Enteric glial cell interaction network: Core mechanisms and targeting strategies from support function to homeostasis regulation

Enteric glial cells (EGCs), once regarded as passive support cells, are now recognized as key regulators of gastrointestinal diseases through molecular and cellular interactions. Recent studies have revealed considerable heterogeneity among EGCs at the morphological, transcriptional, and functional levels. EGCs can be broadly categorized into protective subpopulations characterized by high expression of glial cell-derived neurotrophic factor (GDNF) and pro-inflammatory subpopulations marked by expression of S100 calcium-binding protein B (S100β). This functional dichotomy positions EGCs as signal-integrating hubs within the gut microenvironment. Through mediators such as GDNF, IL-22, and ICAM-1, EGCs establish bidirectional communication networks with neurons, epithelial cells, and immune cells. Under chronic inflammation, stress, or oncogenic signaling, EGCs undergo context-dependent functional remodeling, shifting from a protective phenotype to a disease-promoting phenotype. This transition has been linked to colorectal cancer, visceral hypersensitivity, postoperative ileus, and inflammatory bowel disease. Several signaling pathways, including TLR4, P2X7, PPARγ, the GDNF–rearranged during transfection (RET) axis, and ICAM-1 signaling, have been identified as critical regulators of this phenotypic switch. Because these pathways are enriched in specific EGC subpopulations, they represent promising targets for selective therapeutic intervention. This review examines the heterogeneity of EGCs and their multilayered communication within the neuro–epithelial–immune axis. We summarize current pharmacological strategies targeting EGCs, including selective inhibition of pathogenic subpopulations, enhancement of protective functions, and blockade of abnormal intercellular communication. These approaches may provide novel therapeutic opportunities for gastrointestinal and neuroimmune disorders.