Fetal Programming of infant microbiome development and consequences for neurodevelopment

婴儿微生物组发育的胎儿编程及其对神经发育的影响

• 批准号: 513319150
• 负责人: Professorin Dr. Claudia Buß, Ph.D.
• 金额: --
• 依托单位: Forschungsgruppe Wirt-Mikrobiom Faktoren in Herz-Kreislauferkrankungen
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/513319150?language=en
• 关键词: Fetal; Programming; infant; microbiome; development

Disease susceptibility is determined by the dynamic interplay between genetic makeup and environmental conditions, like maternal stress, during intrauterine and early postnatal life (i.e., developmental programming of health and disease). The brain represents a prominent target for developmental programming due to its protracted and active pre- and postnatal development. In particular, alterations in stress-related maternal-placental-fetal (MPF) biological processes appear to play a key role in modifying developmental outcomes generally and offspring brain development specifically. One potential mediator, strongly linked to metabolism, the immune system and to endocrine signaling, is the gut microbiome, which is known to be associated with somatic and psychiatric disorders due to its reciprocal interaction with the brain via the gut-brain axis. While specific microbiome development is known to take place postnatally, the structures (e.g. gastrointestinal tract) which later constitute the microbiome “niche” are established prenatally, and variation like integrity of the gut (e.g., permeability) can be shaped by environmental conditions during pregnancy (e.g., maternal stress). This is likely mediated by variation in MPF endocrine, immune, and metabolic biology, which in the proposed study will be represented by an allostatic load index. Based on this framework, the overarching goal of this project is to elucidate the association of maternal allostatic load during pregnancy with microbiome maturation and neurodevelopment in early life. Towards this goal we aim to first create a model for human gut microbiome maturation (a “microbiome age index”) based on existing data sets, and to use this model to characterize the role of variation in maternal allostatic load during pregnancy in shaping offspring gut microbiota development, as well as to characterize the association between offspring gut microbiota development and neurodevelopment from birth to four years of age. We then plan to explore the role of the gut microbiome as a mediator of the association between allostatic load and neurodevelopment, and to validate observed associations in two external cohorts. We have the opportunity to address these aims in an existing cohort of pregnant women and their fetuses/infants followed from early pregnancy until 24-mo age. We plan to extend this study and seek funding for adding a timepoint for data collection at 48-mo age, a developmental time point when the microbiome is assumed to have stabilized. Our study will contribute to a better understanding which biological cues in early life shape the developing brain, which is key to translating the developmental programming paradigm into novel intervention strategies that are mechanism-informed and harness the unique opportunity of sensitive developmental periods when interventions are most effective.

疾病易感性是由遗传组成和环境条件之间的动态相互作用决定的，如母体压力，在子宫内和出生后早期（即，健康和疾病的发展规划）。由于大脑在出生前和出生后的长期和活跃的发育，大脑是发育规划的一个突出目标。特别是，压力相关的母体-胎盘-胎儿（MPF）生物学过程的改变似乎在改变发育结果中起着关键作用，特别是后代的大脑发育。一种与代谢、免疫系统和内分泌信号密切相关的潜在介质是肠道微生物组，已知其与躯体和精神疾病相关，因为其通过肠-脑轴与大脑相互作用。虽然已知特定的微生物组发育发生在出生后，但后来构成微生物组“生态位”的结构（例如胃肠道）是在出生前建立的，并且如肠道完整性的变化（例如，渗透性）可由怀孕期间的环境条件形成（例如，母亲的压力）。这可能是由MPF内分泌、免疫和代谢生物学的变化介导的，在拟议的研究中，这将由非稳态负荷指数表示。基于这一框架，该项目的总体目标是阐明妊娠期间母体非稳态负荷与生命早期微生物组成熟和神经发育的关系。为了实现这一目标，我们的目标是首先基于现有数据集创建人类肠道微生物组成熟模型（“微生物组年龄指数”），并使用该模型来表征妊娠期间母体非稳态负荷的变化在塑造后代肠道微生物群发育中的作用，以及表征从出生到四岁的后代肠道微生物群发育和神经发育之间的关联。然后，我们计划探索肠道微生物组作为非稳态负荷和神经发育之间关联的介导者的作用，并验证在两个外部队列中观察到的关联。我们有机会在一个现有的孕妇队列及其从妊娠早期到24个月大的胎儿/婴儿中解决这些目标。我们计划延长这项研究，并寻求资金，以增加48个月的数据收集时间点，这是一个假定微生物组已经稳定的发育时间点。我们的研究将有助于更好地了解生命早期的哪些生物线索塑造了发育中的大脑，这是将发育规划范式转化为新的干预策略的关键，这些策略是机制信息，并利用干预最有效的敏感发育期的独特机会。