Department of Neuroscience, Karolinska Institutet, 171 77, Stockholm, Sweden; University of Rouen Normandy, INSERM, NorDIC, UMR, 1239, F-76000, Rouen, France.
Department of Neuroscience, Karolinska Institutet, 171 77, Stockholm, Sweden.
Neuropharmacology. 2023 May 15;229:109479. doi: 10.1016/j.neuropharm.2023.109479. Epub 2023 Mar 2.
The gut microbiota is increasingly recognized as a key environmental factor that shapes host development and physiology, including neural circuits formation and function. Concurrently, there has been growing concern that early-life antibiotic exposure may alter brain developmental trajectories, increasing the risk for neurodevelopmental disorders such as autism spectrum disorder (ASD). Here, we assessed whether perturbation of the maternal gut microbiota in mice during a narrow critical perinatal window (last week of pregnancy and first three postnatal days), induced by exposure to a commonly used broad-spectrum oral antibiotic (ampicillin), influences offspring neurobehavioral outcomes relevant to ASD. Our results demonstrate that neonatal offspring from antibiotic-treated dams display an altered pattern of ultrasonic communication, which was more pronounced in males. Moreover, juvenile male, but not female, offspring from antibiotic-treated dams showed reduced social motivation and social interaction, as well as context-dependent anxiety-like behavior. However, no changes were observed in locomotor or exploratory activity. This behavioral phenotype of exposed juvenile males was associated with reduced gene expression of the oxytocin receptor (OXTR) and several tight-junction proteins in the prefrontal cortex, a key region involved in the regulation of social and emotional behaviors, as well as a mild inflammatory response in the colon. Further, juvenile offspring from exposed dams also showed distinct alterations in several gut bacterial species, including, Lactobacillus murinus, and Parabacteroides goldsteinii. Overall, this study highlights the importance of the maternal microbiome in early-life, and how its perturbation by a widely used antibiotic could contribute to atypical social and emotional development of offspring in a sex-dependent manner.
肠道微生物群越来越被认为是塑造宿主发育和生理的关键环境因素，包括神经回路的形成和功能。与此同时，人们越来越担心，生命早期接触抗生素可能会改变大脑发育轨迹，增加自闭症谱系障碍（ASD）等神经发育障碍的风险。在这里，我们评估了在狭窄的围产期关键窗口期（妊娠最后一周和出生后前三天）期间，通过暴露于常用的广谱口服抗生素（氨苄西林）来干扰小鼠的母体肠道微生物群，是否会影响与 ASD 相关的后代神经行为结果。我们的研究结果表明，来自接受抗生素治疗的母鼠的新生后代表现出超声交流模式的改变，雄性更为明显。此外，来自接受抗生素治疗的母鼠的幼鼠雄性（而非雌性）表现出社交动机和社交互动减少，以及情境依赖性焦虑样行为。然而，运动或探索活动没有观察到变化。暴露于幼年雄性的这种行为表型与前扣带回皮层中催产素受体（OXTR）和几种紧密连接蛋白的基因表达减少有关，前扣带回皮层是调节社会和情绪行为的关键区域，以及结肠中的轻度炎症反应。此外，来自暴露于抗生素的母鼠的幼崽在几种肠道细菌物种中也表现出明显的改变，包括乳酸乳球菌和拟杆菌。总体而言，这项研究强调了母体微生物群在生命早期的重要性，以及广泛使用的抗生素对其的干扰如何以性别依赖的方式导致后代出现异常的社交和情绪发育。
