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Gut microbiota-mediated Gene-Environment interaction in the TashT mouse model of Hirschsprung disease
- Source :
- Scientific Reports, Vol 9, Iss 1, Pp 1-14 (2019), Scientific Reports
- Publication Year :
- 2019
- Publisher :
- Nature Publishing Group, 2019.
-
Abstract
- Based on the bilateral relationship between the gut microbiota and formation/function of the enteric nervous system (ENS), we sought to determine whether antibiotics-induced dysbiosis might impact the expressivity of genetically-induced ENS abnormalities. To address this, we took advantage of the TashT mouse model of Hirschsprung disease, in which colonic aganglionosis and hypoganglionosis are both much more severe in males. These defects result into two male-biased colon motility phenotypes: either megacolon that is lethal around weaning age or chronic constipation in adults, the latter being also associated with an increased proportion of nitrergic neurons in the distal ENS. Induction of dysbiosis using a cocktail of broad-spectrum antibiotics specifically impacted the colonic ENS of TashTTg/Tg mice in a stage-dependent manner. It further decreased the neuronal density at post-weaning age and differentially modulated the otherwise increased proportion of nitrergic neurons, which appeared normalized around weaning age and further increased at post-weaning age. These changes delayed the development of megacolon around weaning age but led to premature onset of severe constipation later on. Finally, local inhibition of nitric oxide signaling improved motility and prevented death by megacolon. We thus conclude that exposure to antibiotics can negatively influence the expressivity of a genetically-induced enteric neuropathy.
- Subjects :
- 0301 basic medicine
medicine.medical_specialty
Colon
lcsh:Medicine
Mice, Transgenic
Gut flora
Article
03 medical and health sciences
Mice
0302 clinical medicine
Internal medicine
medicine
Weaning
Animals
Hirschsprung Disease
lcsh:Science
Chronic constipation
Multidisciplinary
Megacolon
biology
Enteric neuropathy
business.industry
lcsh:R
medicine.disease
biology.organism_classification
Gastrointestinal Microbiome
Disease Models, Animal
030104 developmental biology
Endocrinology
Enteric nervous system
Gene-Environment Interaction
lcsh:Q
business
Nitrergic Neuron
Dysbiosis
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 20452322
- Volume :
- 9
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....7592bb92bbd0bca11563a3818702ff84