Antibiotic-induced microbiota dysbiosis impairs neuromuscular function in juvenile mice

Background and Purpose Gut microbiota is essential for the development of the gastrointestinal system, including the enteric nervous system (ENS). Early life perturbations of gut microbiota can potentially impact neurodevelopment leading to functional bowel disorders later in life. We examined the hypothesis that gut dysbiosis impairs ENS structural and functional integrity leading to gut dysmotility in juvenile mice. Experimental Approach To induce gut dysbiosis broad-spectrum antibiotics were administered by gavage to juvenile male C57Bl/6 mice for 14 days. Bile acid composition in the intestinal lumen was analysed by liquid chromatography-mass spectrometry. Changes in intestinal motility were evaluated by stool frequency, transit of a fluorescent-labelled marker and isometric muscle response of ileal full-thickness preparations to receptor and non-receptor-mediated stimuli. Alterations in ENS integrity were assessed by immunohistochemistry and western blot analysis. Key Results Antibiotic treatment affected gastrointestinal transit, luminal bile acid metabolism and bowel architecture. Gut dysbiosis resulted in distorted glial network, loss of myenteric plexus neurons, altered cholinergic, tachykininergic and nitrergic neurotransmission associated with reduced number of nNOS neurons and different ileal distribution of Toll-like receptor 2 (TLR2). Functional defects were partially reversed by TLR2 signalling activation. Conclusions and Implications Gut dysbiosis determined complex morpho-functional neuromuscular rearrangements, characterized by ENS structural defects and increased tachykininergic neurotransmission. Altogether, our findings support the beneficial role of enteric microbiota for ENS homeostasis instrumental to ensure proper gut neuromuscular function during critical developmental stages.