O2165: Gut Hormone Glucagon-peptide 1 and 2 Receptor Agonist Modulates Gut-brain Axis Signaling in Experimental NEC

Background: Necrotizing enterocolitis (NEC) is a serious gastrointestinal emergency that affects premature infants and is often linked with delayed neurodevelopment. NEC is associated with feeding and gastrointestinal motility impairment, indicating potential issues with the secretion of gut hormones. We have recently shown that certain gut hormones, specifically the incretin glucagon-like peptides (GLP), may play a significant role in the gut-brain connection, affecting brain resilience in NEC. This study aims to investigate how modifying GLP1 and GLP2 signaling may promote neuroprotection in NEC.

Methods: NEC was induced in postnatal day 5 (p5) mice using hypoxia, gavage feeding (hyperosmolar formula), and oral lipopolysaccharide (4mg/kg). Breastfed pups at p9 served as control. Exendin 4 (Ex4), a GLP1 receptor (GLP1R) agonist, and/or Teduglutide, a GLP2 receptor (GLP2R), agonist was injected intraperitoneally, twice a day on p6-p9. To characterize the pattern of GLP1/2R receptor expression in the brain, glp1r and glp2r receptor gene expression was measured via RT-qPCR at three time points (postnatal day 1, 6, 9) in early neonatal life during which NEC injury was induced. Protein expression (Western blott) of microglia activation marker CD68 and astrocyte proliferation marker GFAP was evaluated in the hippocampus of control, NEC, and NEC +GLP1R and/or 2R agonist pups.

Results: glp1r expression was present on the first day life and maintained whereas glp2r expression gradually increased during the first period of neonatal life (Fig. a). In line with our previously reported findings, we confirmed CD68 (microglia activation) and GFAP (astrocyte proliferation) increase in the brain of NEC pups compared to control suggesting the presence of neuroinflammation. Furthermore, pups that received Ex4 (GLP1R) agonist or cocktail of Ex4 and Teduglutide in combination, but not Teduglutide alone, most significantly decreased microglia and astrocyte proliferation markers reducing neuroinflammation in the brain (Fig b).

Conclusion: The brain of neonatal mice has distinct glp1r and glp2r expression during early neonatal life suggesting distinct mechanistic roles in response to brain injury. For the first time, we showed that modulation of GLP1R signaling had a more pronounced anti-inflammatory effect compared to pups who received Teduglutide alone suggesting that GLP1R signaling is occurring in immune cells. This study highlights the therapeutic potential of a novel hormonal treatment to counteract the neurological damage caused by NEC.