Glucagon-like peptides agonists promote maturation of intestinal organoids derived from neonates with necrotizing enterocolitis.

Abstract

Purpose: Necrotizing enterocolitis (NEC) majorly affects premature infants, causing not only necrosis and inflammation but also feeding intolerance and gastrointestinal dysmotility, hinting at gut hormone secretion impairment. Particularly critical is the gestation period before 26 weeks where intestinal hormonal activity is partially developed, rendering preterm neonates highly susceptible to NEC. Emerging evidence suggests a role of gut hormones, especially glucagon-like peptides (GLP) in ileum development. Herein, the aim of this study was to determine the effect of modulating GLP signaling during normal intestinal development and during intestinal injury.

Methods: We employed a human intestinal organoid (HIO) model derived from ileum tissue. After ethical approval, we obtained ileal biopsies from infants with NEC in uninjured (distant from site of NEC injury) and injured intestine (site of injury). After collection, crypt isolation was performed, and HIOs were cultured for 2-3 days before glucagon peptide agonists added daily in culture media. Organoids were harvested and analyzed for morphological measures of maturation including organoid size and budding.

Results: Within the same patient, injured HIOs had a decreased budding compared to uninjured HIOs. Treatment with GLP agonists improved morphology and promoted maturation compared to the untreated organoid in both uninjured and injured HIOs.

Conclusion: Patient-derived organoids provide a suitable ex vivo model to study NEC pathogenesis. Increasing GLP signaling in HIOs enhanced maturation of organoids derived from uninjured and injured neonatal human intestine. Further studies are underway to assess in vivo, the efficacy of GLP agonist administration in NEC. This study opens the way to future development of precision medicine in the treatment of NEC.