The impact of ampicillin and breast milk oligosaccharides on the infant microbiome and immune functions

氨苄西林和母乳低聚糖对婴儿微生物组和免疫功能的影响

基本信息

批准号：
10681295
负责人：
Victor Nizet
金额：
$ 20.36万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-10 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10681295
关键词：
Adverse effects Affect Age Ampicillin Antibacterial Response Antibiotic Prophylaxis Antibiotic Therapy Antibiotics Area Attention Bacterial Infections Bacterial Vaccines Basic Science Birth Breast Feeding Breastfed infant Childhood Clinical Pharmacology Communicable Diseases Development Diagnosis Disease Drug Kinetics Experimental Models Guidelines Helper-Inducer T-Lymphocyte Hepatitis B Vaccines Human Human Milk Immune Immune response Immune system Immunology Incidence Infant Infant Health Infection Investigation Length Leukocytes Life Measurable Morbidity - disease rate Mothers Mucous Membrane Mus Natural Immunity Neonatal Newborn Infant Oligosaccharides Perinatal Infection Pharmacology Physicians Predisposition Pregnancy Pregnant Women Prevention Property Prophylactic treatment Recommendation Research Personnel Risk Reduction Scientist Sepsis Serum Shapes Streptococcal Infections Streptococcus Group B Streptococcus pneumoniae Testing Therapeutic Toxicology Training Vaccination Vaccines Virulence Factors Weaning antimicrobial early onset gut microbiome gut microbiota immune function improved infant gut microbiome infection risk innate immune pathways insight intrapartum metabolome metabolomics microbial microbiome mortality mouse model neonatal infection novel pathogen pathogenic bacteria polarized cell prevent promote resilience prophylactic response translational research program vaccine response vaccinology

项目摘要

PROJECT SUMMARY Intrapartum antibiotic prophylaxis (IAP) of pregnant women with ampicillin (AMP) to prevent neonatal group B Streptococcus (GBS) disease has had a major impact to reduce infection-associated morbidity and mortality in the immediate newborn period over recent decades. However, with this reduced incidence of early-onset GBS disease, antibiotic exposure has the potential to cause significant collateral damage by perturbing the infant gut microbiota and its developing immune system. Breast milk, conversely, supplies the infant with oligosaccharides that possess unique immune-modulatory (and sometimes antimicrobial) properties beneficial for shaping the development of a normal gut microbiome. Current pediatric guidelines that recommend the use of AMP for GBS prophylaxis and the appropriate duration of breastfeeding are now receiving significant new attention because of their clear impacts upon the health of the infant accrued through changes, deleterious or beneficial, on the development of a healthy microbiome and infant immune system. Co-PIs Victor Nizet and George Liu of this Basic Science Project entitled “The impact of Ampicillin and Breast Milk Oligosaccharides on the Infant Microbiome and Immune Functions” are pediatric physician-scientists large and successful translational research programs built around GBS and related bacterial pathogens, antibiotic therapeutics and host immune responses. This current proposal will apply experimental mouse models in which the labs have long standing expertise to provide key mechanistic insights in this highly novel area of maternal-infant clinical pharmacology. Namely, we will be studying the novel aspects of toxicology or adverse impact of empiric prophylactic antibiotic therapy given to (millions of) mothers during pregnancy, or alternatively, to the infant afterbirth for empiric treatment of suspected sepsis. These antibiotic exposures reduce risk of infection, but simultaneously affect the infant microbiome and metabolome in both the short and long term, likely impacting subsequent immune responses of the infant to infections and vaccinations. Our overarching hypothesis is that AMP, given prophylactically to the mother or empirically to the infant, has a measurable detrimental effect on infants’ gut microbiome and developing immune system, and consequently adversely affect the infant’s subsequent response to bacterial infections and vaccines and the clinical pharmacology of later antibiotic administration. Conversely, we hypothesize that maternal milk oligosaccharides (MMO) provide a benefit to the infant by improving the resilience of the gut microbiome, consequently mitigating the antibiotic adverse effects, and improving subsequent response to GB S infections and pneumococcal and hepatitis B vaccine responses. Successful completion of this Basic Science Project will help determine the benefits and adverse effects of antibiotics and MMOs on the infant microbiome and immune system and further inform the appropriateness of current GBS antibiotic prophylaxis guidelines and recommendations for the length of breastfeeding.

项目摘要氨苄青霉素（AMP）的孕妇抗生素预防（IAP）链球菌（GBS）疾病对减少感染相关的病态和死亡率产生了重大影响近几十年以来，即将到来的新生儿。疾病，抗生素暴露有可能通过扰动婴儿肠道造成严重的附带损害微生物群及其发展的免疫系统。具有独特的免疫 - 模块化（有时是抗菌）特性，有益于塑造开发正常的肠道微生物组。预防和适当的母乳喂养持续时间正在接受大量的新注意力。他们对婴儿的健康有害或有益的明确影响。健康的微生物组和婴儿免疫系统的发展。基础科学项目的标题为“氨苄青霉素和母乳寡糖对婴儿的影响微生物组和免疫功能”是小儿医师科学家大而成功的翻译围绕GB和相关双臂病原体，抗生素治疗和宿主免疫的研究计划当前的提议将实验实验室模型专业知识可以在这一高度新颖的产妇临床药理学领域提供关键的机械见解。也就是说，我们将研究毒理学的新方面或经验性预防性抗生素的不利影响怀孕期间（数百万）母亲或替代的治疗给婴儿后生外生的治疗可疑的败血症治疗。婴儿微生物组和代谢组在短期和长期内都可能影响随后的免疫婴儿对感染和疫苗接种的反应。对母亲进行预防或经验对婴儿的经验，对婴儿的肠有可测量的有害作用微生物组和开发免疫系统，而Consec则意味着不利的影响对细菌感染和疫苗的反应以及后来抗生素给药的临床药理学。相反，我们假设母体牛奶寡糖（MMO）为婴儿提供了婴儿的好处提高肠道微生物组的弹性，从而减轻抗生素不良反应，并改善了对GB的感染以及肺炎和肝炎B疫苗反应的随后反应。这个基础科学项目的成功梳理将有助于确定好处和对手婴儿微生物组和免疫系统上的抗生素和MMO，并进一步告知拨款人当前的GBS抗生素预防指南和有关母乳喂养长度的建议。