总结/摘要 小儿炎症性肠病（IBD）的发病率在全球范围内不断增加。成因机制 参与疾病发病机制的基因目前尚不清楚。然而，由于 影响回肠上皮内环境稳定的营养不良可能导致疾病表现。因此，在本发明中， 了解儿童IBD的饮食危险因素是当务之急。含有微量营养素的饮食（例如， 维生素）在功能上控制新生肠细胞的基因组机制。宿主缺陷 营养回路，特别是在怀孕的产前和产后期间，不仅可能损害宿主， 细菌相互作用控制肠道内稳态，但也会恶化所需的代谢网络 细菌互养生长维生素B12（VB 12）是由一些肠道细菌合成的。维生素B12缺乏症可能 表达VB 12受体的功能障碍回肠上皮细胞（iEC）（例如，cubilin，megalin） 出生后的疾病我们最近报道了新发现的丙酸杆菌菌株P.UF1， 新生和成年小鼠对肠道病原体感染的吞噬和保护性T细胞反应。此外，本发明还 P. UF 1产生VB 12，并通过一种新的假定核糖开关关键地控制这种维生素的生物合成， cbiMCbl.我们现在证明，VB 12关键控制回肠上皮细胞（iEC）的分子和代谢 体内平衡，特别是线粒体呼吸，以潜在地限制好氧沙门氏菌（STm）感染， 新生小鼠本研究的目的是进一步阐明：（a）VB 12在功能上维持 在STm感染期间，iEC发挥功能。（B）VB 12调节iEC中的氧水平，导致管腔缺氧， 控制需氧STm感染和（c）VB 12增强回肠上皮完整性并支持效应子辅助性T细胞（Th） 细胞对STm攻击的应答。总体假设是：（1）VB 12重新编程的分子机器 （2）VB 12对回肠氧合的调节诱导了肠腔缺氧， 需氧STm感染和（3）通过VB 12控制IEC功能有助于上皮完整性， 保护性Th细胞对需氧STm感染的应答。下面的具体目标将测试这些假设：1。 阐明STm感染期间VB 12维持iEC功能的分子机制。2.详细说明 VB 12控制需氧STm感染对iEC线粒体氧的调节。和3.调查障碍 VB 12的完整性调节和对STm感染的保护性Th细胞应答。所得结果 拟议的机制研究将是第一个深入的报告，强调VB 12的效力，在调节iEC 功能的可持续治疗策略，可能会改善新生儿的健康。

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.