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Mechanisms of L. reuteri in regulating intestinal inflammation

罗伊氏乳杆菌调节肠道炎症的机制

基本信息

批准号：
8913894
负责人：
Yuying Liu
金额：
$ 33.17万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8913894
关键词：
Abdominal colic Address Adoptive Transfer Adult Affect Anti-Inflammatory Agents Anti-inflammatory Antibodies Attenuated Bacteria Biological Markers Blood CD4 Positive T Lymphocytes Cell Communication Cell Count Cell Shape Cells Dendritic Cells Development Disease Dose Epithelial Epithelial Cells Evolution Functional disorder Gastrointestinal Diseases Gastrointestinal tract structure Generations Health Helper-Inducer T-Lymphocyte Human IL2RA gene Immune Immune Tolerance Immune response In Vitro Incidence Infant Inflammation Inflammatory Inflammatory disease of the intestine Intestinal Diseases Intestinal Mucosa Intestines Laboratory Study Lactobacillus reuteri Leukocytes Lipopolysaccharides Low Birth Weight Infant Measures Mediating Mucosal Immune Responses Mus Necrotizing Enterocolitis Neonatal Newborn Infant Outcome Pattern recognition receptor Phase Premature Infant Prevalence Prevention Probiotics Production Property Rattus Regulation Regulatory T-Lymphocyte Research Risk Safety Sentinel Severities Supplementation T cell differentiation T-Lymphocyte T-Lymphocyte Subsets TLR2 gene TLR4 gene Toll-like receptors Very Low Birth Weight Infant attenuation cell type conditioning congenic cytokine feeding gastrointestinal human disease ileum in vivo insight intestinal homeostasis microbial mortality mouse model novel prevent receptor response

项目摘要

DESCRIPTION (provided by applicant): Lactobacillus reuteri (LR) has beneficial effects in several human diseases. Necrotizing enterocolitis (NEC) is the most common severe gastrointestinal condition affecting 7% of premature infants. Our preliminary studies demonstrated in neonatal mice with experimental NEC that LR feeding reduces mortality and intestinal inflammation, while increasing intestinal mucosal regulatory T cells (Tregs), cells with anti-inflammatory properties. Specific Aims: 1. To determine whether LR facilitates the generation of tolerogenic dendritic cells (DCs) via bacterial recognition receptors on DC ("sentinel cells") called Toll like receptors (TLRs). Gut inflammation is believed to be sustained by DC interaction with mucosal helper T cells (Th1 and Th17) and reduced by Tregs. We will measure NEC severity, response to LR, percentage of Tregs, Th1, and Th17 effectors in mice genetically deficient in TLRs. 2. To elucidate if LR-conditioned Tregs will be more efficient to suppress Th1/Th17 effectors in the inflamed gut, we will adoptively transfer Tregs bearing congenic markers from LR-fed mice to newborn mice undergoing NEC to determine if exogenous Tregs protect. 3. To determine whether LR is capable of inducing Tregs (iTregs) in the intestinal mucosa when natural Tregs (nTreg) are depleted, we will deplete nTregs by anti-CD25 antibody and determine if LR enhances iTreg development and remains capable of reducing intestinal inflammation. These aims will provide novel insights into mechanisms of Lactobacillus reuteri regulation of neonatal intestinal inflammation. Results will facilitate the selection of biomarkers to follow the evolution of NEC and to compare the potency of different probiotics in the human infant.

描述（由申请人提供）：罗伊氏乳杆菌（LR）对几种人类疾病具有有益作用。坏死性小肠结肠炎（NEC）是最常见的严重胃肠道疾病，影响7%的早产儿。我们的初步研究表明，在患有实验性NEC的新生小鼠中，LR喂养降低了死亡率和肠道炎症，同时增加了肠粘膜调节性T细胞（T细胞），抗炎特性。具体目标：1。确定LR是否通过DC上的细菌识别受体（“哨兵细胞”）（称为Toll样受体（TLR））促进致耐受性树突状细胞（DC）的产生。肠道炎症被认为是通过DC与粘膜辅助T细胞（Th 1和Th 17）的相互作用来维持的，并被Tcl 4减少。我们将测量NEC的严重程度，对LR的反应，TLRs基因缺陷小鼠中TlR，Th 1和Th 17效应子的百分比。2.为了阐明LR条件化的TCLs是否会更有效地抑制发炎肠道中的Th 1/Th 17效应子，我们将携带TCLs的同源标记物从LR喂养的小鼠过继转移到经历NEC的新生小鼠，以确定外源性TCLs是否具有保护作用。3.为了确定当天然T细胞（nTreg）耗尽时LR是否能够在肠粘膜中诱导T细胞（iT细胞），我们将通过抗CD 25抗体耗尽nT细胞，并确定LR是否增强iTreg发育并保持能够减少肠道炎症。这些目标将为罗伊氏乳杆菌调节新生儿肠道炎症的机制提供新的见解。结果将有助于选择生物标志物来跟踪NEC的演变，并比较不同益生菌在人类婴儿中的效力。