Associations between fentanyl exposure, gut microbiome and neurodevelopmental outcomes in preterm infants

BACKGROUND: Fentanyl, an opioid medication commonly given to hospitalized preterm infants, may alter gut microbiome development and subsequent neurodevelopmental outcomes. METHODS: We compare a cohort of preterm infants with and without postnatal fentanyl exposure, using their hospitalization stool samples and neurodevelopmental outcomes. The study examines the association between fentanyl exposure, fecal microbiome differences during NICU stay, and neurodevelopmental outcomes up to age 8. RESULTS: Fentanyl exposure during NICU hospitalization is associated with a decrease in fecal microbiome richness, negative association with the microbial taxa Actinobacteriota and Bacteroidia, increase in constipation, an increase of microbiome derived metabolites involved in inflammation and gastrointestinal (GI) homeostasis, and altered microbial virulence (i.e. factors that contribute to pathogenicity). Increased fentanyl exposure is associated with worse cognitive scores on the Bayley Scales of Infant and Toddler Development at 2 years of age and the intelligence quotient composite score on the Wechsler Preschool and Primary Scale of Intelligence at 3-8 years of age. Virulence factors present in the microbiome mediated the association between fentanyl and cognitive outcomes at 2 years old. CONCLUSION: Increased duration of postnatal fentanyl exposure in preterm infants is associated with gut microbiome differences (i.e. richness and virulence) and later cognitive impairment. IMPACT: Postnatal fentanyl exposure of premature infants in the neonatal intensive care unit is associated with microbiome differences that manifest during their hospital stay. Fentanyl-associated microbiome differences during hospitalization include differences in fecal richness, microbial taxa composition, gastrointestinal transit time, microbiome-derived metabolites, and microbial virulence. Early gut fentanyl-associated microbiota differences are associated with worse cognitive outcomes in preterm infants at 2-8 years old.