Alterations in the brain-gut system have been implicated in various disease states, but little is known about how early-life adversity (ELA) impacts development and adult health as mediated by brain-gut interactions. We hypothesize that ELA disrupts components of the brain-gut system, thereby increasing susceptibility to disordered mood. In a sample of 128 healthy adult participants, a history of ELA and current stress, depression, and anxiety were assessed using validated questionnaires. Fecal metabolites were measured using liquid chromatography tandem mass spectrometry-based untargeted metabolomic profiling. Functional brain connectivity was evaluated by magnetic resonance imaging. Sparse partial least squares-discriminant analysis, controlling for sex, body mass index, age, and diet was used to predict brain-gut alterations as a function of ELA. ELA was correlated with four gut-regulated metabolites within the glutamate pathway (5-oxoproline, malate, urate, and glutamate gamma methyl ester) and alterations in functional brain connectivity within primarily sensorimotor, salience, and central executive networks. Integrated analyses revealed significant associations between these metabolites, functional brain connectivity, and scores for perceived stress, anxiety, and depression. This study reveals a novel association between a history of ELA, alterations in the brain-gut axis, and increased vulnerability to negative mood and stress. Results from the study raise the hypothesis that select gut-regulated metabolites may contribute to the adverse effects of critical period stress on neural development via pathways related to glutamatergic excitotoxicity and oxidative stress.

脑-肠系统的改变与各种疾病状态有关，但人们对早年逆境 (ELA) 如何影响脑-肠相互作用介导的发育和成人健康知之甚少。我们假设 ELA 破坏了脑-肠系统的组成部分，从而增加了对情绪紊乱的易感性。在 128 名健康成人参与者的样本中，使用经过验证的问卷评估了 ELA 的病史和当前的压力、抑郁和焦虑。使用基于液相色谱串联质谱法的非靶向代谢组学分析测量粪便代谢物。通过磁共振成像评估功能性脑连接。稀疏偏最小二乘判别分析，控制性别、体重指数、年龄、和饮食被用来预测脑-肠改变作为 ELA 的函数。ELA 与谷氨酸途径中的四种肠道调节代谢物（5-氧代脯氨酸、苹果酸、尿酸盐和谷氨酸γ甲酯）以及主要感觉运动、显着性和中央执行网络中功能性脑连接的改变相关。综合分析揭示了这些代谢物、功能性大脑连接以及感知压力、焦虑和抑郁的分数之间存在显着关联。这项研究揭示了 ELA 病史、脑-肠轴改变以及对消极情绪和压力的脆弱性增加之间的新关联。