Letter

Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring

  • Nature volume 549, pages 528532 (28 September 2017)
  • doi:10.1038/nature23910
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Abstract

Maternal immune activation (MIA) contributes to behavioural abnormalities associated with neurodevelopmental disorders in both primate and rodent offspring1,2,3,4. In humans, epidemiological studies suggest that exposure of fetuses to maternal inflammation increases the likelihood of developing autism spectrum disorder5,6,7. 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 MIA8. 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.

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Acknowledgements

We thank S. Hang, D. Paik and N. Silverstein for valuable discussions and Y. Yang, M. Xu, N. Geva-Zatorsky, D. Kasper, C. Benoist and D. Mathis for reagents. We thank M. Trombly, N. Silverstein and A. Park for critical reading of the manuscript. We also thank E. Bridge, E. Jaskolski and other staff members at the Department of Animal Medicine at University of Massachusetts Medical School. This work was supported by the Simons Foundation Autism Research Initiative 274443 (D.R.L.) and 402005 (J.R.H.), the Simons Foundation to the Simons Center for the Social Brain at MIT (Y.S.Y., J.R.H and G.B.C.), Hock E. Tan and K. Lisa Yang Center for Autism Research (G.B.C.), the Howard Hughes Medical Institute (D.R.L.), Robert Buxton (G.B.C.), the National Research Foundation of Korea grants MEST-35B-2011-1-E00012 (S.K.) and NRF-2014R1A1A1006089 (H.K.), the Searle Scholars Program (J.R.H.), the Pew Scholar for Biomedical Sciences (J.R.H.), the Kenneth Rainin Foundation (J.R.H.), and the National Institutes of Health grants R01DK106351 and R01DK110559 (J.R.H.).

Author information

Author notes

    • Jun R. Huh

    Present address: Division of Immunology, Department of Microbiology and Immunobiology and Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA

    • Sangdoo Kim
    •  & Hyunju Kim

    These authors contributed equally to this work.

Affiliations

  1. Division of Infectious Diseases and Immunology and Program in Innate Immunity, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA

    • Sangdoo Kim
    • , Hyunju Kim
    • , Soyoung Ha
    •  & Jun R. Huh
  2. The McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Yeong Shin Yim
    •  & Gloria B. Choi
  3. Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan

    • Koji Atarashi
    •  & Kenya Honda
  4. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Tze Guan Tan
  5. The Jill Roberts Institute for Research in IBD, Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, New York 10021, USA

    • Randy S. Longman
  6. The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA

    • Dan R. Littman
  7. Howard Hughes Medical Institute, New York, New York 10016, USA

    • Dan R. Littman

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Contributions

S.K., T.G.T., R.S.L., K.H., D.R.L., G.B.C. and J.R.H. designed the experiments and/or provided advice, reagents and technical expertise. S.K., H.K., Y.S.Y., S.H. and K.A. performed the experiments. S.K., G.B.C. and J.R.H. wrote the manuscript with inputs from the co-authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Gloria B. Choi or Jun R. Huh.

Reviewer Information Nature thanks C. Powell, M. Prinz and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

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    Supplementary Information

    This file contains Supplementary Tables 1-3 and statistics for behavioural analyses.

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    Reporting Summary

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