Infant gut microbiome neuroactive pathways link to social disadvantage, toddler neurodevelopment, cognitive and behavioural outcomes: a longitudinal cohort study
Abstract
Background: Early life is a critical window for co-development of the brain and gut microbiome (GM). Evidence supports a role for the GM in brain development, but longitudinal human data remain limited, particularly regarding the influence of social disadvantage (SD), a powerful determinant of child mental health and neurodevelopment. Here, we examine longitudinal relationships between the GM and neurodevelopmental outcomes over the first three years of life, and the impact of SD on them. Methods: We sequenced and analysed stool samples of 187 children, collected at 5 timepoints over 4–36 months of life (MOL; 905 samples) using a whole-metagenome sequencing approach. Associations between GM-derived Gut-Brain Modules (GBM) and neuroactive potential were assessed using generalised linear mixed models, adjusting for covariates. Neurodevelopmental outcomes were evaluated by Bayley-III (cognitive, language, and motor), and neurobehavioural dysregulation and externalising/internalising-behaviour by the Infant-Toddler Social and Emotional Assessment (ITSEA) and Preschool Age Psychiatric Assessment (PAPA). Findings: Temporal changes were observed in GBMs, including glutamate/GABA synthesis and degradation pathways, as well as short-chain fatty acids. GM community structure and GBMs were significantly associated with concurrent and later Bayley-III outcomes, most consistently for cognition and language (FDR < 0.10). Several GBMs were associated with both neurobehavioural outcomes and SD, including S-adenosylmethionine (SAM) synthesis, butyrate synthesis, and glutamate and GABA synthesis II (FDR < 0.10). A partial mediating effect between SD and 36 MOL language outcomes was observed using SAM synthesis at 4 MOL (β = −0.042, P = 0.048). Interpretation: This longitudinal cohort study of GM neuroactive metabolic capacity across early transitional developmental windows reveals a dynamic pattern of GM-derived neuroactive metabolic pathways and identifies specific pathways associated with later neurodevelopmental (cognitive, language) and neurobehavioural outcomes, even after controlling for important covariates. These pathways are shaped by the socioeconomic status of mothers, starting with in-utero exposure, and GBMs partially mediated this effect. The study identifies microbial pathways associated with both SD and neurodevelopmental outcomes, highlighting potential biological processes that may contribute to neurodevelopmental risk and warrant further investigation. Funding: This work was supported by the National Institute of Mental Health , March of Dimes , Children’s Discovery Institute , National Institute of Diabetes and Digestive and Kidney Diseases , and National Center for Advancing Translational Sciences .
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BibTeX
@article{lee2026infant,
title = {{Infant gut microbiome neuroactive pathways link to social disadvantage, toddler neurodevelopment, cognitive and behavioural outcomes: a longitudinal cohort study}},
author = {Giljae Lee and Bruce A. Rosa and I. Malick Ndao and John Martin and Simone Anzà and Joan L. Luby and Christopher D. Smyser and Cynthia E. Rogers and Deanna M. Barch and Mary C. Kimmel and Carla Hall-Moore and Renay E. Bryant and Barbara B. Warner and Makedonka Mitreva},
journal = {eBioMedicine},
year = {2026},
month = oct,
doi = {10.1016/j.ebiom.2026.106533},
url = {https://linkinghub.elsevier.com/retrieve/pii/S2352396426004172},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Infant gut microbiome neuroactive pathways link to social disadvantage, toddler neurodevelopment, cognitive and behavioural outcomes: a longitudinal cohort study
AU - Giljae Lee
AU - Bruce A. Rosa
AU - I. Malick Ndao
AU - John Martin
AU - Simone Anzà
AU - Joan L. Luby
AU - Christopher D. Smyser
AU - Cynthia E. Rogers
AU - Deanna M. Barch
AU - Mary C. Kimmel
AU - Carla Hall-Moore
AU - Renay E. Bryant
AU - Barbara B. Warner
AU - Makedonka Mitreva
PY - 2026
DA - 2026/10/22
JO - eBioMedicine
DO - 10.1016/j.ebiom.2026.106533
UR - https://linkinghub.elsevier.com/retrieve/pii/S2352396426004172
AB - Background: Early life is a critical window for co-development of the brain and gut microbiome (GM). Evidence supports a role for the GM in brain development, but longitudinal human data remain limited, particularly regarding the influence of social disadvantage (SD), a powerful determinant of child mental health and neurodevelopment. Here, we examine longitudinal relationships between the GM and neurodevelopmental outcomes over the first three years of life, and the impact of SD on them. Methods: We sequenced and analysed stool samples of 187 children, collected at 5 timepoints over 4–36 months of life (MOL; 905 samples) using a whole-metagenome sequencing approach. Associations between GM-derived Gut-Brain Modules (GBM) and neuroactive potential were assessed using generalised linear mixed models, adjusting for covariates. Neurodevelopmental outcomes were evaluated by Bayley-III (cognitive, language, and motor), and neurobehavioural dysregulation and externalising/internalising-behaviour by the Infant-Toddler Social and Emotional Assessment (ITSEA) and Preschool Age Psychiatric Assessment (PAPA). Findings: Temporal changes were observed in GBMs, including glutamate/GABA synthesis and degradation pathways, as well as short-chain fatty acids. GM community structure and GBMs were significantly associated with concurrent and later Bayley-III outcomes, most consistently for cognition and language (FDR < 0.10). Several GBMs were associated with both neurobehavioural outcomes and SD, including S-adenosylmethionine (SAM) synthesis, butyrate synthesis, and glutamate and GABA synthesis II (FDR < 0.10). A partial mediating effect between SD and 36 MOL language outcomes was observed using SAM synthesis at 4 MOL (β = −0.042, P = 0.048). Interpretation: This longitudinal cohort study of GM neuroactive metabolic capacity across early transitional developmental windows reveals a dynamic pattern of GM-derived neuroactive metabolic pathways and identifies specific pathways associated with later neurodevelopmental (cognitive, language) and neurobehavioural outcomes, even after controlling for important covariates. These pathways are shaped by the socioeconomic status of mothers, starting with in-utero exposure, and GBMs partially mediated this effect. The study identifies microbial pathways associated with both SD and neurodevelopmental outcomes, highlighting potential biological processes that may contribute to neurodevelopmental risk and warrant further investigation. Funding: This work was supported by the National Institute of Mental Health , March of Dimes , Children’s Discovery Institute , National Institute of Diabetes and Digestive and Kidney Diseases , and National Center for Advancing Translational Sciences .
SN - 2352-3964
ER -