Neonatal gut Bifidobacterium associates with indole-3-lactic acid levels in blood and risk of ADHD at age 10

The gut microbiome has been associated with brain health. The neuromodulatory effects of microbial-derived metabolites is supported by experimental evidence, and alterations of gut microbiota have been associated with the pathophysiology of certain neuropsychiatric disorders.Research on the gut microbiome's role in attention-deficit/hyperactivity disorder (ADHD) have been predominantly cross-sectional and seldomly within the neonatal period, missing its potential impact on critical periods shaping long-term neurodevelopmental outcomes. This study addresses how initial colonization and timing of specific gut bacteria, and their metabolic byproducts, may influence the risk of future ADHD. Using the highly-phenotyped COPSAC2010 birth cohort, we show that a higher level of Bifidobacterium in the child's one-week gut microbiome, after extensively adjusting for genetic and early-life factors, is associated with ADHD at age 10. Our analyses also reveal that the tryptophan-derived metabolite indole-3-lactic acid (ILA) in the neonatal dried blood spot (DBS) mediates the relationship between Bifidobacterium and ADHD risk. The association between neonatal DBS ILA and ADHD was replicated in two independent cohorts. Bifidobacterium is known to promote healthy neurodevelopmental outcomes; however, these findings suggest that the initial temporal colonization pattern of Bifidobacterium may be particularly important for neurodevelopment. In particular, elevated Bifidobacterium-derived metabolite ILA levels may have adverse consequences on the child's neurodevelopment during the first week of life. This suggests that by promoting a suitable temporal colonization pattern for Bifidobacterium and its production of ILA in the newborn may represent potential strategies for clinical interventions for supporting adequate neurodevelopment, and mitigating the risk of future ADHD.