Gut microbiota-mediated Gene-Environment interaction in the TashT mouse model of Hirschsprung disease

Touré, Aboubacrine Mahamane; Landry, Mathieu; Souchkova, Ouliana; Kembel, Steven W. et Pilon, Nicolas (2019). « Gut microbiota-mediated Gene-Environment interaction in the TashT mouse model of Hirschsprung disease ». Scientific Reports, 9(1), p. 492.

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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 postweaning 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 geneticallyinduced enteric neuropathy.

Type: Article de revue scientifique
Mots-clés ou Sujets: Antibiotics, Dysbiosis, Enteric Nervous System, Hirschsprung disease, Gastrointestinal motility, Gut microbiota, Mouse model, NOS signaling
Unité d'appartenance: Centres institutionnels > Centre de recherches biomédicales (BIOMED)
Faculté des sciences > Département des sciences biologiques
Déposé par: Jean-Jacques Rondeau
Date de dépôt: 04 janv. 2019 10:54
Dernière modification: 30 juill. 2020 10:37
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