Investigation of Ghrelin Effects in Experimental Necrotizing Enterocolitis

Abstract

Objective

This study was aimed to investigate the effects of exogenous ghrelin pretreatment in an experimental necrotizing enterocolitis (NEC) model.

Study Design

Neonatal rats were randomized into four groups: NEC, GH-NEC, Control, and GH-Control. Experimental NEC was induced in the NEC groups using hypoxia, hypothermia, and hyperosmolar formula. Ghrelin was administered intraperitoneally to the GH-NEC and GH-Control groups. Throughout the experiment, pups were monitored using clinical scoring. On day 4, they were sacrificed, followed by macroscopic scoring, and tissue samples were collected for histopathological and biochemical analysis.

Results

The NEC groups had significantly higher mean clinical, macroscopic, and histological scores compared with the control groups (p < 0.05). The GH-NEC group exhibited both a higher mean clinical score and a higher mean macroscopic score than the NEC group (p < 0.05). The mean survival time was significantly lower in the GH-NEC group compared with the NEC group (p = 0.003). However, histopathological scores and apoptotic cell counts were similar between the GH-NEC and NEC groups (p > 0.05).

Conclusion

In this experimental NEC model, ghrelin pretreatment worsened clinical outcomes, negatively affected the macroscopic appearance of intestinal segments, and was associated with a decreased survival rate up to the time of sacrifice. Further studies are needed to determine the effects of ghrelin in experimental NEC.

Key Points

• The effects of ghrelin in NEC remain largely unknown.

• Ghrelin pretreatment decreased survival in NEC model.

