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

• 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
• 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

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 孕妇产时抗生素预防（IAP）用氨苄青霉素（AMP）预防新生儿B组 链球菌（GBS）疾病对减少感染相关的发病率和死亡率有重大影响， 近几十年来的新生期。然而，随着早发性GBS发病率的降低， 疾病，抗生素暴露有可能通过扰乱婴儿肠道而造成重大的附带损害 微生物群及其发育中的免疫系统。母乳则相反，为婴儿提供低聚糖 具有独特的免疫调节（有时是抗微生物）特性，有利于塑造 正常肠道微生物组的发展。推荐使用AMP治疗GBS的现行儿科指南 预防和适当的母乳喂养时间现在受到了新的重视， 它们对婴儿健康的明显影响是通过改变，有害的或有益的， 健康的微生物组和婴儿免疫系统的发展。联合私家侦探维克托尼泽特和乔治刘 题为“氨苄青霉素和母乳寡糖对婴儿的影响”的基础科学项目 微生物组和免疫功能”是儿科医生，科学家大，成功的翻译 围绕GBS和相关细菌病原体、抗生素治疗和宿主免疫 应答目前的提议将应用实验室长期以来一直使用的实验小鼠模型 专业知识，在母婴临床药理学这一高度新颖的领域提供关键的机制见解。 也就是说，我们将研究经验性预防性抗生素的毒理学或不良影响的新方面 在怀孕期间给予（数百万）母亲的治疗，或者对婴儿的胎衣进行经验性治疗， 治疗疑似败血症。这些抗生素暴露降低了感染的风险，但同时也影响了 短期和长期的婴儿微生物组和代谢组，可能影响随后的免疫 婴儿对感染和疫苗的反应。我们的首要假设是，鉴于 无论是对母亲还是对婴儿，都对婴儿的肠道有可测量的有害影响 微生物组和发育中的免疫系统，从而对婴儿的后续发育产生不利影响。 对细菌感染和疫苗的反应以及后期抗生素给药的临床药理学。 相反，我们假设母乳低聚糖（MMO）通过以下方式对婴儿有益： 改善肠道微生物组的弹性，从而减轻抗生素的不良反应，以及 改善随后对GB S感染和肺炎球菌和乙型肝炎B疫苗的反应。 这个基础科学项目的成功完成将有助于确定的好处和不利影响， 抗生素和MMO对婴儿微生物组和免疫系统的影响，并进一步告知 目前的GBS抗生素预防指南和母乳喂养时间的建议。