Purinergic signaling in the gut neuro-glial-immune axis: mechanisms of homeostasis, inflammation, and gastrointestinal dysfunction

The gastrointestinal (GI) tract contains a highly integrated network composed of the enteric nervous system (ENS), epithelial cells, resident immune populations, and intestinal microbiota. Communication among these components is essential for maintaining intestinal homeostasis and coordinating responses to environmental and inflammatory stimuli. Purinergic signaling regulates synaptic transmission, neuronal excitability, enteric neuron-glia communication, intestinal motility, and epithelial secretion. In parallel, purinergic receptors expressed by epithelial and immune cells modulate barrier integrity, cytokine production, leukocyte recruitment, immune tolerance, and tissue repair. Growing evidence indicates that dysregulated purinergic pathways contribute to neuroinflammation, enteric neuronal loss, intestinal dysmotility, visceral hypersensitivity, and inflammatory bowel disease (IBD). Among purinergic receptors, P2X7 has been strongly implicated in neuroimmune inflammatory responses, particularly in experimental models of IBD, whereas adenosine receptors generally exert immunomodulatory and tissue-protective effects, although these actions are highly context- and cell-dependent. This review summarizes current knowledge on purinergic signaling within the intestinal neuro-glial-immune network, highlighting its roles in gastrointestinal homeostasis and disease. We also discuss emerging therapeutic opportunities targeting purinergic receptors and ectonucleotidases to restore intestinal function and limit chronic inflammation.