Maternal immune activation (MIA) contributes to behavioural abnormalities associated with neurodevelopmental disorders in both primate and rodent offspring. In humans, epidemiological studies suggest that exposure of fetuses to maternal inflammation increases the likelihood of developing autism spectrum disorder. In pregnant mice, interleukin-17a (IL-17a) produced by T helper 17 (TH17) cells (CD4+ T helper effector cells involved in multiple inflammatory conditions) induces behavioural and cortical abnormalities in the offspring exposed to MIA. However, it is unclear whether other maternal factors are required to promote MIA-associated phenotypes. Moreover, the underlying mechanisms by which MIA leads to T cell activation with increased IL-17a in the maternal circulation are not well understood. Here we show that MIA phenotypes in offspring require maternal intestinal bacteria that promote TH17 cell differentiation. Pregnant mice that had been colonized with mouse commensal segmented filamentous bacteria or human commensal bacteria that induce intestinal TH17 cells were more likely to produce offspring with MIA-associated abnormalities. We also show that small intestine dendritic cells from pregnant, but not from non-pregnant, females secrete IL-1β, IL-23 and IL-6 and stimulate T cells to produce IL-17a upon exposure to MIA. Overall, our data suggest that defined gut commensal bacteria with a propensity to induce TH17 cells may increase the risk of neurodevelopmental disorders in the offspring of pregnant mothers undergoing immune system activation owing to infections or autoinflammatory syndromes.

中文翻译：

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母体肠道细菌促进小鼠后代的神经发育异常

母体免疫激活 (MIA) 导致与灵长类动物和啮齿动物后代的神经发育障碍相关的行为异常。在人类中，流行病学研究表明，胎儿暴露于母体炎症会增加患自闭症谱系障碍的可能性。在怀孕的小鼠中，由 T 辅助 17 (TH17) 细胞（参与多种炎症条件的 CD4+ T 辅助效应细胞）产生的白细胞介素 17a (IL-17a) 诱导暴露于 MIA 的后代的行为和皮质异常。然而，尚不清楚是否需要其他母体因素来促进 MIA 相关表型。此外，MIA 导致 T 细胞活化和母体循环中 IL-17a 增加的潜在机制尚不清楚。在这里，我们表明后代的 MIA 表型需要促进 TH17 细胞分化的母体肠道细菌。已被小鼠共生分段丝状细菌或诱导肠道 TH17 细胞的人类共生细菌定植的怀孕小鼠更有可能产生具有 MIA 相关异常的后代。我们还表明，来自怀孕而非非怀孕雌性的小肠树突状细胞分泌 IL-1β、IL-23 和 IL-6，并在暴露于 MIA 时刺激 T 细胞产生 IL-17a。总体而言，我们的数据表明，具有诱导 TH17 细胞倾向的特定肠道共生细菌可能会增加因感染或自身炎症综合征而经历免疫系统激活的怀孕母亲的后代神经发育障碍的风险。