Caesarean Delivery's Effect on the Early Life Microbiome and Neurodevelopment

剖腹产对生命早期微生物组和神经发育的影响

• 批准号: 10537858
• 负责人: Jeremy K Lessing
• 金额: $ 3.7万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537858
• 关键词: Affect; Anesthesia procedures; Animal Model; Antibiotics; Atopobium vaginae; Attention deficit hyperactivity disorder; Bacteria; Bacterial Genes; Biological; Birth; Brain; Brain region; Cecum; Cells; Cerebellum; Cesarean section; Child; Childhood; Cohort Studies; Communication; Communities; Development; Disease; Ecology; Emotional; Epidemiology; Etiology; Exhibits; Experimental Designs; Feces; Food; Fostering; Future; Gene Expression; Gene Expression Profile; Genes; Genetic Predisposition to Disease; Goals; Hippocampus (Brain); Histology; Human; Impairment; Infant; Intervention; Knowledge; Label; Language; Large Intestine; Learning; Learning Disabilities; Life; Mammals; Medial; Medical; Memory; Messenger RNA; Methods; Microbe; Modeling; Mothers; Motor; Mus; Neurodevelopmental Disorder; Neurosciences; Newborn Infant; Pathogenesis; Pathway interactions; Pattern; Phenotype; Physicians; Population; Prefrontal Cortex; Prevalence; Proliferating; Prosencephalon; Regulation; Research; Research Personnel; Ribosomal RNA; Risk; S phase; Sampling; Schizophrenia; Scientist; Sensory; Social Interaction; Structure; System; Technology; Testing; Tissues; Training; Transplantation; Universities; Vagina; Vaginal delivery procedure; Virus; Weaning; Work; Writing; autism spectrum disorder; autistic behaviour; base; beta diversity; critical period; design; developmental disease; fungus; gastrointestinal; gut colonization; gut microbiome; gut microbiota; gut-brain axis; human disease; human fetal brain; hypoxic ischemic injury; ileum; mRNA Expression; maternal microbiota; microbial; microbial community; microbial composition; microbiome; microbiome alteration; microbiome analysis; microbiota; mouse model; myelination; neonatal period; neurodevelopment; neurogenesis; next generation sequencing; offspring; postnatal; postnatal development; postnatal period; pregnant; protein expression; pup; response; restoration; skills; stressor; transcriptomics; transmission process; vaginal microbiota

PROJECT SUMMARY / ABSTRACT The microbiome is the community of bacteria, fungi, and viruses that live in and on a host. Over the past few decades, advances in sequencing technology have allowed us to better understand the composition of the mammalian microbiome and the ways it affects host development. Recent evidence shows that Caesarean- section delivery, though a medical necessity for some births, may disrupt the vertical transfer of microbiota from mother to child. This can cause different microbial communities during critical periods of development. The brain may be particularly sensitive to microbiome changes because neurogenesis in many brain regions and myelination continue through childhood. This may be one explanation for the increased prevalence of neurodevelopmental disorders like autism spectrum disorder and attention deficit hyperactivity disorder that are associated with Caesarean delivery. Nevertheless, it remains unknown whether microbial communities, and specifically those caused by differential birth mode, can cause neuroanatomical changes. To advance our understanding of Caesarean delivery’s effect on neurodevelopment, we will use a mouse model of Caesarean delivery that will allow us to separately quantify the effect of birth mode on both the offsprings’ microbial communities (Aim 1) and neurodevelopment (Aim 2). We hypothesize that perturbation of the infant microbiome by Caesarean delivery will disrupt the normal pattern of neurodevelopment in pre-weaning mice (≤ postnatal day 21). To test this hypothesis, in Aim 1 we will study microbial communities through next generation sequencing, community structure analysis, and predicted bacterial gene content . Additionally, the direct and local effects of the microbial community will be quantified by mRNA transcriptomic analysis of gastrointestinal tissues. In Aim 2, we will study brain development through histology and transcriptomics of the cerebellum and hippocampus. Both regions exhibit neurodevelopment in the early postnatal period and are implicated in the pathogenesis of neurodevelopmental diseases. Gene expression will be quantified in each brain region through mRNA transcriptomics. The results of this proposed study may inform targeted microbiome-based interventions that restore microbial composition and function and facilitate proper neurogenesis. This research will be completed between two labs at Rutgers university that have expertise in microbiome analysis and neurodevelopment. The fellow will receive training to achieve his goal of becoming an independent physician-scientist. This will entail field-specific training in microbial ecology and neuroscience, as well as the generalizable skills necessary to become an independent investigator, including: experimental design, scientific writing and communication, and presentation skills.

项目总结/摘要 微生物组是生活在宿主体内和宿主上的细菌、真菌和病毒的群落。过去几 几十年来，测序技术的进步使我们能够更好地了解 哺乳动物微生物组及其影响宿主发育的方式。最近的证据表明，剖腹产- 尽管部分分娩是医疗上的必要，但可能会破坏微生物群的垂直转移 从母亲到孩子这可能会在发育的关键时期导致不同的微生物群落。 大脑可能对微生物组的变化特别敏感，因为许多大脑区域的神经发生 和髓鞘形成持续到童年。这可能是一种解释，为增加患病率， 神经发育障碍，如自闭症谱系障碍和注意缺陷多动障碍， 与剖腹产有关。然而，仍然不清楚微生物群落， 特别是那些由不同的出生模式引起的，可能会导致神经解剖学的变化。把我们的 为了了解剖腹产对神经发育的影响，我们将使用剖腹产的小鼠模型， 这将使我们能够分别量化出生模式对后代微生物的影响， 社区（目标1）和神经发育（目标2）。我们假设婴儿的扰动 通过剖腹产的微生物组将破坏断奶前小鼠（≤ 产后第21天）。为了验证这一假设，在目标1中，我们将研究微生物群落， 世代测序、群落结构分析和预测细菌基因含量。另夕h 微生物群落的直接和局部影响将通过mRNA转录组学分析来量化， 胃肠道组织在目标2中，我们将通过组织学和转录组学研究大脑发育， 小脑和海马。这两个区域都在出生后早期表现出神经发育， 与神经发育疾病的发病机制有关。基因表达将在每一个 通过mRNA转录组学研究大脑区域。这项拟议研究的结果可能会为目标提供信息 基于微生物组的干预措施，恢复微生物的组成和功能， 神经发生这项研究将在罗格斯大学的两个实验室之间完成， 微生物组分析和神经发育。这位研究员将接受培训，以实现他成为一名 独立的物理学家和科学家这将需要在微生物生态学和神经科学方面进行针对具体领域的培训， 以及成为独立调查员所需的概括技能，包括： 设计，科学写作和沟通，以及演讲技巧。