Necrotizing entercolitis, the brain-gut axis and pain in adolescence:abstract

Background: Necrotizing enterocolitis (NEC) is a severe gastro-intestinal condition associated with prolonged, extreme visceral pain and recurrent procedural pain. Pain management in infants with NEC remains challenging. Pain symptoms range from being absent to not responding to analgesics. Cumulative neonatal pain is also associated with long term adverse effects beyond school age. A growing body of evidence suggests a complex interplay between gut innervation, gut microbiota and neurodevelopment through the Brain-GutAxis. Ourobjective was to develop a hypothesis linking disruption of gut microbiota in early life to long term effects of neonatal pain in NEC survivors.
Methods: We analyzed data from own research and recent literature. Own data included analysis from The Project on Preterm and Small for Gestational Age Infants in the Netherlands (POPS). POPS is a large population based cohort of newborns with a gestational age of less than 32 weeks and/or birth weight below 1500 g. At the age of 19 years, survivors participated in an extensive follow-up program, comprising a Cold Pressor Task and a validated Pain Coping Questionnaire that assessed pain coping styles. Furthermore, participants completed a standardized intelligence quotient (IQ) test (MCT-IL). Recent reviews on associations between changes in gut microbiota, the Brain-Gut Axis and NEC were studied.
Results: Our data showed that NEC was significantly associated with lower pain threshold and pain tolerance in adolescence. In contrast, NEC was not associated with altered pain coping styles.
Changes in microbiota are associated with the onset of NEC, and antibiotics during the disease may further disrupt normal gut microbiota. Microbiota composition is thought to affect neurode-velopment by immunomodulation, and by production of neuro-transmitters and short chain fatty acids (SCFA). In an animal model, associations between microbiota producing SCFA, inflam-mation and pain have been found. Although we did not find studies on the innervation of the gut in conditions of NEC and preterm birth, evidence suggests that gut microbiota modulates visceral sensory pathways in early life.
Conclusions: NEC, a condition accompanied by severe and prolonged visceral pain, was associated with lower pain tolerance and pain threshold. The association may indicate clinically relevant long term effects of severe neonatal pain in ex preterm infants, up to the age of 19 years. We hypothesize that changes in gut microbiota, influencing the bioactivity of SCFA may contribute to this effect through the Brain-Gut Axis.