Hypoganglionosis in the gastric antrum causes delayed gastric emptying

Background Enteric nervous system (ENS) abnormalities have been implicated in delayed gastric emptying but studies exploring potential treatment options are limited by the lack of an experimental animal model. We examined the ENS abnormalities in the mouse stomach associated with aging, developed a novel model of gastroparesis, and established a new approach to measure gastric emptying. Methods A modified gastric emptying assay was developed, validated in nNOS (-/-) mice, and tested in mice at multiple ages. Age-related changes in ENS structure were analyzed by immunohistochemistry. Gastric aganglionosis was generated in Wnt1-iDTR mice using focal administration of diphtheria toxin (DT) into the anterior antral wall. Key Results Older mice (>5 months) exhibit hypoganglionosis in the gastric antrum and a decreased proportion of nNOS neurons as compared to younger mice (age 5-7 weeks). This was associated with a significant age-dependent decrease in liquid and solid gastric emptying. A novel model of gastric antrum hypoganglionosis was established using neural crest-specific expression of diphtheria toxin receptor. In this model, a significant reduction in liquid and solid gastric emptying is observed. Conclusions & Inferences Older mice exhibit delayed gastric emptying associated with hypoganglionosis and a reduction in nNOS-expressing neurons in the antrum. The causal relationship between antral hypoganglionosis and delayed gastric emptying was verified using a novel experimental model of ENS ablation. This study provides new information regarding the pathogenesis of delayed gastric emptying and provides a robust model system to study this disease and develop novel treatments.