• Ghrelin pretreatment worsened clinical and macroscopic intestinal scores

Keywords

necrotizing enterocolitis - premature - newborn - ghrelin - experimental

Publikationsverlauf

Eingereicht: 13. Mai 2025

Angenommen: 30. August 2025

Artikel online veröffentlicht:
24. September 2025

• References

• 1 Battersby C, Santhalingam T, Costeloe K, Modi N. Incidence of neonatal necrotising enterocolitis in high-income countries: a systematic review. Arch Dis Child Fetal Neonatal Ed 2018; 103 (02) F182-F189
• 2 Jones IH, Hall NJ. Contemporary outcomes for infants with necrotizing enterocolitis-a systematic review. J Pediatr 2020; 220: 86-92.e3
• 3 Good M, Caplan M. Pathophysiology and prevention of neonatal necrotizing enterocolitis. In: Polin RA, Abman SH, Rowitch DH, Benitz WE, Fox WW. eds. Fetal and Neonatal Physiology. 6th ed.. Philadelphia: Elsevier; 2022: 1732-1737
• 4 Scheese DJ, Sodhi CP, Hackam DJ. New insights into the pathogenesis of necrotizing enterocolitis and the dawn of potential therapeutics. Semin Pediatr Surg 2023; 32 (03) 151309
• 5 Jiao ZT, Luo Q. Molecular mechanisms and health benefits of ghrelin: a narrative review. Nutrients 2022; 14 (19) 4191
• 6 Wu R, Dong W, Qiang X. et al. Orexigenic hormone ghrelin ameliorates gut barrier dysfunction in sepsis in rats. Crit Care Med 2009; 37 (08) 2421-2426
• 7 Jiang M, Gao PF, Li HQ, Tian PY, Fan XM. Ghrelin inhibition of ethanol-induced gastric epithelial cell apoptosis is mediated by miR-21. Int J Clin Exp Pathol 2015; 8 (05) 4662-4672
• 8 Ezquerro S, Frühbeck G, Rodríguez A. Ghrelin and autophagy. Curr Opin Clin Nutr Metab Care 2017; 20 (05) 402-408
• 9 Zhang L, Cheng J, Shen J, Wang S, Guo C, Fan X. Ghrelin inhibits intestinal epithelial cell apoptosis through the unfolded protein response pathway in ulcerative colitis. Front Pharmacol 2021; 12: 661853
• 10 Yuan PQ, Wu SV, Wang L, Taché Y. The ghrelin agonist, HM01 activates central vagal and enteric cholinergic neurons and reverses gastric inflammatory and ileus responses in rats. Neurogastroenterol Motil 2023; 35 (05) e14561
• 11 Meister AL, Burkholder CR, Doheny KK, Travagli RA. Ghrelin ameliorates the phenotype of newborn rats induced with mild necrotizing enterocolitis. Neurogastroenterol Motil 2019; 31 (11) e13682
• 12 Lu J, Pierce M, Franklin A, Jilling T, Stafforini DM, Caplan M. Dual roles of endogenous platelet-activating factor acetylhydrolase in a murine model of necrotizing enterocolitis. Pediatr Res 2010; 68 (03) 225-230
• 13 Korkut S, Özdemir A, Yay AH. et al. Obestatin reduces intestinal damage in experimental necrotizing enterocolitis in newborn rats. Am J Perinatol 2019; 36 (11) 1179-1187
• 14 Coşkun ZM, Saçan O, Karatuğ A. et al. Regulation of oxidative stress and somatostatin, cholecystokinin, apelin gene expressions by ghrelin in stomach of newborn diabetic rats. Acta Histochem 2013; 115 (07) 740-747
• 15 Caplan MS, Lickerman M, Adler L, Dietsch GN, Yu A. The role of recombinant platelet-activating factor acetylhydrolase in a neonatal rat model of necrotizing enterocolitis. Pediatr Res 1997; 42 (06) 779-783
• 16 Yazıcı S, Akşit H, Korkut O, Sunay B, Çelik T. Effects of boric acid and 2-aminoethoxydiphenyl borate on necrotizing enterocolitis. J Pediatr Gastroenterol Nutr 2014; 58 (01) 61-67
• 17 Zani A, Cordischi L, Cananzi M. et al. Assessment of a neonatal rat model of necrotizing enterocolitis. Eur J Pediatr Surg 2008; 18 (06) 423-426
• 18 Dvorak B, Halpern MD, Holubec H. et al. Epidermal growth factor reduces the development of necrotizing enterocolitis in a neonatal rat model. Am J Physiol Gastrointest Liver Physiol 2002; 282 (01) G156-G164
• 19 Burri PH. The postnatal growth of the rat lung. 3. Morphology. Anat Rec 1974; 180 (01) 77-98
• 20 Lohmiller JL, Swing SP. Reproduction and breeding. In: Suckow MA, Weisbroth SH, Franklin CL. eds. The Laboratory Rat. Academic Press; 2006: 148-153
• 21 Khalaji A, Babajani N, Amirsardari Z. et al. Unveiling the ghrelin and obestatin roles in inflammatory bowel diseases: a systematic review and meta-analysis assessing their pathogenic implications and biomarker utility. Inflamm Bowel Dis 2024; 30 (04) 629-640
• 22 Good M, Caplan M. Pathophysiology and prevention of neonatal necrotizing enterocolitis. In: Polin RA, Abman SH, Rowitch DH, Benitz WE, Fox WW. eds. Fetal and Neonatal Physiology. Philadelphia: Elsevier; 2022. ;162:732–737
• 23 Konturek PC, Burnat G, Rau T, Hahn EG, Konturek S. Effect of adiponectin and ghrelin on apoptosis of Barrett adenocarcinoma cell line. Dig Dis Sci 2008; 53 (03) 597-605
• 24 Hosomi S, Oshitani N, Kamata N. et al. Endogenous and exagenous ghrelin enhance the colonic and gastric manifestations of dextran sodium sulphate-induced colitis in mice. Inflamm Bowel Dis 2008; 14: 1205-1213
• 25 De Smet B, Thijs T, Moechars D. et al. Endogenous and exogenous ghrelin enhance the colonic and gastric manifestations of dextran sodium sulphate-induced colitis in mice. Neurogastroenterol Motil 2009; 21 (01) 59-70
• 26 Liu ZZ, Wang WG, Li Q. et al. Growth hormone secretagogue receptor is important in the development of experimental colitis. Cell Biosci 2015; 5: 12
• 27 Li XY, Zhong CR, Wu JC, Yuan CH, Ran JM. Ghrelin improves glucolipotoxicity-induced pancreatic β-cellular dysfunction and apoptosis by inhibiting endoplasmic reticulum stress-induced IRE1/JNK pathway. Discov Med 2024; 36 (186) 1370-1377
• 28 Ma J, Wang X, Lv T. et al. Effects of ghrelin on the apoptosis of rheumatoid arthritis fibroblast-like synoviocyte MH7A cells. Biol Pharm Bull 2019; 42 (02) 158-163
• 29 Maduzia D, Matuszyk A, Ceranowicz D. et al. The influence of pretreatment with ghrelin on the development of acetic-acid-induced colitis in rats. J Physiol Pharmacol 2015; 66 (06) 875-885
• 30 Pamukçu O, Kumral ZN, Ercan F, Yegen BC, Ertem D. Anti-inflammatory effect of obestatin and ghrelin in dextran sulfate sodium-induced colitis in rats. J Pediatr Gastroenterol Nutr 2013; 57 (02) 211-218
• 31 Wu W, Zhu L, Dou Z. et al. Ghrelin in focus: dissecting its critical roles in gastrointestinal pathologies and therapies. Curr Issues Mol Biol 2024; 46 (01) 948-964