Necrotizing enterocolitis (NEC) is the most prevalent and devastating bowel disease in the neonatal intensive care unit (NICU), affecting 6-10% of preterm infants with a mortality rate of 15-25%. The inflammation and sepsis associated with NEC results from an excessive and uncontrolled intestinal immune response. Currently, NEC is diagnosed by a combination of serological tests and abdominal radiographic imaging conducted when NEC is already clinically significant. Given its acute onset and rapid progression, a non- invasive predictive biomarker of NEC that allows early detection is required as a matter of urgency. Heart rate variability (HRV) in the high frequency (HF) domain is linked to parasympathetic (vagal) nerve activity and our preliminary clinical data indicates that a decrease in HF-HRV can be used as an early marker (0.5-9 days in advance) of newborn premature infants susceptible developing NEC. Our preliminary data in rodents suggests that vagal control of GI motility and HF-HRV are correlated closely. GI motility and heart rate are controlled by distinct brainstem vagal neurocircuits, but both are modulated by descending projections from the paraventricular nucleus of the hypothalamus (PVN). Maternal care, by strengthening hypothalamic-vagal- visceral axes connectivity, ameliorates stress-induced adverse outcomes in GI function. In the present proposal will adopt a translational approach to investigate the central hypothesis that re-establishing appropriate vagal functions will prevent the development of NEC. We will test our overarching central hypothesis with the following specific aims: 1: establish the cut-off values of decreased HF-HRV power predictive of NEC development. 2: stress-induced inhibition of the brainstem dorsal vagal complex and/or the hypothalamus contributes to the dysregulation of vagal outflow which ultimately favors the development of NEC. 3: interventions aimed at increasing vagal output will attenuate, or even reverse, the autonomic dysfunction which favors development of NEC. 4: specific interventions to enhance maternal sensitivity will improve vagal tone and attenuate or prevent the development of NEC. This proposal will generate translational data linking basic and clinical research that will: ) validate an urgently needed non-invasive predictive biomarker for the detection of pre-clinical NEC in the NICU;ii) define the cellular mechanisms behind the use of HF-HRV in the prediction of NEC;iii) lead to an improved understanding of the role of vagal dysfunction in the development of NEC and other GI neuropathologies;and, iv) to help targeting appropriate preventative measures aimed at decreasing, if not preventing altogether, the incidence and severity of NEC in the NICU.

Public Health Relevance

Necrotizing enterocolitis (NEC) is one of the most common and damaging diseases in the neonatal intensive care unit (NICU), affecting 6-10% of preterm infants with a mortality rate of 15-25% and an estimated burden to the US healthcare system of $500million - $1billion annually. A non-invasive, easy to obtain, inexpensive predictive biomarker that allows the early detection of NEC is required as a matter of urgency. The present project will adopt a translational approach, combining clinical and basic research, to identify i) non-invasive biomarkers predictive of NEC, ii) the cellular mechanisms behind these predictive biomarkers and iii) to develop targeted interventions to reduce the adverse outcome associated with NEC

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
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Hamilton, Frank A
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Pennsylvania State University
Schools of Medicine
United States
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Jiang, Yanyan; Coleman, F Holly; Kopenhaver Doheny, Kim et al. (2018) Stress Adaptation Upregulates Oxytocin within Hypothalamo-Vagal Neurocircuits. Neuroscience 390:198-205
Meister, Alissa L; Doheny, Kim K; Travagli, R Alberto (2018) Necrotizing enterocolitis attenuates developmental heart rate variability increases in newborn rats. Neurogastroenterol Motil :e13484
Marvin, Megan M; Gardner, Fumiyuki C; Sarsfield, Kristin M et al. (2018) Increased Frequency of Skin-to-Skin Contact Is Associated with Enhanced Vagal Tone and Improved Health Outcomes in Preterm Neonates. Am J Perinatol :
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Glass, Kristen M; Greecher, Coleen P; Doheny, Kim K (2017) Oropharyngeal Administration of Colostrum Increases Salivary Secretory IgA Levels in Very Low-Birth-Weight Infants. Am J Perinatol 34:1389-1395
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