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Sex-specific relationships of the infant microbiome and early-childhood behavioral outcomes

Pediatric Research (2021)Cite this article

Abstract

Background

A link between the gut microbiome and behavior is hypothesized, but most previous studies are cross-sectional or in animal models. The modifying role of host sex is poorly characterized. We aimed to identify sex-specific prospective associations between the early-life gut microbiome and preschool-age neurobehavior.

Methods

In a prospective cohort, gut microbiome diversity and taxa were estimated with 16S rRNA sequencing at 6 weeks, 1 year, and 2 years. Species and gene pathways were inferred from metagenomic sequencing at 6 weeks and 1 year. When subjects were 3 years old, parents completed the Behavioral Assessment System for Children, second edition (BASC-2). A total of 260 children contributed 523 16S rRNA and 234 metagenomics samples to analysis. Models adjusted for sociodemographic characteristics.

Results

Higher diversity at 6 weeks was associated with better internalizing problems among boys, but not girls [βBoys = −1.86 points/SD Shannon diversity; 95% CI (−3.29, −0.42), pBoys = 0.01, βGirls = 0.22 (−1.43, 1.87), pGirls = 0.8, pinteraction = 0.06]. Among other taxa-specific associations, Bifidobacterium at 6 weeks was associated with Adaptive Skills scores in a sex-specific manner. We observed relationships between functional features and BASC-2 scores, including vitamin B6 biosynthesis pathways and better Depression scores.

Conclusions

This study advances our understanding of microbe−host interactions with implications for childhood behavioral health.

Impact

  • This is one of the first studies to examine the early-life microbiome and neurobehavior, and the first to examine prospective sex-specific associations.

  • Infant and early-childhood microbiomes relate to neurobehavior including anxiety, depression, hyperactivity, and social behaviors in a time- and sex-specific manner.

  • Our findings suggest future studies should evaluate whether host sex impacts the relationship between the gut microbiome and behavioral health outcomes.

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Fig. 1: Effect estimates and 95% confidence intervals for a standard deviation increase in Shannon Index on BASC-2 scores (SDSixWeeks = 0.54, SDOneYear = 0.55, SDTwoYears = 0.46).
Fig. 2: Effect estimates and 95% confidence intervals for the difference in percent relative abundance per point increase on the given BASC-2 scale.
Fig. 3: Associations between select bacterial taxa (shotgun metagenomics) and BASC-2 scores.
Fig. 4: Volcano plots of associations between metabolic functional pathways and BASC-2 scores.

Data availability

The sequencing data used in this study are available through the National Center for Biotechnology Information (NCBI) Sequence Read Archive: https://ncbi.nlm.nih.gov/sra under accession number PRJNA296814. Epidemiologic data are not publicly available due to their sensitive and identifiable nature. Requests to work with the New Hampshire Birth Cohort Study should be directed to Margaret R. Karagas (Margaret.R.Karagas@Dartmouth.edu).

Code availability

Code is available upon request from Hannah E. Laue (Hannah.E.Laue@dartmouth.edu).

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Acknowledgements

This study was supported by grants from the National Institutes of Health Office of the Director (UH3OD023275), National Institute of Environmental Health (P01ES022832, P20ES018175, P42ES007373), the National Institute of General Medical Sciences (P20GM104416), and the U.S. Environmental Protection Agency (RD-83544201).

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Author notes

  1. These authors contributed equally: Susan A. Korrick, Juliette C. Madan.

Authors and Affiliations

  1. Department of Epidemiology, Geisel School of Medicine at Dartmouth College, Hanover, NH, USA

    Hannah E. Laue, Margaret R. Karagas, Modupe O. Coker & Juliette C. Madan

  2. School of Dental Medicine, Rutgers, The State University of New Jersey, Newark, NJ, USA

    Modupe O. Coker

  3. Department of Neurology, Harvard Medical School and Boston Children’s Hospital, Boston, MA, USA

    David C. Bellinger

  4. Department of Obstetrics and Gynecology, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA

    Emily R. Baker

  5. Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Susan A. Korrick

  6. Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Susan A. Korrick

  7. Departments of Pediatrics and Psychiatry, Children’s Hospital at Dartmouth, Lebanon, NH, USA

    Juliette C. Madan

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Contributions

Conceptualization, H.E.L., M.R.K., S.A.K., and J.C.M.; Methodology, H.E.L., M.R.K., M.O.C., D.C.B., S.A.K., and J.C.M.; Formal analysis, H.E.L.; Investigation, E.R.B.; Writing—original draft, H.E.L.; Writing—review and editing, H.E.L., M.R.K., M.O.C., D.C.B., E.R.B., S.A.K., and J.C.M.; Funding acquisition, M.R.K, S.A.K., J.C.M. All authors approved of the final manuscript to be published.

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Correspondence to Hannah E. Laue.

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Parents of participants provided written informed consent. All study protocols were approved by the Center for the Protection of Human Subjects at Dartmouth, and all methods were carried out in accordance with relevant guidelines and regulations.

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Laue, H.E., Karagas, M.R., Coker, M.O. et al. Sex-specific relationships of the infant microbiome and early-childhood behavioral outcomes. Pediatr Res (2021). https://doi.org/10.1038/s41390-021-01785-z

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