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

项目总结 孕期预防性应用氨苄西林预防新生儿B组感染的研究 链球菌(GBS)疾病在减少感染相关发病率和死亡率方面产生了重大影响 近几十年来的新生儿时期。然而，随着早发性GBS发病率的降低 疾病，接触抗生素有可能通过扰乱婴儿的肠道而造成重大的附带损害 微生物区系及其发育中的免疫系统。反之，母乳为婴儿提供低聚糖。 具有独特的免疫调节(有时还有抗菌)特性，有利于塑造 正常肠道微生物群的发育。推荐使用AMP治疗GBS的当前儿科指南 预防措施和适当的母乳喂养持续时间现在正受到重大的新关注，因为 这些变化对婴儿健康的明显影响，无论是有害的还是有益的， 发展健康的微生物群和婴儿免疫系统。合作伙伴维克多·尼泽特和乔治·刘 名为《氨苄西林和母乳低聚糖对婴儿的影响》的基础科学项目 微生物组和免疫功能》是儿科医生-科学家成功的大型翻译 围绕GBS和相关细菌病原体、抗生素疗法和宿主免疫建立的研究计划 回应。目前的提案将应用实验室长期存在的实验小鼠模型 在母婴临床药理学这一极具新颖性的领域提供关键的机械见解的专业知识。 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。 在怀孕期间为(数百万)母亲提供的治疗，或者为婴儿的经验性分娩而进行的治疗 疑似败血症的治疗。这些抗生素的接触降低了感染的风险，但同时也影响了 婴儿短期和长期的微生物组和代谢组，可能影响随后的免疫 婴儿对感染和接种疫苗的反应。我们的首要假设是，给定的AMP 对母亲的预防或对婴儿的经验，对婴儿的肠道有可测量的有害影响 微生物群和发育中的免疫系统，从而对婴儿的后续 对细菌感染和疫苗的反应以及后来使用抗生素的临床药理学。 相反，我们假设母乳寡糖(MMO)通过以下方式为婴儿提供好处 改善肠道微生物群的弹性，从而减轻抗生素的不良影响，以及 改善对GB S感染的后续反应以及肺炎球菌和乙肝疫苗的反应。 这项基础科学项目的成功完成将有助于确定 抗生素和MMO对婴儿微生物群和免疫系统的影响，并进一步告知 目前的GBS抗生素预防是关于母乳喂养时间的指南和建议。

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.