Department of Psychiatry, The University of Pennsylvania Perelman School of Medicine, 3535 Market St., Philadelphia, PA 19104, United States.
Department of Pharmacology, Center for Epigenetic Research in Child Health and Brain Development, University of Maryland School of Medicine, 670 W Baltimore St. HSF3, 9-173, Baltimore, MD 21201, United States.
Brain Behav Immun. 2019 Jan;75:240-250. doi: 10.1016/j.bbi.2018.11.005. Epub 2018 Nov 3.
Adverse childhood experiences (ACEs), such as abuse or chronic stress, program an exaggerated adult inflammatory response to stress. Emerging rodent research suggests that the gut microbiome may be a key mediator in the association between early life stress and dysregulated glucocorticoid-immune response. However, ACE impact on inflammatory response to stress, or on the gut microbiome, have not been studied in human pregnancy, when inflammation increases risk of poor outcomes. The aim of this study was to assess the relationships among ACE, the gut microbiome, and cytokine response to stress in pregnant women.
Physically and psychiatrically healthy adult pregnant women completed the Adverse Childhood Experiences Questionnaire (ACE-Q) and gave a single stool sample between 20 and 26 weeks gestation. Stool DNA was isolated and 16S sequencing was performed. Three 24-hour food recalls were administered to assess dietary nutrient intake. A subset of women completed the Trier Social Stress Test (TSST) at 22-34 weeks gestation; plasma interleukin-6 (IL-6), interleukin-1β (IL-1β), high sensitivity C-reactive protein (hsCRP), tumor necrosis factor α (TNF-α), and cortisol were measured at four timepoints pre and post stressor, and area under the curve (AUC) was calculated.
Forty-eight women completed the ACE-Q and provided stool; 19 women completed the TSST. Women reporting 2 or more ACEs (high ACE) had greater differential abundance of gut Prevotella than low ACE participants (q = 5.7 × 10^-13). Abundance of several gut taxa were significantly associated with cortisol, IL-6, TNF-α and CRP AUCs regardless of ACE status. IL-6 response to stress was buffered among high ACE women with high intake of docosahexaenoic acid (DHA) (p = 0.03) and eicosapentaenoic acid (EPA) (p = 0.05).
Our findings suggest that multiple childhood adversities are associated with changes in gut microbiota composition during pregnancy, and such changes may contribute to altered inflammatory and glucocorticoid response to stress. While preliminary, this is the first study to demonstrate an association between gut microbiota and acute glucocorticoid-immune response to stress in a clinical sample. Finally, exploratory analyses suggested that high ACE women with high dietary intake of ω-3 polyunsaturated fatty acids (PUFAs) had a dampened inflammatory response to acute stress, suggesting potentially protective effects of ω-3s in this high-risk population. Given the adverse effects of inflammation on pregnancy and the developing fetus, mechanisms by which childhood adversity influence the gut-brain axis and potential protective factors such as diet should be further explored.
不良的童年经历（ACEs），如虐待或慢性压力，会导致成年人对压力的炎症反应过度。新兴的啮齿动物研究表明，肠道微生物组可能是早期生活压力与糖皮质激素免疫反应失调之间关联的关键介质。然而，ACE 对压力下的炎症反应或肠道微生物组的影响，在人类怀孕期间尚未研究过，而怀孕期间炎症会增加不良结局的风险。本研究旨在评估孕妇 ACE、肠道微生物组和细胞因子对压力反应之间的关系。
身体健康和精神健康的成年孕妇完成了不良童年经历问卷（ACE-Q），并在 20 至 26 周妊娠期间提供了一份粪便样本。提取粪便 DNA 并进行 16S 测序。进行了三次 24 小时食物回忆，以评估膳食营养素摄入情况。一部分女性在 22-34 周妊娠期间完成了特里尔社会压力测试（TSST）；在应激前和应激后四个时间点测量了血浆白细胞介素-6（IL-6）、白细胞介素-1β（IL-1β）、高敏 C 反应蛋白（hsCRP）、肿瘤坏死因子-α（TNF-α）和皮质醇，并计算了曲线下面积（AUC）。
48 名女性完成了 ACE-Q 并提供了粪便；19 名女性完成了 TSST。报告有 2 个或更多 ACE（高 ACE）的女性肠道普雷沃氏菌的丰度高于低 ACE 参与者（q=5.7×10^-13）。无论 ACE 状态如何，肠道几个分类群的丰度与皮质醇、IL-6、TNF-α 和 CRP AUC 均显著相关。高 ACE 女性的 IL-6 对压力的反应在高 DHA（二十二碳六烯酸）（p=0.03）和 EPA（二十碳五烯酸）（p=0.05）摄入时得到缓冲。
我们的研究结果表明，多次童年逆境与孕妇肠道微生物群组成的变化有关，而这种变化可能导致应激时炎症和糖皮质激素反应的改变。虽然这是初步研究，但这是第一项在临床样本中证明肠道微生物群与急性糖皮质激素-免疫应激反应之间存在关联的研究。最后，探索性分析表明，高 ACE 女性高摄入 ω-3 多不饱和脂肪酸（PUFA）时，对急性应激的炎症反应减弱，这表明 ω-3 在这种高危人群中可能具有保护作用。鉴于炎症对怀孕和发育中胎儿的不良影响，应进一步探讨童年逆境影响肠道-大脑轴的机制以及饮食等潜在保护因素。
