Mucosal immune biomarkers to detect neonatal leaky gut

用于检测新生儿肠漏的粘膜免疫生物标志物

基本信息

批准号：
10646527
负责人：
Bing Ma
金额：
$ 23.18万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10646527
关键词：
16S ribosomal RNA sequencing Address Affect Age Antibiotics Bacterial Translocation Bifidobacterium Biodiversity Biological Assay Biological Markers Classification Clinical Clinical Research Cohort Studies Computer Models Dependence Detection Development Diagnosis Diagnostic Early Diagnosis Early Intervention Emergency Situation Etiology Feces Future Gestational Age Goals Health Human Milk Immune Immune Targeting Immune response Immunity Immunologic Markers Impairment Incidence Infant Infant Development Inflammation Inflammatory Injury Interleukin-10 Intestinal permeability Intestines Knowledge Laboratories Lactulose Leaky Gut Life Measures Methods Mucous Membrane Nature Necrosis Necrotizing Enterocolitis Neonatal Newborn Infant Onset of illness Phenotype Population Predisposition Pregnancy Premature Infant Prevention Prevention strategy Preventive Proteins Research Resources Rhamnose Risk Risk Factors Sampling Scheme Screening procedure Severity of illness Surveys Symptoms Technology Testing Therapeutic Time Urine Weight Gain chemokine claudin 3 cohort cytokine diagnostic tool diagnostic value dysbiosis effective therapy feeding gastrointestinal gut microbiome gut microbiota high risk improved insight intestinal barrier intestinal fatty acid binding protein intestinal maturation metagenome metagenomic sequencing microbiome microbiota milk intake mortality neonatal care neonatal health neonate novel novel strategies postnatal predictive marker preterm newborn prevent rational design research clinical testing sex stool sample sugar tool trefoil factor tumor-immune system interactions

项目摘要

PROJECT SUMMARY Necrotizing enterocolitis (NEC) is a life-threatening, gastrointestinal emergency affecting 7-10% of preterm infants with mortality as high as 30-50%. "Leaky gut", or intestinal barrier immaturity with elevated intestinal permeability (IP), is the proximate cause of susceptibility to NEC in preterm neonates. Early detection of leaky gut is essential to identify infants at risk for NEC to reduce disease severity. No clinical factor, routine laboratory test or biomarker alone or in combination have been described that identify newborns susceptible to develop NEC. We postulate that a mucosal immune phenotype detectable in fecal extracts, is reflective of the intestinal microenvironment and postnatal barrier maturation and can distinguish infants at high risk for developing NEC. The goal of this study is to investigate the diagnostic value of fecal immune biomarkers to identify “at-risk” neonates with leaky gut prior to NEC onset. When used alone or in combination with other IP-associated neonatal factors (i.e., postmenstrual age, feeding, microbiota), the immune phenotype can provide the basis of a non- invasive, stool-based method to detect neonatal leaky gut. To achieve this goal, we will leverage existing stool samples collected from a cohort of 205 preterms (<33 weeks gestation), from whom both gut microbiome (16S rRNA gene sequencing and metagenome) and IP (urine non-metabolized sugar probes lactulose and rhamnose) are known. Two aims are proposed: 1) to conduct an in-depth characterization of cytokines and chemokines in fecal extracts of preterm infants during the first 7-10 days of life, and to determine the diagnostic value of fecal immune biomarkers in identification of aberrantly elevated IP as a major risk factor for NEC; 2) to define longitudinal changes of fecal immune biomarkers associated with improved or persistently elevated IP. At the completion of this study, we will have identified a discriminatory mucosal immune phenotype representing a novel, non-invasive stool-based diagnostic/screening tool to identify preterm newborn “at risk” for developing NEC. This study will also provide new insights into the interplay between host immunity and gut microbiota dysbiosis that contributes to heightened barrier injury in early life. These results will facilitate clinical studies to evaluate rationally designed interventions for early NEC prevention and to promote healthy intestinal barrier functions and newborn health.

项目概要坏死性小肠结肠炎 (NEC) 是一种危及生命的胃肠道急症，影响 7-10% 的早产儿婴儿死亡率高达 30-50% “肠漏症”，或肠道屏障不成熟导致肠道升高。渗透性 (IP) 是早产儿漏气早期发现 NEC 的直接原因。肠道对于识别有 NEC 风险的婴儿以降低疾病严重程度至关重要无临床因素，常规实验室。已经描述了单独或组合的测试或生物标志物，可以识别易患发育的新生儿 NEC。我们假设粪便提取物中可检测到的粘膜免疫表型反映了肠道的情况。微环境和产后屏障成熟，可以区分发生 NEC 的高风险婴儿。本研究的目的是调查粪便免疫生物标志物的诊断价值，以识别“高危人群” NEC 发病前肠漏的新生儿单独使用或与其他 IP 相关新生儿联合使用时。因素（即经后年龄、喂养、微生物群），免疫表型可以提供非- 基于粪便的侵入性方法来检测新生儿肠漏为了实现这一目标，我们将利用现有的粪便。从 205 名早产儿（妊娠 <33 周）的队列中采集样本，其中肠道微生物组（16S rRNA 基因测序和宏基因组）和 IP（尿液非代谢糖探针乳果糖和鼠李糖）提出了两个目标：1）对细胞因子和趋化因子进行深入表征。早产儿出生后 7-10 天内的粪便提取物，并确定粪便的诊断价值免疫生物标志物识别异常升高的 IP 作为 NEC 的主要危险因素 2) 定义；粪便免疫生物标志物的纵向变化与 IP 改善或持续升高相关。完成这项研究后，我们将识别出一种歧视性粘膜免疫表型，代表新型非侵入性基于粪便的诊断/筛查工具，用于识别“有风险”发育的早产儿 NEC。这项研究还将为宿主免疫和肠道微生物群之间的相互作用提供新的见解。这些结果将有助于临床研究。评估合理设计的早期 NEC 预防干预措施并促进健康的肠道屏障功能和新生儿健康。