Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring

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

Research output: Contribution to journalArticle

119 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)528-532
Number of pages5
JournalNature
Volume549
Issue number7673
DOIs
Publication statusPublished - 2017 Sep 28
Externally publishedYes

Fingerprint

Mothers
Bacteria
Th17 Cells
Interleukin-17
Interleukin-23
T-Lymphocytes
Phenotype
Maternal Exposure
Helper-Inducer T-Lymphocytes
Interleukin-1
Dendritic Cells
Primates
Small Intestine
Epidemiologic Studies
Cell Differentiation
Immune System
Rodentia
Interleukin-6
Fetus
Inflammation

ASJC Scopus subject areas

  • General

Cite this

Kim, S., Kim, H., Yim, Y. S., Ha, S., Atarashi, K., Tan, T. G., ... Huh, J. R. (2017). Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring. Nature, 549(7673), 528-532. https://doi.org/10.1038/nature23910

Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring. / 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.

In: Nature, Vol. 549, No. 7673, 28.09.2017, p. 528-532.

Research output: Contribution to journalArticle

Kim, S, Kim, H, Yim, YS, Ha, S, Atarashi, K, Tan, TG, Longman, RS, Honda, K, Littman, DR, Choi, GB & Huh, JR 2017, 'Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring', Nature, vol. 549, no. 7673, pp. 528-532. https://doi.org/10.1038/nature23910
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. / Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring. In: Nature. 2017 ; Vol. 549, No. 7673. pp. 528-532.
@article{19ecf98f0a464cbaabbbf6bc9bd33afe,
title = "Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring",
abstract = "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.",
author = "Sangdoo Kim and Hyunju Kim and Yim, {Yeong Shin} and Soyoung Ha and Koji Atarashi and Tan, {Tze Guan} and Longman, {Randy S.} and Kenya Honda and Littman, {Dan R.} and Choi, {Gloria B.} and Huh, {Jun R.}",
year = "2017",
month = "9",
day = "28",
doi = "10.1038/nature23910",
language = "English",
volume = "549",
pages = "528--532",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "7673",

}

TY - JOUR

T1 - Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring

AU - Kim, Sangdoo

AU - Kim, Hyunju

AU - Yim, Yeong Shin

AU - Ha, Soyoung

AU - Atarashi, Koji

AU - Tan, Tze Guan

AU - Longman, Randy S.

AU - Honda, Kenya

AU - Littman, Dan R.

AU - Choi, Gloria B.

AU - Huh, Jun R.

PY - 2017/9/28

Y1 - 2017/9/28

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85030631674&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85030631674&partnerID=8YFLogxK

U2 - 10.1038/nature23910

DO - 10.1038/nature23910

M3 - Article

C2 - 28902840

AN - SCOPUS:85030631674

VL - 549

SP - 528

EP - 532

JO - Nature Cell Biology

JF - Nature Cell Biology

SN - 1465-7392

IS - 7673

ER -