The role of purinergic pathways in the pathophysiology of gut diseases: pharmacological modulation and potential therapeutic applications

Gut homeostasis results from complex neuro-immune interactions aimed at triggering stereotypical and specific programs of coordinated mucosal secretion and powerful motor propulsion. A prominent role in the regulation of this highly integrated network, comprising a variety of immune/inflammatory cells and the enteric nervous system, is played by purinergic mediators. The cells of the digestive tract are literally plunged into a "biological sea" of functionally active nucleotides and nucleosides, which carry out the critical task of driving regulatory interventions on cellular functions through the activation of P1 and P2 receptors. Intensive research efforts are being made to achieve an integrated view of the purinergic system, since it is emerging that the various components of purinergic pathways (i.e., enzymes, transporters, mediators and receptors) are mutually linked entities, deputed to finely modulating the magnitude and the duration of purinergic signaling, and that alterations occurring in this balanced network could be intimately involved in the pathophysiology of several gut disorders. This review article intends to provide a critical appraisal of current knowledge on the purinergic system role in the regulation of gastrointestinal functions, considering these pathways as a whole integrated network, which is capable of finely controlling the levels of bioactive nucleotides and nucleosides in the biophase of their respective receptors. Special attention is paid to the mechanisms through which alterations in the various compartments of the purinergic system could contribute to the pathophysiology of gut disorders, and to the possibility of counteracting such dysfunctions by means of pharmacological interventions on purinergic molecular targets.