Introduction. Child stunting is still a major concern worldwide with 148 million under-5 children affected in 2022. Stunting is likely to affect brain development and prevent children from reaching their full potential. This study aimed at evaluating the contribution of stunting, the fecal microbiota and other related factors in brain development in children from Madagascar. Methods. Severely stunted, moderately stunted and non-stunted 2-5 years old children from the AFRIBIOTA cross-sectional study in Madagascar were submitted to the Ages and Stages Questionnaire version III, covering 5 developmental domains (communication, personal-social, problem-solving, fine motor and gross motor). Fecal samples were used for 16S rRNA gene amplicon sequencing for fecal microbiota characterization. A Structural Equation Modelling (SEM) approach was used to evaluate statistical associations, including latent variables, with direct and indirect effects. Results. In all models, stunting was negatively associated with neurodevelopment, as well as low socioeconomic status. β-diversity of the microbiota was neither directly nor indirectly associated with cognitive performance but α-diversity was, in one of the tested models. Socioeconomic status, branched-chain amino acids and hemoglobin levels were associated with stunting in the SEM models tested. Conclusion. Neurodevelopment was associated in this cross-sectional study with socioeconomic status and stunting. The gut microbiota α- and β-diversity were not associated with neurodevelopmental score, except for the Shannon diversity index in the complex SEM model tested. In the future, longitudinal studies assessing not only taxonomic composition but also the functional potential of the microbiome at different timepoints throughout the first years of life could shed better light on a possible, maybe also transient, role of the microbiome and metabolites released thereof on neurodevelopment.

The authors have declared no competing interest.

The Afribiota project was funded by the Total Foundation, Institut Pasteur, the Bill and Melinda Gates Foundation (OPP1204689, INV-004352 and INV-002525), the Fondation Petram and a donation by the Odyssey Re-Insurance company. PV was supported by an Early Postdoctoral Fellowship (P2EZP3_152159), an Advanced Postdoctoral Fellowship (P300PA_177876) as well as a Return Grant (P3P3PA_177877), an Eccellenza Professorial Fellowship (PCEFP3_194545) and a SNSF Starting Grant (TMSGI3_218455) from the Swiss National Science Foundation. This study has been further supported as a part of the NCCR Microbiome, a National Center of Competence and research, funded by the Swiss National Science Foundation (Grant number 180575). JT is a Marie Curie Slodowska Actions Global Fellow.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study protocol of AFRIBIOTA was approved by the Institutional Review Board of the Institut Pasteur (2016-06/IRB) and the National Ethical Review Boards of Madagascar (55/MSANP/CE, 19 May 2015). All participants received oral and written information about the study. The legal representatives of the children provided written consent to participate in the study. The present analysis (AfriGutBrain) was approved by the Swiss CER-VD (BASEC-ID 2023-01834).

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All data produced in the present study are available upon reasonable request to the authors