Despite substantial gains in survival of preterm infants, concerns remain regarding the significant neurological morbidity and long-term adverse outcomes related to insults on the immature immune and brain-gut-microbiota systems affected by painful/stressful early life experience during the neonatal intensive care (NICU) stay. Our preliminary K23 results show that cumulative pain/stress events are significantly associated with higher abundance of gut Enterobacteria (Phylum: Proteobacteria), a characteristic pattern of dysbiosis, which may contribute to neurodevelopmental deficits during the NICU stay. In light of these results, the primary hypothesis driving this research is that cumulative pain/stress experienced in early life combined with gut dysbiosis and specific genetic susceptibilities increase the risk of neurodevelopmental morbidity in preterm infants during infancy and early childhood. A prospective longitudinal design will be used to examine: 1) the impact of cumulative pain/stress events in the NICU along with gut microbiome development on infant neurodevelopmental outcomes over the short- (NICU stay) and long-term (follow-up); 2) interaction effects of host genetics, gut microbiome, and early life pain/stress events on infant neurodevelopmental outcomes, while controlling for sex, feeding and other environmental factors over time; and 3) the impact of different levels of pain/stress experiences on the gut microbiome and neurodevelopment outcomes as well as other growth parameters using twin- pairs. The proposed 4-year project will recruit and follow 200 preterm infants (160 infants in the final analysis considering the attrition) during NICU hospitalization and until 18-24 months corrected age (CA). Primary measures in the NICU include daily pain/stress events (NICU Infant Stressor Scale), gut microbiome patterns and function (stool sample: twice/week; 16S rRNA gene and metagenomic sequencing), host genetics (whole exome sequencing to identify genetic variants that effect neuro-gut-immune signaling), autonomic responses (weekly; heart rate variability) and neurodevelopmental outcomes (at 36 weeks CA; NICU Network Neurobehavioral Scale). At follow-up visits, gut microbiome, neurodevelopmental outcomes, including pain sensitivity will be measured at 4, 8-12, and 18-24 months CA.

Public Health Relevance

Neurodevelopmental deficits associated with preterm birth cost the United States over 26 billion annually and include hidden burdens for families. Cumulative stress and painful events have been shown to alter neuro-gut-immune signaling in preterm infants cared for in the neonatal intensive care (NICU), however, the precise mechanisms by which these events impact neurodevelopmental outcomes remains unclear. The proposed research aims to use multi-omic approaches to elucidate the specific causal pathways between pain/stress events, neuro-gut- immune signaling, genetic variation and neurodevelopmental outcomes over time in order to improve preterm infant health, decrease costs, and reduce burdens to preterm infants' families and society.

National Institute of Health (NIH)
National Institute of Nursing Research (NINR)
Research Project (R01)
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Nursing and Related Clinical Sciences Study Section (NRCS)
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Tully, Lois
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University of Connecticut
Schools of Nursing
United States
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