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Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring

机译：母体肠道细菌促进小鼠后代的神经发育异常

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摘要

Maternal immune activation (MIA) contributes to behavioural abnormalities associated with neurodevelopmental disorders in both primate and rodent offspring(1-4). In humans, epidemiological studies suggest that exposure of fetuses to maternal inflammation increases the likelihood of developing autism spectrum disorder(5-7). In pregnant mice, interleukin-17a (IL-17a) produced by T helper 17 (T(H)17) cells (CD4(+) T helper effector cells involved in multiple inflammatory conditions) induces behavioural and cortical abnormalities in the offspring exposed to MIA(8). 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 T(H)17 cell differentiation. Pregnant mice that had been colonized with mouse commensal segmented filamentous bacteria or human commensal bacteria that induce intestinal T(H)17 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-1 beta, 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 T(H)17 cells may increase the risk of neurodevelopmental disorders in the offspring of pregnant mothers undergoing immune system activation owing to infections or autoinflammatory syndromes.
机译：母体免疫激活（MIA）导致灵长类和啮齿动物后代神经发育障碍相关的行为异常（1-4）。在人类中，流行病学研究表明，胎儿暴露于母体炎症会增加自闭症谱系障碍的可能性（5-7）。在怀孕的小鼠中，由T辅助17（T（H）17）细胞（CD4（+）T辅助效应细胞参与多种炎性疾病）产生的白介素17a（IL-17a）会在暴露于此的后代中诱发行为和皮质异常MIA（8）。但是，尚不清楚是否需要其他母亲因素来促进MIA相关表型。此外，MIA导致母体循环中IL-17a升高导致T细胞活化的潜在机制尚不清楚。在这里，我们显示后代的MIA表型需要促进T（H）17细胞分化的母体肠道细菌。已经被小鼠共生节段性丝状细菌或人类共生细菌定居的妊娠小鼠更易产生与MIA相关异常的后代。我们还显示，来自孕妇而非小孕妇的小肠树突状细胞在暴露于MIA后会分泌IL-1 beta，IL-23和IL-6并刺激T细胞产生IL-17a。总体而言，我们的数据表明，明确的肠道共生细菌倾向于诱导T（H）17细胞，这可能会增加由于感染或自体炎症综合症而导致免疫系统激活的孕妇母亲后代神经发育障碍的风险。

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  • 来源
    《Nature》 |2017年第7673期|528-532|共5页
  • 作者

    Kim Sangdoo; Kim Hyunju; Yim Yeong Shin; Ha Soyoung; Atarashi Koji; Tan Tze Guan; Longman Randy S. .; Honda Kenya; Littman Dan R.; Choi Gloria B. .; Huh Jun R.;

  • 作者单位

    Univ Massachusetts, Med Sch, Div Infect Dis & Immunol, Worcester, MA 01605 USA|Univ Massachusetts, Med Sch, Dept Med, Program Innate Immun, Worcester, MA 01605 USA;

    Univ Massachusetts, Med Sch, Div Infect Dis & Immunol, Worcester, MA 01605 USA|Univ Massachusetts, Med Sch, Dept Med, Program Innate Immun, Worcester, MA 01605 USA;

    MIT, Dept Brain & Cognit Sci, McGovern Inst Brain Res, Cambridge, MA 02139 USA;

    Univ Massachusetts, Med Sch, Div Infect Dis & Immunol, Worcester, MA 01605 USA|Univ Massachusetts, Med Sch, Dept Med, Program Innate Immun, Worcester, MA 01605 USA;

    Keio Univ, Sch Med, Dept Microbiol & Immunol, Tokyo 1608582, Japan;

    Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA;

    Weill Cornell Med, Div Gastroenterol & Hepatol, Jill Roberts Inst Res IBD, New York, NY 10021 USA;

    Keio Univ, Sch Med, Dept Microbiol & Immunol, Tokyo 1608582, Japan;

    NYU, Sch Med, Skirball Inst, Kimmel Ctr Biol & Med, New York, NY 10016 USA|Howard Hughes Med Inst, New York, NY 10016 USA;

    MIT, Dept Brain & Cognit Sci, McGovern Inst Brain Res, Cambridge, MA 02139 USA;

    Univ Massachusetts, Med Sch, Div Infect Dis & Immunol, Worcester, MA 01605 USA|Univ Massachusetts, Med Sch, Dept Med, Program Innate Immun, Worcester, MA 01605 USA|Harvard Med Sch, Dept Microbiol & Immunobiol, Div Immunol, Boston, MA 02115 USA|Harvard Med Sch, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA|Brigham & Womens Hosp, Boston, MA 02115 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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