Corey Baker1, Minhal Ahmed2, Katarina Cheng3, Emily Arciero3, Sukhada Bhave3, Wing Lam N Ho3, Allan M Goldstein3, Ryo Hotta3. 1. Department of Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital, Harvard Medical School, Boston, MA. 2. College of Engineering, Northeastern University, Boston, MA. 3. Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Abstract
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.
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.
Authors: Ferenc Izbeki; David T Asuzu; Andrea Lorincz; Michael R Bardsley; Laura N Popko; Kyoung Moo Choi; David L Young; Yujiro Hayashi; David R Linden; Makoto Kuro-o; Gianrico Farrugia; Tamas Ordog Journal: J Physiol Date: 2010-06-25 Impact factor: 5.182
Authors: Jian-Kan Guo; Arnaud Marlier; Hongmei Shi; Alan Shan; Thomas A Ardito; Zhao-Peng Du; Michael Kashgarian; Diane S Krause; Daniel Biemesderfer; Lloyd G Cantley Journal: J Am Soc Nephrol Date: 2011-12-22 Impact factor: 10.121
Authors: Gianluca Cipriani; Simon J Gibbons; Katie E Miller; Daniel S Yang; Matthew L Terhaar; Seth T Eisenman; Tamas Ördög; David R Linden; Gabriela B Gajdos; Joseph H Szurszewski; Gianrico Farrugia Journal: Gastroenterology Date: 2018-03-06 Impact factor: 33.883
Authors: Othman A Al-Shboul; Mona S Nazzal; Ayman G Mustafa; Ahmed N Al-Dwairi; Mohammad A Alqudah; Amal Abu Omar; Mahmoud A Alfaqih; Mohammad I Alsalem Journal: Exp Ther Med Date: 2018-07-04 Impact factor: 2.447