Optimization of Antibiotics in Mothers and their Breastfed Infants Using Pharmacomicrobiomic and Metabolomic Analyses

项目摘要 加州大学圣地亚哥分校MPRINT CET，题为“母亲及其母乳喂养婴儿的抗生素优化 使用药物微生物组学和代谢组学分析”，汇集了一支经验丰富， 在孕产妇和儿科临床药理学方面具有领导作用的经过验证的合作研究者， 基础研究方法和技术。在其高度集成和协同的组成部分中， UCSD MPRINT CET解决了母婴药理学中的关键障碍，涉及（1） 婴儿通过母乳或密切接触暴露于母体抗生素治疗的药代动力学，（2） 母亲抗生素治疗或预防对建立正常婴儿微生物组和肠道的影响 代谢组学，（3）此类抗生素暴露对婴儿免疫功能和肝脏的潜在下游影响 细胞色素P450药物代谢酶，和（4）母乳的关键作用都作为一个管道， 抗生素转移和有益的人/哺乳动物乳低聚糖（HMO/MMO）的来源， 在面对抗生素压力时支持微生物组和免疫完整性。成功的手术和结果 我们的MPRINT CET通过3个项目（临床，基础科学和数据科学）完成， 管理核心和两个技术核心，牛奶分析核心（MAC）和药物计量学， 分析化学核心（PACC）。在临床项目“母乳喂养母亲的抗生素治疗： 我们拥有成熟的专业知识和基础设施，并可获得高质量的 招募母婴临床队列，研究母体抗生素如何改变母乳成分， 以临床上有意义的方式影响婴儿的结局。在基础科学项目“氨苄青霉素的影响， 母乳寡聚物对婴儿微生物组和免疫功能的影响”，我们利用广泛的 在新生儿宿主-病原体相互作用小鼠模型中探索氨苄青霉素功能作用的经验， MMO对婴儿免疫功能的影响，包括野生型和MMO缺陷型的新型交叉培养策略 妈妈们在我们的数据科学项目“产妇抗生素对母乳喂养婴儿微生物组的影响， 代谢组”，我们部署先进的MS技术、非侵入性采样和创新的分子网络 在一项关于母乳抗生素暴露对婴儿微生物组影响的前沿研究中， 代谢组和肝CYP酶。MAC提供牛奶收集协议和套件，近红外 光谱和HPLC、HMO/MMO和营养成分分析，以及新的分析验证扩展 我们的MPRINT CET分析能力，而PAC开发和验证新的定量分析， 生理和半生理模型，以描述和预测孕产妇和婴儿的抗生素PK， 母乳喂养。我们的行政核心监督我们的研究项目/核心的整合和性能 以及他们的里程碑，将他们与国家MPRINT CET HUB和独特的培训/试点项目联系起来。

PROJECT SUMMARY The UC San Diego MPRINT CET, entitled “Optimization of Antibiotics in Mothers and Their Breastfed Infants Using Pharmacomicrobiomic and Metabolomic Analyses”, brings together a team of highly experienced and proven collaborative investigators with leadership roles in maternal and pediatric clinical pharmacology, fundamental research methods and technologies. Across its highly integrated and synergistic components, the UCSD MPRINT CET addresses critical barriers in maternal-infant pharmacology regarding (1) the pharmacokinetics of infant exposure to maternal antibiotic treatment via breastmilk or close contact, (2) the impact of maternal antibiotic therapy or prophylaxis on establishment of the normal infant microbiome and gut metabolome, (3) potential downstream effects of such antibiotic exposure on infant immune function and hepatic cytochrome P450 drug metabolizing enzymes, and (4) the pivotal role of breast milk both as a conduit for antibiotic transfer and source of beneficial human/mammalian milk oligosaccharides (HMOs/MMOs) that may support microbiome and immune integrity in face of antibiotic stress. The successful operation and outcome of our MPRINT CET is accomplished through 3 Projects (Clinical, Basic Science and Data Science) an Administrative Core and two Technology Cores, the Milk Analytics Core (MAC) and Pharmacometrics and Analytical Chemistry Core (PACC). In the Clinical Project “Antibiotic Treatment in Breastfeeding Mothers: Effects on Milk, Microbiome, and Infant Outcomes”, we have proven expertise and infrastructure and access to a high enrolling maternal-infant clinical cohort to study how maternal antibiotics alter breast milk composition and impact infant outcomes in clinical meaningful ways. In the Basic Science Project “The Impact of Ampicillin and Breast Milk Oligosaccharides on the Infant Microbiome and Immune Functions”, we leverage extensive experience in mouse models of neonatal host-pathogen interactions to probe functional effects of ampicillin and MMOs on infant immune function, including a novel cross-fostering strategy with wild-type and MMO-deficient mothers. In our Data Science Project “Impact of Maternal Antibiotics on the Breastfeeding Infant Microbiome and Metabolome”, we deploy advanced MS technology, non-invasive sampling and innovative molecular networking analytics in a cutting-edge study of the impact of breast milk antibiotic exposure on the infant microbiome, metabolome and hepatic Cyp enzymes. The MAC provides milk collection protocols and kits, near infrared spectroscopy and HPLC, HMO/MMO and nutritional composition analysis, and new assay validation expanding our MPRINT CET analytical capabilities, while the PAC develops and validates novel quantitative assays and physiologic and semi-physiologic models to describe and predict maternal and infant antibiotic PK during breastfeeding. Our Administrative Core oversees integration and performance of our research projects/cores and their milestones, connecting them to the national MPRINT CET HUB and unique training/pilot projects.