Background We have shown previously that an attenuated rodent model of mild necrotizing enterocolitis (NEC) increases intestinal histopathological severity grade, prevents typical developmental increases in the high‐frequency spectrum of heart rate variability (HF‐HRV), alters the nitrergic myenteric phenotype, and increases IL‐6 and IL‐1β when combined with anterior subdiaphragmatic vagotomy. The aims of the present study were to test the hypotheses that in mild NEC‐induced pups, administration of the orexigenic hormone ghrelin (a) reduces the histopathological score, (b) increases the HF‐HRV power, (c) improves the altered myenteric phenotype, and (d) subdiaphragmatic vagotomy prevents the effects of ghrelin. Methods Newborn Sprague Dawley rats were subjected to seven days of brief periods of cold stress and hypoxia to induce mild NEC with or without anterior subdiaphragmatic vagotomy. HRV was measured at postnatal days one, five, and ten; intraperitoneal ghrelin (0.05 mg kg−1) was administered postnatal days five through ten b.i.d. Pups were sacrificed at day 12, and whole brains, gastrointestinal tissues, and blood were collected for immunohistochemical, corticosterone, and cytokine analysis. Key Results Ghrelin treatment reduced the intestinal histopathological score, increased the HF‐HRV power, improved the altered intestinal myenteric phenotype, and subdiaphragmatic vagotomy prevented the effects of ghrelin. There were no differences in serum cytokines or corticosterone between groups. Conclusions and Inferences Our data suggest that ghrelin administration is able to recover the mild NEC‐induced changes to the histology, HF‐HRV, and myenteric phenotype in a vagally dependent manner.

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Necrotizing enterocolitis (NEC) is the leading cause of mortality from gastrointestinal (GI) disease in preterm neonates. Its precise pathogenesis is unknown, but early stages of NEC are thought to be characterized by damage to the intestinal mucosa; while full intestinal necrosis and perforation occur during the later stages.The high‐frequency power spectra of heart rate variability (HF‐HRV) is a non‐invasive measure of vagal tone, our laboratory has shown that decreases in HF‐HRV may predict which neonates are at increased risk for NEC before the onset of clinical signs (Doheny et al. Neurogastroenterol. Motil., 2014). Furthermore, experimental NEC in newborn rat pups reduces HF‐HRV and increases NOS immunoreactivity in the myenteric neurons of the lower GI tract (Meister et al., Neurogastroenterol. Motil., 2018). Ghrelin is a GI hormone known to increase gastric motility via actions at several sites, including an excitation of dorsal vagal motoneurons upon brainstem microinjection, hence leading to an increase in vagal output to the GI tract.The aim of the present study was to test the hypotheses that ghrelin administration in a rodent model of NEC will: i) increase HF‐HRV values, and ii) restore the neurochemical phenotype of myenteric neurons of the lower GI tract.Newborn Sprague‐Dawley rats were randomly separated in the following groups: i) control, ii) mild NEC (<grade 2) induced via exposure to cold stress and hypoxia twice daily, and iii) mild NEC and anterior subdiaphragmatic vagotomy (grade >2). All groups underwent twice daily intraperitoneal injections of saline or ghrelin (0.05mg/kg) on postnatal days (PD)‐5 to PD‐10. Electrocardiogram recordings using bilateral electrodes to measure HF‐HRV were conducted on PD‐1, ‐5, and ‐10, prior to sacrifice on PD12. Upon sacrifice, GI tissues were collected to confirm NEC grade via H&E staining, and to assess the neurochemical phenotype of myenteric neurons through fluorescence immunohistochemistry.Mild NEC was confirmed via grade >2 histological examination; these pups did not display typical developmental increases in HF‐HRV. Ghrelin, but not saline, treatment reduced the NEC histological scale, increased HF‐HRV values and restored NOS‐immunoreactivity (NOS‐IR) in neurons of the myenteric plexus to levels similar to controls. Data are summarized in the Table below.Our data indicate that ghrelin administration in rodent model of NEC: i) decreased the histological severity of NEC, ii) increased HF‐HRV values, and iii) restored the neurochemical phenotype of myenteric neurons of the lower GI tract. We suggest that ghrelin may be a promising treatment to attenuate, or even reverse, the impaired HF‐HRV and altered neurochemical phenotype observed after NEC induction.Support or Funding InformationAmerican Physiological Society grant to C.R.B. & NIH 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.