Ghrelin ameliorates the phenotype of newborn rats induced with mild necrotizing enterocolitis

Abstract

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.

Necrotizing enterocolitis: It’s not all in the gut

“…115 We have also shown that ghrelin, an orexigenic GI peptide, is able to attenuate the effects of mild NEC in rats, in a vagally dependent mechanism. 136 Other models also include treatments such as intragastric LPS or commensal bacteria from stool samples to determine the roles of IL-18, 137 IL-12, 137 intestinal epithelial apoptosis, 138 maternal milk, 71,72 probiotics, 139 NF-κB, 140 nitric oxide dysregulation, 42,141 and many more. Some models also include ischemia-reperfusion injury to mimic intestinal injuries occurring in NEC, 142 but these models are more controversial as the direct connection to NEC remains uncertain.…”

Fluoroquinolones-Associated Disability: It Is Not All in Your Head

“…This strongly suggests that FQs might indeed decrease vagal output by blocking GABA transmission at the mNTS, rather than the DMV. Moreover, if vagal activity is suppressed following FQs we could also expect plastic changes to occur in the myenteric plexus in a similar fashion described by Meister et al in their model of Necrotizing Enterocolitis, with a pathological increase of the NANC pathway over the cholinergic pathway that caused, or resulted from a decrease of the vagal output to the GI tract [130,169].…”

Precision-based modeling approaches for necrotizing enterocolitis

“…This model led to the demonstration that breast milk protects against NEC (Barlow et al, 1974;Caplan et al, 1994), and also identified a role for nitric oxide in the pathogenesis of NEC (Nadler et al, 2000), the importance of bacterial colonization and TLR4 activation (Jilling et al, 2006), and the protective effects of beneficial commensal bacteria (Caplan et al, 1999), epidermal growth factor (Dvorak et al, 2002) and HMOs (Jantscher-Krenn et al, 2012). More-recent studies using the rat NEC model have identified mechanisms underlying intestinal barrier dysfunction (Ares et al, 2019), the protective effects of the hormone ghrelin (Meister et al, 2019), thrombomodulin (Li et al, 2019a) and fecal microbiota transplantation (Prado et al, 2019), and the deficiency of intestinal alkaline phosphatase that occurs in experimental NEC (Rentea et al, 2019), a finding that is also seen in human disease (Heath et al, 2019).…”