Influence of perinatal and childhood exposure to tobacco and mercury in children gut microbiota
Objective: In this exposome-wide study, we aimed at identifying the contribution of exposures to tobacco and mercury from the prenatal period to childhood to individual differences in the fecal microbiome composition of 7-year-old children from the Spanish INMA birth cohort.  Methods: Gut microbiome was studied by 16S rRNA amplicon sequencing in 151 children at genus level. Exposure to tobacco was quantified during pregnancy (tobacco consumption, secondhand smoking -SHS-, urinary cotinine), at 4 years (urinary cotinine, SHS) and at 7 years (SHS). Exposure to mercury was quantified during pregnancy (cord blood) and at 4y (hair). Forty nine potential determinants (12 at pregnancy/birth/infancy, 15 at 4y and 22 at 7y, 4 exposome categories) were registered. Sensitivity analysis was performed including genetic data (GWAS) in a subset of 107 children. For ß-diversity (wUnifrac, Bray-Curtis, Aitchison distances), we used multivariate association analysis (envfit ) to study the contribution of all the determinants and exposures and univariate association analysis (nMDS, PERMANOVA, wUnifrac, Bray-Curtis) of each contaminant exposure adjusted by specific confounders. For genus abundance, a multivariate association model (MaAsLin2) was used with each contaminant.  Results: Active smoking at pregnancy and having siblings at birth were associated with Aitchison ß-diversity (envfit, p<0.05), independently of genetics. In the adjusted univariate model, we did not find any significant association. Considering the effect of siblings, higher relative abundance of Dorea and lower relative abundance of Akkermansia were associated with smoking during pregnancy (MaAsLin2, q< 0.05, BH correction), independently of genetics.  Discussion: Our findings suggest a long term sustainable effect of prenatal tobacco exposure on the children's gut microbiota. This effect was not found for mercury exposure or tobacco exposure during childhood. Assessing the role of these exposures on the children's microbiota considering multiple environmental factors should be further investigated.