The Enteric Glia and Its Modulation by the Endocannabinoid System, a New Target for Cannabinoid-Based Nutraceuticals?

Abstract

The enteric nervous system (ENS) is a part of the autonomic nervous system that intrinsically innervates the gastrointestinal (GI) tract. Whereas enteric neurons have been deeply studied, the enteric glial cells (EGCs) have received less attention. However, these are immune-competent cells that contribute to the maintenance of the GI tract homeostasis through supporting epithelial integrity, providing neuroprotection, and influencing the GI motor function and sensation. The endogenous cannabinoid system (ECS) includes endogenous classical cannabinoids (anandamide, 2-arachidonoylglycerol), cannabinoid-like ligands (oleoylethanolamide (OEA) and palmitoylethanolamide (PEA)), enzymes involved in their metabolism (FAAH, MAGL, COX-2) and classical (CB1 and CB2) and non-classical (TRPV1, GPR55, PPAR) receptors. The ECS participates in many processes crucial for the proper functioning of the GI tract, in which the EGCs are involved. Thus, the modulation of the EGCs through the ECS might be beneficial to treat some dysfunctions of the GI tract. This review explores the role of EGCs and ECS on the GI tract functions and dysfunctions, and the current knowledge about how EGCs may be modulated by the ECS components, as possible new targets for cannabinoids and cannabinoid-like molecules, particularly those with potential nutraceutical use.

From the Gut to the Brain: The Role of Enteric Glial Cells and Their Involvement in the Pathogenesis of Parkinson’s Disease

“…Other nutraceuticals, mainly those with antioxidant activity, might also be useful to modulate EGCs in PD, because they seem to be beneficial in other pathological conditions [28,35]. Another possible target to consider could be the modulation of the endocannabinoid system, since cannabinoids and cannabinoid-like compounds can regulate EGC activity, directly through peroxisome proliferator-activated receptors (PPAR)α receptors by palmitoylethanolamide and indirectly through activation of PPARγ or cannabinoid type 2 receptors (under GI inflammatory conditions) [97]. Moreover, the fact that dysbiosis is present in PD patients points to the possibility of treatment with probiotics, prebiotics, or combinations (synbiotics), and others such as postbiotics or paraprobiotics [98].…”

Phytocannabinoids Reduce Inflammation of Primed Macrophages and Enteric Glial Cells: An In Vitro Study

“…The glial cells in the gut represent the morphological and functional equivalent of astrocytes and microglia in the central nervous system, and they play essential roles as regulators of intestinal homeostasis [60,61]. Although no CBr have been detected in EGCs, there is mounting evidence on the effects of modulation of EGCs by the ECS [62]. During intestinal inflammatory reaction, EGCs release glial markers such as S100B and GFAP.…”

“…Altered expression of S100B and GFAP has been reported in several intestinal inflammatory disorders in humans, such as inflammatory bowel disease [16,45], celiac disease [17], and postoperative colitis [40]. However, EGCs were not in the focus of cannabinoid research [62].…”

Therapeutic applicability of cannabidiol and other phytocannabinoids in epilepsy, multiple sclerosis and Parkinson's disease and in comorbidity with psychiatric disorders

“…However, there are a myriad of factors influencing the interactions between cannabinoids and PPARs that need to be elucidated. [105][106][107] PEA (a compound related to cannabinoids) is currently used to treat pain and inflammation. Like other cannabinoid-related molecules, PEA has a very complex mechanism of action that includes direct and/or indirect interactions with CB1, TRPV1, PPAR, GPR55 and GPR18, among other receptors.…”

“…Although the data are more significant for some cannabinoids, such as N‐oleoylethanolamine (OEA) and N‐palmitoylethanolamine (PEA), neuroprotective, anti‐inflammatory and analgesic effects have been considered to be mediated, in part, by their activation of PPARs. However, there are a myriad of factors influencing the interactions between cannabinoids and PPARs that need to be elucidated 105–107 …”