Mini-review: Enteric glial cell reactions to inflammation and potential therapeutic implications for GI diseases, motility disorders, and abdominal pain

•This Mini-Review is focused on recent novel aspects of reactive glia and enteric gliosis in response to inflammation.•EGCs react to inflammation by promoting neuroinflammation, enteric neuropathy, colonic dysmotility, visceral pain, and ‘leaky gut’ in intestinal diseases or disorders.•EGCs can also drive neurogenesis and immune mediator release to protect against injury.•There is a growing number of glial molecular targets with potential therapeutic implications.•Glial therapeutic targets include IL-1R, PPARα, LPAR1, P2X2R, A2BR, TLR4, ERβ, adrenergic α-2R, EGC/NK2R/TRPV1 pain signaling, Cx43 hemichannels, and s100β signaling. Enteric glial cells are emerging as critical players in the regulation of intestinal motility, secretion, epithelial barrier function, and gut homeostasis in health and disease. Enteric glia react to intestinal inflammation by converting to a ‘reactive glial phenotype’ and enteric gliosis, contributing to neuroinflammation, enteric neuropathy, bowel motor dysfunction and dysmotility, diarrhea or constipation, ‘leaky gut’, and visceral pain. The focus of the minireview is on the impact of inflammation on enteric glia reactivity in response to diverse insults such as intestinal surgery, ischemia, infections (C. difficile infection, HIV-Tat-induced diarrhea, endotoxemia and paralytic ileus), GI diseases (inflammatory bowel diseases, diverticular disease, necrotizing enterocolitis, colorectal cancer) and functional GI disorders (postoperative ileus, chronic intestinal pseudo-obstruction, constipation, irritable bowel syndrome). Significant progress has been made in recent years on molecular pathogenic mechanisms of glial reactivity and enteric gliosis, resulting in enteric neuropathy, disruption of motility, diarrhea, visceral hypersensitivity and abdominal pain. There is a growing number of glial molecular targets with therapeutic implications that includes receptors for interleukin-1 (IL-1R), purines (P2X2R, A2BR), PPARα, lysophosphatidic acid (LPAR1), Toll-like receptor 4 (TLR4R), estrogen-β receptor (ERβ) adrenergic α-2 (α-2R) and endothelin B (ETBR), connexin-43 / Colony-stimulating factor 1 signaling (Cx43/CSF1) and the S100β/RAGE signaling pathway. These exciting new developments are the subject of the minireview. Some of the findings in pre-clinical models may be translatable to humans, raising the possibility of designing future clinical trials to test therapeutic application(s). Overall, research on enteric glia has resulted i