Department of Integrative Biology & Physiology, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Department of Integrative Biology & Physiology, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Behav Brain Res. 2021 Jul 23;410:113353. doi: 10.1016/j.bbr.2021.113353. Epub 2021 May 9.
Selective serotonin reuptake inhibitors (SSRIs) are the most widely used treatment by women experiencing depression during pregnancy. However, the effects of maternal SSRI use on early offspring development remain poorly understood. Recent studies suggest that SSRIs can modify the gut microbiota and interact directly with particular gut bacteria, raising the question of whether the gut microbiome impacts host responses to SSRIs. In this study, we investigate effects of prenatal SSRI exposure on fetal neurodevelopment and further evaluate potential modulatory influences of the maternal gut microbiome. We demonstrate that maternal treatment with the SSRI fluoxetine induces widespread alterations in the fetal brain transcriptome during midgestation, including increases in the expression of genes relevant to synaptic organization and neuronal signaling and decreases in the expression of genes related to DNA replication and mitosis. Notably, maternal fluoxetine treatment from E7.5 to E14.5 has no overt effects on the composition of the maternal gut microbiota. However, maternal pretreatment with antibiotics to deplete the gut microbiome substantially modifies transcriptional responses of the fetal brain to maternal fluoxetine treatment. In particular, maternal fluoxetine treatment elevates localized expression of the opioid binding protein/cell adhesion molecule like gene Opcml in the fetal thalamus and lateral ganglionic eminence, which is prevented by maternal antibiotic treatment. Together, these findings reveal that maternal fluoxetine treatment alters gene expression in the fetal brain through pathways that are impacted, at least in part, by the presence of the maternal gut microbiota.
选择性 5-羟色胺再摄取抑制剂（SSRIs）是治疗孕期抑郁症女性最常用的药物。然而，母体使用 SSRIs 对早期后代发育的影响仍知之甚少。最近的研究表明，SSRIs 可以改变肠道微生物群，并与特定的肠道细菌直接相互作用，这就提出了一个问题，即肠道微生物组是否会影响宿主对 SSRIs 的反应。在这项研究中，我们研究了产前 SSRIs 暴露对胎儿神经发育的影响，并进一步评估了母体肠道微生物组的潜在调节作用。我们证明，母体用 SSRIs 氟西汀治疗会在妊娠中期广泛改变胎儿大脑转录组，包括与突触组织和神经元信号相关的基因表达增加，以及与 DNA 复制和有丝分裂相关的基因表达减少。值得注意的是，从 E7.5 到 E14.5 期间母体氟西汀治疗对母体肠道微生物组的组成没有明显影响。然而，母体用抗生素预处理以耗尽肠道微生物组会显著改变母体氟西汀治疗对胎儿大脑的转录反应。特别是，母体氟西汀治疗会增加胎儿丘脑和外侧神经节隆起中阿片结合蛋白/细胞黏附分子样基因 Opcml 的局部表达，而母体抗生素治疗可预防这种表达。总之，这些发现表明，母体氟西汀治疗通过至少部分受母体肠道微生物组影响的途径改变胎儿大脑中的基因表达。
