Enteric glia and neuroprotection: basic and clinical aspects

Abstract

The enteric nervous system (ENS), a major regulatory system for gastrointestinal function, is composed of neurons and enteric glial cells (EGCs). Enteric glia have long been thought to provide only structural support to neurons. However, recent evidence indicates enteric glia-neuron cross talk significantly contributes to neuronal maintenance, survival, and function. Thus damage to EGCs may trigger neurodegenerative processes thought to play a role in gastrointestinal dysfunctions and symptoms. The purpose of this review is to provide an update on EGCs, particularly focusing on their possible neuroprotective features and the resultant enteric neuron abnormalities subsequent to EGC damage. These neuroprotective mechanisms may have pathogenetic relevance in a variety of functional and inflammatory gut diseases. Basic and clinical (translational) studies support a neuroprotective role mediated by EGCs. Different models have been developed to test whether selective EGC damage/ablation has an impact on gut functions and the ENS. Preclinical data indicated that selective EGC alterations were associated with changes in gut physiology related to enteric neuron abnormalities. In humans, a substantial loss of EGCs was described in patients with various functional and/or inflammatory gastrointestinal diseases. However, whether EGC changes precede or follow neuronal degeneration and loss and how this damage occurs is not defined. Additional studies on EGC neuroprotective capacity are expected to improve knowledge of gut diseases and pave the way for targeted therapeutic strategies of underlying neuropathies. enteric glia; enteric neurons; enteric neuropathy; neuroprotection; neurodegeneration DIGESTION, I.E., THE BREAKDOWN and mixing of food with secretions, nutrient digestion and absorption, propulsion of the contents throughout the gut, and, finally, the expulsion of undigested material, requires a vast repertoire of highly integrated regulatory mechanisms. These are finely tuned by a variety of cell types, including endocrine cells [distributed throughout the gastrointestinal (GI) mucosa], smooth muscle cells (final effectors of contractility and/or relaxation), interstitial cells of Cajal (ICC) (pacemakers of gut motility and regulators of neuromuscular transmission), and neurons of both intrinsic (enteric) and extrinsic (sympathetic and parasympathetic) origin (50). The neural network of the digestive system, including the enteric nervous system (ENS), exerts a prominent regulatory role. From a structural standpoint, the ENS contains about 100 to 500 million neuronal cell bodies organized in two major ganglionated plexuses (i.e., myenteric and submucosal), neural processes connecting the ganglia among them, and nerve fibers targeting many different effector cells. In addition to neurons, enteric glial cells (EGCs) were recently identified as key players in the ENS. EGCs, which form the largest cell population of the ENS, have long been thought to exert a mere mechanical property by supporting neurons (hence the ancient...

Imaging neuron-glia interactions in the enteric nervous system

“…Enteric glial cells share many phenotypical features with astrocytes, and were for a long time also believed to function mainly as support cells for neurons. However, in the last two decades this dogma has gradually been abandoned and considerable progress has been made in understanding enteric glial function, most of which has been covered in recent reviews (De Giorgio et al, 2012; Gulbransen and Sharkey, 2012; Neunlist et al, 2013). …”

3‐D imaging, illustration, and quantitation of enteric glial network in transparent human colon mucosa

“…The networks are most noticeable at the myenteric and submucosal plexuses as an essential component of the enteric nervous system in association with neurons . In the mucosa, glial cells have been suggested to engage in multidirectional interactions with the epithelium, blood vessels, nerves, and immune system . In functional studies, conditional ablation of the enteric glia using transgenic approaches resulted in gut inflammation with compromised epithelial seal and vascular integrity .…”

Clostridium difficile-related postinfectious IBS: a case of enteroglial microbiological stalking and/or the solution of a conundrum?

“…The important role of EGC, besides mechanical/trophic support function [27], involves regulation of gut barrier functions [28], maintenance and modulation of enteric neurotransmission [29], enteric neurons homeostasis [30], and acting as mediators of interactions between the enteric nervous system and the immune system [25,31]. These functions are particularly interesting in the setting of PI-IBS, in that there are emerging data that immune-mediated barrier defects are found in IBS patients [32,33].…”