Neonatal necrotizing enterocolitis alters the development of brainstem neurocircuitry controlling gastrointestinal functions

Abstract

Necrotizing enterocolitis (NEC) is the leading cause of gastrointestinal (GI)‐related death in premature infants and is most often characterized by a slow progressive onset of symptoms including feeding intolerance and abdominal distention prior to the development of sepsis and necrosis with potentially life‐long effects on both GI health and neurodevelopmental outcomes. The high‐frequency power spectra of heart rate variability (HF‐HRV) is a non‐invasive measure of vagal tone, our laboratory has previously shown that HF‐HRV is decreased in NEC in both human neonates (Doheny et al., Neurogastroenterol. Motil., 2014) and in rodent pups (Meister et al., Neurogastroenterol. Motil., 2018). The present study examined the hypothesis that NEC induces long term alterations in central and peripheral control of the intestine including i) attenuated developmental maturation of brainstem neurocircuits and ii) decreased transit.Mild NEC (stage≤2) was induced in newborn Sprague‐Dawley rats through twice daily exposure to cold stress and hypoxia and HRV was measured using bilateral electrodes to collect an electrocardiogram before and after stress exposure on postnatal days (PD) 1, 5, 10 and 28. Whole cell patch clamp recordings examined whether, in young adult rats (4–8 weeks of age), dorsal motor nucleus of the vagus (DMV) neurons innervating the intestine received inhibitory synaptic currents that were entirely GABAergic (indicating normal development, i.e., unaffected by the glycine antagonist, strychnine; 1mM) or were mixed GABA‐glycine (indicating arrested developmental maturation; inhibitory currents prolonged by strychnine). Intestinal transit was measured using the non‐invasive lactose ureide breath test at the same time‐points.The induction of mild NEC was confirmed by histological grading, these pups showed a significant reduction in HF‐HRV at all time points, except for baseline before stress induction, as compared to controls. Mild NEC rats showed no change in gastric emptying as compared to controls, but a significant increase in gastro‐cecal transit time. In control rats, 0/11 adult DMV neurons showed evidence of inhibitory glycinergic inputs whereas 9/12 DMV neurons from rats in which mild NEC was induced displayed mixed GABA‐glycine currents. Data are summarized in the table below.Our data suggest that mild NEC is associated with adult comorbidities including arrested development of brainstem neurocircuits innervating the intestine as well as delayed intestinal transit. Neonatal insults, such as NEC, may have long term developmental consequences that impair intestinal functions at both central and peripheral sites.Support or Funding InformationNIH grant DK99350 to R.A.T. & K.K.D.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.