Gut-derived metabolites mediating cognitive development in 5 years old children: early-life transplant in mice has lasting effects throughout adulthood

Gut microbiota have been causally linked to cognitive development. We aimed to identify metabolites mediating the effect of gut microbiota on cognitive development, and foods or nutrients related to the most promising candidate metabolites. Feces obtained by 20 5-year-old children from the DORIAN-PISAC cohort (90 families, infants born in 2011-2014, representing the general population) were transplanted to C57BL/6 germ-free mice. Children, and corresponding recipient mice, were stratified based on the cognitive phenotype, as objectively measured by the Griffiths Mental Developmental Scales (GMDS), or based on protective metabolites to unveil the mechanistic aspects of the FMT effect. Nutritional information was obtained by food frequency questionnaires. Mice cognitive-behavioural development was assessed for 23 weeks by using Y-maze, brain metabolism and radiodensity were measured by PET-CT, and vascular function was assessed by ultrasound. Metabolome was measured in children (faeces and urine) and in mice (faeces and blood) by 1H-NMR spectroscopy, and gut microbiome composition was assessed in mice by 16S rRNA sequencing. The panel of faecal metabolites mediating the gut-cognitive axis in children consisted of xanthine, hypoxanthine, formate, fumarate, mannose, alanine, tyrosine, phenylalanine, and glycine. Synergy with urinary catabolism of choline and TMA was detected.Mice receiving FMT from high-cognitive (vs. low-cognitive) or metabolite-enriched (vs. metabolite-depleted) children developed superior cognitive-behavioural performance. However, only the metabolite-based stratification was able to highlight a panel of faecal metabolites in association with levels of candidate metabolites, confirming their causal role. Children's consumption of legumes, whole-milk yogurt and eggs, and intake of iron, zinc and vitamin D seemed to stimulate protective gut metabolites. Overall, the gut-cognitive axis in children is mediated by metabolites involved in inflammation, purine metabolism and neurotransmitter synthesis (dopamine, glutamine, acetylcholine). Our panel of gut-derived biomarkers holds promise for screening. The related dietary and nutritional findings offer leads to microbiota-targeted intervention for cognitive protection, with short time-to-implementation and long-lasting effects.