Fetal Programming of infant microbiome development and consequences for neurodevelopment

疾病易感性是由基因组成和环境条件之间的动态相互作用决定的，如在宫内和产后早期生活期间的产妇压力（即健康和疾病的发展规划）。大脑由于其长期和活跃的产前和产后发育，是发育规划的一个突出目标。特别是，压力相关的母-胎盘-胎儿（MPF）生物学过程的改变似乎在改变发育结果和后代大脑发育方面起着关键作用。与代谢、免疫系统和内分泌信号密切相关的一个潜在中介是肠道微生物群，由于其通过肠-脑轴与大脑相互作用，已知与躯体和精神疾病有关。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）是在产前建立的，并且肠道完整性（例如渗透性）等变异可以由怀孕期间的环境条件（例如母体压力）塑造。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，这些变化将由适应负荷指数表示。基于这一框架，本项目的总体目标是阐明怀孕期间母体适应负荷与生命早期微生物群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群成熟模型（“微生物群年龄指数”），并使用该模型表征怀孕期间母体适应负荷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4岁的后代肠道微生物群发育与神经发育之间的关系。然后，我们计划探索肠道微生物组作为适应负荷和神经发育之间关联的中介的作用，并在两个外部队列中验证观察到的关联。我们有机会在现有的孕妇及其胎儿/婴儿队列中实现这些目标，这些队列从妊娠早期一直跟踪到24个月。我们计划扩展这项研究，并寻求资金，以增加48月龄的数据收集时间点，这是一个微生物组被认为已经稳定的发育时间点。我们的研究将有助于更好地理解生命早期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，这些策略是机制知情的，并利用敏感发育时期的独特机会，当干预最有效时。

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.