Neurogastroenterology and Motility: Ammonia modifies enteric neuromuscular transmission through glialγ-aminobutyric acid signaling

摘要

Impaired gut motility may contribute, at least in part, to the development of systemic hyperammonemia and systemic neurological disorders in inherited metabolic disorders, or in severe liver and renal disease. It is not known whether enteric neurotransmission regulates intestinal luminal and hence systemic ammonia levels by induced changes in motility. Here, we propose and test the hypothesis that ammonia acts through specific enteric circuits to influence gut motility. We tested our hypothesis by recording the effects of ammonia on neuromuscular transmission in tissue samples from mice, pigs, and humans and investigated specific mechanisms using novel mutant mice, selective drugs, cellular imaging, and enzyme-linked immunosorbent assays. Exogenous ammonia increased neurogenic contractions and decreased neurogenic relaxations in segments of mouse, pig, and human intestine. Enteric glial cells responded to ammonia with intracellular Ca²⁺ responses. Inhibition of glutamine synthetase and the deletion of glial connexin-43 channels in hGFAP::CreER^T2+/−/connexin43^f/f mice potentiated the effects of ammonia on neuromuscular transmission. The effects of ammonia on neuromuscular transmission were blocked by GABAA receptor antagonists, and ammonia drove substantive GABA release as did the selectivepharmacological activation of enteric glia in GFAP::hM3Dq transgenicmice. We propose a novel mechanism whereby local ammonia is operational throughGABAergic glial signaling to influence enteric neuromuscular circuits that regulateintestinal motility. Therapeutic manipulation of these mechanisms may benefit anumber of neurological, hepatic, and renal disorders manifesting hyperammonemia.>NEW & NOTEWORTHY We propose that local circuits in the entericnervous system sense and regulate intestinal ammonia. We show that ammonia modifiesenteric neuromuscular transmission to increase motility in human, pig, and mouseintestine model systems. The mechanisms underlying the effects of ammonia on entericneurotransmission include GABAergic pathways that are regulated by enteric glialcells. Our new data suggest that myenteric glial cells sense local ammonia anddirectly modify neurotransmission by releasing GABA.