Effects of breast milk antibodies on neonatal intestinal immunity and host-microbe mutualism

母乳抗体对新生儿肠道免疫及宿主-微生物互利共生的影响

• 批准号: 10516734
• 负责人: Bingjie Beth Pecha
• 金额: $ 5.27万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-16 至 2025-03-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10516734
• 关键词: Activities of Daily Living; Advanced Development; Affinity; Antibodies; Antigens; B-Cell Activation; B-Lymphocytes; Bacteria; Biological Models; Birth; Breast Feeding; Cell Communication; Cells; Child; Colitis; Coupled; Data; Development; Digestion; Disease; Elements; Enteral; Estrogen Receptors; Flow Cytometry; Fostering; Genetic; Germ-Free; Growth Factor; Health; Helper-Inducer T-Lymphocyte; Homeostasis; Human Milk; Immune; Immune response; Immune system; Immunity; Impairment; Infant; Inflammation; Intestinal Diseases; Intestines; Knock-out; Label; Lactation; Life; Link; Location; Lymphoid Tissue; Maternal antibody; Mediating; Memory B-Lymphocyte; Metabolic; Metabolic Diseases; Methods; Microbe; Mucosal Immunity; Mucous Membrane; Mus; Neonatal; Nutrient; Outcome; Phenotype; Physiology; Plasma; Predisposition; Process; Risk; Salmonella typhimurium; Shapes; Structure; Structure of germinal center of lymph node; System; T-Lymphocyte; Testing; Therapeutic; Tissues; Variant; Weaning; Wild Type Mouse; Work; adaptive immune response; colonization resistance; commensal microbes; cytokine; gut bacteria; gut microbes; gut microbiota; host microbiome; host microbiota; humoral immunity deficiency; immunoregulation; inducible Cre; insight; intestinal homeostasis; mesenteric lymph node; microbial colonization; microbiota; mouse model; mutualism; neonate; novel; offspring; pathogenic bacteria; pup; response; therapy design; therapy development

Project Summary/Abstract Breast milk is a key regulator of host-microbiome interactions in early life. In addition to nutrients, breast milk contains cytokines, growth factors and antibodies, which help shape the composition of the microbiota and regulate infant immunity to gut microbes. Accumulating evidence links breastfeeding with a decreased risk of developing immune-mediated and metabolic diseases later in life. However, the specific components of breast milk and the mechanism underlying these associations are currently lacking. Using a mouse model, our lab discovered that mice deficient in breast milk antibodies mount increased mucosal T cell- dependent immune responses, including elevated T follicular helper (Tfh) cells and germinal center (GC) B cells in the gut-draining lymphoid tissues. This process is driven by microbes as germ-free mice lacking breast milk antibodies do not generate aberrant mucosal Tfh and GC B cell responses. Due to the profound impact of the gut microbiota on the development of the immune system coupled with the lifelong persistence of activated adaptive immune cells, a current paradigm is that inappropriate adaptive immune responses to gut bacteria drive adverse health outcomes in the long-term. The hypothesis of this proposal is that inappropriate adaptive immune responses to resident gut bacteria resulting from the absence of breast milk antibodies drives persistent impairments in intestinal homeostasis. To test this hypothesis, two aims are proposed. Aim 1 investigates the persistence, localization, and phenotype of B cells activated in the absence of maternal antibodies via fate-tracking activated GC B cells and flow cytometry. Aim 2 assesses the function of the T cell dependent adaptive immune response on intestinal homeostasis. The comprehensive phenotypic and functional characterization of the novel T cell dependent immune response that arises in neonates lacking breast milk antibodies will provide key mechanistic insight on how breastfeeding contributes to long-term health. The studies outlined here will lay the groundwork for the development of interventions and therapies to manipulate host relationships with the microbiota and promote long-term health, particularly in neonates who are not breastfed.

项目概要/摘要 母乳是生命早期宿主与微生物组相互作用的关键调节剂。除了营养之外，母乳 含有细胞因子、生长因子和抗体，有助于塑造微生物群的组成， 调节婴儿对肠道微生物的免疫力。越来越多的证据表明母乳喂养可以降低患病风险 在以后的生活中患上免疫介导的和代谢性疾病。然而，乳房的具体成分 目前还缺乏牛奶和这些关联背后的机制。我们的实验室使用小鼠模型 发现缺乏母乳抗体的小鼠粘膜 T 细胞依赖性免疫增强 反应，包括肠道引流中滤泡辅助 T (Tfh) 细胞和生发中心 (GC) B 细胞升高 淋巴组织。这个过程是由微生物驱动的，因为缺乏母乳抗体的无菌小鼠不会 产生异常的粘膜 Tfh 和 GC B 细胞反应。由于肠道微生物群的深远影响 免疫系统的发展加上激活的适应性免疫细胞的终生持续存在， 当前的一个范式是，对肠道细菌的不适当的适应性免疫反应会导致不良健康 长期结果。该提案的假设是，不适当的适应性免疫反应 由于缺乏母乳抗体而导致的肠道常驻细菌会导致肠道菌群持续受损 肠道稳态。为了检验这一假设，提出了两个目标。目标 1 研究持久性， 通过命运追踪激活在没有母源抗体的情况下激活的 B 细胞的定位和表型 GC B 细胞和流式细胞术。目标 2 评估 T 细胞依赖性适应性免疫反应的功能 关于肠道稳态。新型T细胞的综合表型和功能表征 缺乏母乳抗体的新生儿产生的依赖性免疫反应将提供关键机制 深入了解母乳喂养如何有助于长期健康。这里概述的研究将为 开发干预措施和疗法来操纵宿主与微生物群的关系， 促进长期健康，特别是非母乳喂养的新生儿。