Abstract
Background
Gut-derived metabolites, products of microbial and host co-metabolism, may inform mechanisms underlying children’s neurodevelopment. We investigated whether infant fecal metabolites were related to toddler social behavior.
Methods
Stool samples collected from 6-week-olds (n = 86) and 1-year-olds (n = 209) in the New Hampshire Birth Cohort Study (NHBCS) were analyzed using nuclear magnetic resonance spectroscopy metabolomics. Autism-related behavior in 3-year-olds was assessed by caregivers using the Social Responsiveness Scale (SRS-2). To assess the association between metabolites and SRS-2 scores, we used a traditional single-metabolite approach, quantitative metabolite set enrichment (QEA), and self-organizing maps (SOMs).
Results
Using a single-metabolite approach and QEA, no individual fecal metabolite or metabolite set at either age was associated with SRS-2 scores. Using the SOM method, fecal metabolites of six-week-olds organized into four profiles, which were unrelated to SRS-2 scores. In 1-year-olds, one of twelve fecal metabolite profiles was associated with fewer autism-related behaviors, with SRS-2 scores 3.4 (95%CI: −7, 0.2) points lower than the referent group. This profile had higher concentrations of lactate and lower concentrations of short chain fatty acids than the reference.
Conclusions
We uncovered metabolic profiles in infant stool associated with subsequent social behavior, highlighting one potential mechanism by which gut bacteria may influence neurobehavior.
Impact
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Differences in host and microbial metabolism may explain variability in neurobehavioral phenotypes, but prior studies do not have consistent results.
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We applied three statistical techniques to explore fecal metabolite differences related to social behavior, including self-organizing maps (SOMs), a novel machine learning algorithm.
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A 1-year-old fecal metabolite pattern characterized by high lactate and low short-chain fatty acid concentrations, identified using SOMs, was associated with social behavior less indicative of autism spectrum disorder.
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Our findings suggest that social behavior may be related to metabolite profiles and that future studies may uncover novel findings by applying the SOM algorithm.
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Data availability
The datasets analyzed during the current study may be made available from the corresponding author on reasonable request.
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Funding
This work was supported by the National Institutes of Health Office of the Director (UH3OD023275), the National Institute of Environmental Health Science (K99ES034086, P01ES022832, P42ES007373), the National Institute of General Medical Sciences (P20GM104416), the National Institute of Diabetes and Digestive and Kidney Diseases (U24DK097193), the National Cancer Institute (T32CA134286), and the U.S. Environmental Protection Agency (RD-83544201). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Environmental Protection Agency.
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All authors meet the authorship requirements and approve the final version to be published. H.E.L.: conceptualization, methodology, formal analysis, writing – original draft, writing – review and editing, visualization, funding acquisition; J.A.B.: conceptualization, methodology, writing - review and editing; S.S.: investigation, resources, data curation, writing – review and editing; S.M.: investigation, resources, data curation, writing – review and editing; W.P.: investigation, resources, data curation, writing – review and editing; T.J.P.: investigation, resources, data curation, writing – review and editing; A.G.H.: resources, writing - review and editing, funding acquisition; J.C.M.: resources, writing - review and editing, funding acquisition; M.R.K.: conceptualization, methodology, resources, writing – review and editing, project administration, funding acquisition.
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Laue, H.E., Bauer, J.A., Pathmasiri, W. et al. Patterns of infant fecal metabolite concentrations and social behavioral development in toddlers. Pediatr Res (2024). https://doi.org/10.1038/s41390-024-03129-z
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DOI: https://doi.org/10.1038/s41390-024-03129-z