Maternal gut microbiota in fetal programming of neurodevelopment and related disorders

项目摘要 社会互动是人类最普遍的体验的基础，例如家庭生活、商业和 然而，社交功能障碍是主要神经发育障碍的一个令人衰弱的标志，包括 自闭症和精神分裂症。尽管取得了重大进展，但社会功能障碍和 与神经发育障碍相关的其他核心行为症状仍然难以捉摸，干预措施 有限的。越来越多的人一致支持神经发育障碍的“两次打击”假说。 次要环境因素启动异常的发育编程，从而导致 遗传易感个体的行为障碍。在环境因素中，饮食是最主要的 导致宿主疾病易感性的因素。值得注意的是，饮食是宿主肠道微生物群的主要决定因素。 组成。通过调节宿主的免疫功能，甚至大脑和行为，肠道微生物群 正在成为对寄主健康和福祉的主要影响。肠道微生物群的破坏，或称“生物失调” 进而与几种常见的炎症性疾病有关，包括炎症性肠病和 代谢综合征。在神经精神疾病患者群体中也观察到了生物失调，他们的发病率很高。 胃肠道症状共病；然而，肠道微生物群失调与 人们对神经发育障碍或其他神经精神障碍知之甚少。在这个项目中，我们将确定 孕妇高脂饮食(MHFD)导致的孕期肠道微生物群失调是否有助于 后代神经行为功能障碍及其潜在机制。此前，我们报道了MHFD 导致雄性后代肠道微生物组的失调，以及社会功能障碍和潜在的缺陷 社会奖赏回路中的突触可塑性。最近，我们发现MHFD对人的性二型性影响。 后代行为--男性比女性明显存在更强的社会缺陷--然而，我们观察到了生物失调 雄性和雌性MHFD后代的肠道。我们推断，如果母体肠道微生物群是因果关系 与后代社会功能障碍有关，然后女性MHFD后代肠道微生物组持续失调 F1代可能足以损害F2代雄性的神经发育和行为。事实上，我们观察到 F2代男性有强烈的社交功能障碍，但女性没有。在这里，我们将检验HFD诱导的假说 母体肠道微生物群落的失调导致F1后代胎儿程序异常，这是社交的基础 F1和F2男性都有功能障碍。在目标1中，我们将询问HFD/MHFD如何影响P/F1的重塑 孕期母体肠道微生物群。在目标2中，我们将确定HFD/MHFD对母体的影响 免疫功能、胎儿免疫印记和胚胎大脑。在目标3中，我们将确定是否调制 孕期母体肠道微生物群可以挽救后代的社会功能障碍。这项研究将产生 对MHFD调节胎儿发育的机制和治疗潜力的关键洞察 以母体微生物群为靶点以防止后代的不良神经行为后果。

Project Summary Social interaction is fundamental to the most universal of human experiences, such as family life, business, and romance; however, social dysfunction is a debilitating hallmark of major neurodevelopmental disorders, including autism and schizophrenia. Despite significant advances, the mechanisms underlying social dysfunction and other core behavioral symptoms associated with neurodevelopmental disorders remain elusive and interventions limited. There is growing consensus in support of a ‘two hit’ hypothesis for neurodevelopmental disorders, in which a secondary environmental factor initiates abnormal developmental programming that contributes to behavioral dysfunction in genetically predisposed individuals. Among environmental factors, diet is a leading factor contributing to host disease susceptibility. Notably, diet is the chief determinant of host gut microbiome composition. Through modulation of host immune function, and even the brain and behavior, the gut microbiome is emerging as a major influence on host health and well-being. Disruption, or ‘dysbiosis,’ of the gut microbiome is, in turn, associated with several common inflammatory disorders, including inflammatory bowel disease and metabolic syndrome. Dysbiosis is also observed in neuropsychiatric patient populations, who have a high rate of gastrointestinal symptom comorbidity; yet, the relationship between dysbiosis of the gut microbiome and neurodevelopmental or other neuropsychiatric disorders is poorly understood. In this project, we will determine if maternal high-fat diet (MHFD)-induced dysbiosis of the gut microbiome during pregnancy contributes to descendant neurobehavioral dysfunction and the underlying mechanisms. Previously, we reported that MHFD induces dysbiosis of the male offspring gut microbiome as well as social dysfunction and underlying deficits in synaptic plasticity in the social reward circuit. Recently, we identified a sexually dimorphic effect of MHFD on offspring behavior–stronger social deficits are evident in males versus females–however, we observed dysbiosis of both the male and female MHFD offspring gut. We reasoned that if the maternal gut microbiome is causally related to offspring social dysfunction, then enduring dysbiosis of the female MHFD offspring gut microbiome in the F1 generation may be sufficient to impair neurodevelopment and behavior in F2 males. Indeed, we observed robust social dysfunction in male, but not female, F2 offspring. Here, we will test the hypothesis that HFD-induced dysbiosis of the maternal gut microbiome drives abnormal fetal programming in F1 offspring that underlies social dysfunction in both F1 and F2 males. In Aim 1, we will ask how HFD/MHFD affects remodeling of the P/F1 maternal gut microbiome during pregnancy. In Aim 2, we will determine the effects of HFD/MHFD on maternal immune function, fetal immune imprinting, and the embryonic brain. In Aim 3, we will determine if modulation of the maternal gut microbiome during pregnancy can rescue descendant social dysfunction. This study will yield key insight into the mechanisms by which MHFD modulates fetal development and the potential for therapeutic targeting of the maternal microbiome to prevent adverse neurobehavioral outcomes in descendant generations.