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

• 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
• 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

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.

项目摘要 坏死性小肠结肠炎（NEC）是一种威胁生命的胃肠道紧急情况，影响了7-10％的早产 死亡率高达30-50％的婴儿。 “肠道漏水”或肠道屏障不成熟，肠道升高 渗透性（IP）是对早产新生儿NEC敏感性的近端原因。早期发现漏水 肠道对于识别有NEC危险的婴儿有可能降​​低疾病严重程度。没有临床因素，常规实验室 已经描述了单独或组合的测试或生物标志物，它们识别出容易发育的新生儿 NEC。我们假设在粪便提取物中可检测到的粘膜免疫表型，反映了肠道 微环境和产后屏障的成熟，可以区分患有NEC风险高的婴儿。 这项研究的目的是研究粪便免疫生物标志物的诊断价值，以识别“处于危险中” NEC发作之前的肠道渗漏。单独使用或与其他IP相关的新生儿使用时 因素（即月经后年龄，喂养，微生物群），免疫表型可以提供非 - 侵入性，基于凳子的方法检测新生儿泄漏的肠道。为了实现这一目标，我们将利用现有的粪便 从205个早产的队列中收集的样品（妊娠<33周） rRNA基因测序和元基因组）和IP（尿液非代谢糖探针和鼠李糖） 已知。提出了两个目的：1）对细胞因子和趋化因子的深入表征 早产儿的粪便提取物在生命的前7-10天，并确定粪便的诊断值 免疫生物标志物在鉴定IP异常升高为NEC的主要危险因素方面； 2）定义 与IP的改善或持续升高有关的粪便免疫生物标志物的纵向变化。在 这项研究的完成，我们将确定代表A的歧视性粘膜免疫表型 新颖的，非侵入性粪便的诊断/筛查工具，以确定早产新生儿“有风险”的发展 NEC。这项研究还将为宿主免疫与肠道菌群之间的相互作用提供新的见解 营养不良导致早期障碍损伤的增强。这些结果将促进临床研究 评估了为早期NEC预防的合理设计的干预措施，并促进健康的肠道屏障 功能和新生儿健康。