VAGAL DYSFUNCTION IN NECROTIZING ENTEROCOLITIS
Open Access
- Author:
- Meister, Alissa
- Graduate Program:
- Neuroscience
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- August 07, 2019
- Committee Members:
- Renato A Travagli, Dissertation Advisor/Co-Advisor
Renato A Travagli, Committee Chair/Co-Chair
Kim Kopenhaver Doheny, Committee Member
Kirsteen Nairn Browning, Committee Member
Charles H Lang, Outside Member - Keywords:
- vagus
cytokines
heart rate variability
NEC
immunohistochemistry
preterm - Abstract:
- Necrotizing enterocolitis (NEC) is the leading cause of death due to gastrointestinal (GI) disease in preterm neonates, affecting 5-12% of neonates born at a very-low birth weight. NEC can present with a slow and insidious or fulminant acute onset, with some neonates displaying early symptoms such as feeding intolerance. There is a high mortality rate among neonates with severe NEC requiring surgery, highlighting the critical need for a non-invasive and reliable biomarker to predict NEC before the onset of clinical signs. The high frequency spectrum of heart rate variability (HF-HRV) measures vagal tone non-invasively; our group has previously shown that HF-HRV is decreased significantly in preterm neonates who later develop NEC. The overarching hypothesis of this dissertation is that HF-HRV correlates with gastric motility positively, and this relationship is affected by decreases in vagal tone that predispose premature neonates to developing necrotizing enterocolitis. This multi-layered translation research study investigates how NEC affects HF-HRV and pro-inflammatory cytokine levels in both an animal model of NEC and in preterm human neonates. We further investigated the pathophysiological effects of NEC on the rat myenteric intestinal phenotypes, and the potential for ghrelin, a gastrointestinal peptide, to restore these changes. The principal findings of the present studies can be summarized as i) HF-HRV positively correlates with antral motility in freely moving male and female rats at low estrogen levels, ii) in newborn rats mild NEC attenuates typical developmental increases in HF-HRV and alters the myenteric intestinal phenotype, iii) mild NEC rats undergoing subdiaphragmatic vagotomy have significantly increased levels of pro-inflammatory cytokines IL-1β and IL-6, iv) in rats ghrelin restores mild NEC-induced changes in HF-HRV and myenteric phenotype back to levels similar to controls in a vagally dependent manner, v) in preterm human neonates HF-HRV is a significant predictor of NEC risk before the onset of clinical signs, and vi) preterm human neonates who develop NEC have significantly elevated levels of IL-1β, IL-6, TNF-α, and IL-8 at week three of life. The present studies suggest that HF-HRV is directly correlated to antral motility, and that a rat model of NEC attenuates typical developmental increases in HF-HRV. Similar to the results from the rat model of NEC, our clinical study confirms HF-HRV as a promising predictive biomarker for NEC, especially when used in combination with plasma levels of pro-inflammatory cytokines IL-6 and IL-8. These studies also suggest ghrelin as a potential new therapeutic target in the treatment and prevention of NEC as ghrelin was able to restore NEC-induced changes to HF-HRV and myenteric phenotypes when the vagus nerve was intact.