From microbes to milestones: Gut bacterial abundances and functional pathways associate with neurodevelopment following preterm birth

The early life gut microbiome has been identified as a potential driver of neurocognitive development. Evidence for this relationship in preterm children, who are at increased risk of both gut microbiome disruptions and neurodevelopmental impairment, is scarce. In a sample of 73 very preterm infants drawn from a prospective birth cohort, we assessed associations between the neonatal gut microbiome and neurodevelopmental outcomes at 9 months and 2 years. The gut microbiome taxonomic and functional profiles were obtained from stool samples collected prior to NICU discharge using shotgun metagenomics. Neurodevelopmental outcomes were assessed using a battery of different outcome measures. We took a consensus-based analytic approach, applying several different methods to investigate microbiome-outcome relationships and focussing on results which were consistently significant across methods. We found the most robust evidence for associations between the abundances of several gut bacterial species and measures related to autistic traits (e.g. Klebsiella spp. ), socio-emotional development, including temperament (e.g. Enterobacter cloacae complex, Veillonella parvula ), and executive functioning ( Clostridium perfringens ). The abundances of functional modules involved in gut-brain signalling, particularly those involved in histamine and quinolinic acid metabolism, were associated with measures related to executive functioning and cognitive-behavioural flexibility. This study provides evidence that the neonatal gut microbiome composition may affect longer-term neurodevelopmental profiles following preterm birth, particularly those related to socio-emotional development, autistic traits and executive functioning.