Andy
Senior Member (Voting rights)
Abstract
Background & Aims
Experiencing gut inflammation often produces long-term defects in gut motor function that persist despite the resolution of active inflammation. Such changes are driven by neuroplasticity within enteric nervous system motor neurocircuits and contribute to the pathophysiology of common disorders that include post-infectious irritable bowel syndrome and inflammatory bowel disease in remission. Yet mechanisms that drive and maintain enteric neuroplasticity following inflammation are poorly understood.Methods
We studied cellular activity in enteric motor neurocircuits and gut motor function following the resolution of acute inflammation using genetically encoded Ca2+ sensors and chemogenetics to test the hypothesis that acute inflammation induces glial changes that promote neuron hyperexcitability with subsequent effects on gut motor functions.Results
The data show that enteric glia are hyperexcitable following acute inflammation and drive abnormal excitatory responses in enteric neurons that disrupt gut motor control. Enteric neurons in synaptically connected neural pathways are more excitable following colitis and stimulate greater activity among the surrounding enteric glia. Chemogenetic activation experiments show that enteric glia exhibit intrinsic hyperexcitability and that subsequent gliotransmission mechanisms trigger abnormal responses in neurons that alter motor responses. Mechanisms underlying glial hyperexcitability involve changes to nitrergic inhibition, prostaglandin E2 (PGE2), and enhanced glial connexin-43 hemichannel activity.Conclusions
These observations suggest that therapies targeting enteric glial signaling mechanisms could aid persistent gut dysmotility caused by inflammation.Open access
