Mechanisms of maternal Immunoglobulin A control over the neonatal microbiota and the development of Necrotizing Enterocolitis.

母体免疫球蛋白 A 控制新生儿微生物群和坏死性小肠结肠炎发展的机制。

• 批准号: 10312104
• 负责人: Timothy Wesley Hand
• 金额: $ 44.97万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10312104
• 关键词: 16S ribosomal RNA sequencing; Affect; Animal Model; Anti-Bacterial Agents; Antibodies; Antibody Repertoire; Area; Asthma; B-Lymphocytes; Bacteria; Benign; Binding; Cause of Death; Cells; Child; Chronic Disease; Communities; Dangerousness; Data; Development; Disease; Drops; Enterobacteriaceae; Epithelial; Generations; Genetic Transcription; Gnotobiotic; Health; Heterogeneity; Human Milk; Immune; Immune response; Immune system; Immunoglobulin A; Incidence; Individual; Infant; Infection; Infection prevention; Infiltration; Inflammatory; Intestinal Diseases; Intestinal Mucosa; Intestines; Knowledge; Lead; Link; Mammary gland; Maternal antibody; Measures; Mediating; Milk; Milk Banks; Mothers; Mucosal Immune Responses; Mucous Membrane; Mus; Mutation; Necrotizing Enterocolitis; Neonatal; Obesity; Premature Infant; Premature Infant Diseases; Preventive therapy; Production; Property; Rag1 Mouse; Research; Risk; Role; Sampling; Secretory Immunoglobulin A; Sepsis; Shapes; Source; Structure; T-Lymphocyte; Taxon; Testing; Therapeutic; Variant; Woman; bacterial community; bacterial genome sequencing; base; cost; de novo mutation; donor milk; gut microbiota; host microbiota; improved; intestinal epithelium; microbial community; microbiome; microbiota; mouse model; neonatal mice; neonate; novel; pathogen; premature; prevent; prospective; protective effect; pup; response; transcriptome

Abstract Neonates are particularly susceptible to invasion by colonizing bacteria and thus mammalian mothers protect their children via antibodies and in particular, Immunoglobulin A (IgA), secreted into maternal milk. Necrotizing Enterocolitis (NEC) is a disease of premature infants characterized by invasion of the neonatal intestine by the microbiota. Studies have shown that the incidence of NEC is significantly reduced in infants fed with breast milk, though the mechanism is unclear. Our preliminary studies show that maternal IgA (mIgA) is an important factor in protection against NEC. Analysis of IgA-binding on fecal samples from premature infants indicated that breast milk was the predominant source of IgA in the first month post-delivery and that a relative drop in the fraction of bacteria bound by IgA is associated with the development of NEC. Sequencing of IgA-bound and unbound bacteria indicated that NEC was associated with a unique increase in IgA negative Enterobacteriaceae. Further, we confirmed that IgA is critical in preventing NEC in the murine model, where we demonstrate that pups reared by mIgA deficient mothers are susceptible to disease, indicating that IgA in breast milk is necessary for protection. Together these data indicate that mIgA binding is critical in preventing the development of NEC by shaping the neonatal microbiota. In order to mediate effects on bacterial communities IgA acts on bacterial sub- populations. Therefore, our central hypothesis is that IgA in maternal milk modifies intestinal bacteria directly, preventing their invasion of the neonatal intestine and the induction of inflammatory immune responses. We will test this hypothesis in three aims. In the first aim we will investigate the mechanisms of how individual sub- populations of Enterobacteriaceae change to elude mIgA. Further we will investigate the mIgA repertoire of different breast milk donors to test the hypothesis that variation in this repertoire is important in binding different intestinal bacteria. In aim 2 we will investigate the mechanism of IgA binding on the neonatal microbiota at the community level, via 16S rRNA gene sequencing and by transcriptional analysis of a model organism in gnotobiotic mice. Our hope is to associate these data with analysis of the role of IgA on epithelial association of intestinal bacteria and the downstream immune responses that are induced. In the third aim we will investigate whether the production of mammary gland antibodies that protect against NEC are dependent upon maternal T cells. These aims will lead to a better understanding of how mIgA shapes the nascent microbiome and the neonatal immune response. In addition, our proposal may improve provide strategies to prevent NEC via the targeted provision of breast milk containing protective antibodies to the most at-risk children.

抽象的 新生儿特别容易受到定植细菌的入侵，因此哺乳动物母亲会保护它们 他们的孩子通过抗体，特别是免疫球蛋白 A (IgA)，分泌到母乳中。坏死 小肠结肠炎 (NEC) 是一种早产儿疾病，其特征是新生儿肠道受到结肠炎的侵袭。 微生物群。研究表明，母乳喂养的婴儿NEC的发病率显着降低， 虽然机制尚不清楚。我们的初步研究表明，母体 IgA (mIgA) 是一个重要因素 针对 NEC 的保护。对早产儿粪便样本的 IgA 结合分析表明，母乳 产后第一个月，牛奶是 IgA 的主要来源，并且 IgA 比例相对下降 IgA 结合的细菌与 NEC 的发生有关。 IgA 结合和未结合的测序 细菌表明 NEC 与 IgA 阴性肠杆菌科细菌的独特增加有关。更远， 我们在小鼠模型中证实了 IgA 对于预防 NEC 至关重要，我们证明了饲养的幼崽 缺乏 mIgA 的母亲容易患病，这表明母乳中的 IgA 是婴儿出生所必需的。 保护。这些数据共同表明 mIgA 结合对于预防 NEC 的发展至关重要 塑造新生儿微生物群。为了介导对细菌群落的影响，IgA 作用于细菌亚群 人口。因此，我们的中心假设是母乳中的 IgA 直接改变肠道细菌， 防止它们侵入新生儿肠道并诱导炎症免疫反应。我们将 从三个目标检验这一假设。在第一个目标中，我们将研究个体如何子化的机制 肠杆菌科菌群发生变化以逃避 mIgA。我们将进一步研究 mIgA 的全部功能 不同的母乳捐赠者来检验这一假设，即该库的变异对于结合不同的母乳捐赠者很重要 肠道细菌。在目标 2 中，我们将研究 IgA 与新生儿微生物群结合的机制 群落水平，通过 16S rRNA 基因测序和模式生物的转录分析 限生小鼠。我们希望将这些数据与 IgA 对上皮细胞关联的作用分析联系起来。 肠道细菌和诱导的下游免疫反应。在第三个目标中，我们将调查 预防 NEC 的乳腺抗体的产生是否依赖于母体 T 细胞。这些目标将有助于更好地了解 mIgA 如何塑造新生微生物组和 新生儿免疫反应。此外，我们的建议可能会改进提供策略，通过 有针对性地向高危儿童提供含有保护性抗体的母乳。