ATP modulates immune cell functions, and ATP derived from gut commensal bacteria promotes the differentiation of T helper 17 (Th17) cells in the intestinal lamina propria. We recently reported that Enterococcus gallinarum, isolated from mice and humans, secretes ATP. We have since found and characterized several ATP-secreting bacteria. Of the tested enterococci, Enterococcus mundtii secreted the greatest amount of ATP (>2 M/10 8 cells) after overnight culture. Glucose, not amino acids and vitamins, was essential for ATP secretion from E. mundtii. Analyses of energy-deprived cells demonstrated that glycolysis is the most important pathway for bacterial ATP secretion. Furthermore, exponential-phase E. mundtii and Enterococcus faecalis cells secrete ATP more efficiently than stationary-phase cells. Other bacteria, including Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus, also secrete ATP in exponential but not stationary phase. These results suggest that various gut bacteria, including commensals and pathogens, might secrete ATP at any growth phase and modulate immune cell function.
ATP is the source of energy within living cells and acts as an allosteric effector of numerous cell processes, such as active transport, nucleic acid synthesis, muscle activity, and movement (1-5).In mammalian cells, ATP is the neurotransmitter for purinergic signal transmission (6). ATP is stored in secretory vesicles and exocytosed, leading to various purinergic responses, such as central control of autonomic functions, pain and mechanosensory transduction, neural-glial interactions, control of vessel tone and angiogenesis, and platelet aggregation through purinoceptors, thus establishing its role as a chemical transmitter (7)(8)(9)(10)(11).ATP modulates immune cell function by activating the ATP receptors P2X and P2Y (11-13). Furthermore, ATP has been found in the intestinal lumen, where it promotes differentiation of T helper 17 (Th17) cells in the lamina propria (14). Germ-free (GF) mice exhibited much lower concentrations of fecal ATP, accompanied by fewer lamina propria Th17 cells, than specificpathogen-free (SPF) mice. In addition, antibiotic-treated SPF mice showed marked reductions in the number of Th17 cells and in the concentration of fecal ATP. Systemic or rectal administration of ATP markedly increases the number of lamina propria Th17 cells in GF mice. Thus, ATP driven from commensal bacteria activates the lamina propria, leading to local differentiation of Th17 cells. However, ATP-secreting bacteria have not been identified in the intestinal lumen of SPF mice.Recently, we reported that Enterococcus gallinarum, a vancomycin-resistant Gram-positive coccus isolated from SPF mice, secretes ATP; other tested bacteria, such as Enterococcus faecalis, Enterococcus faecium, Escherichia coli, and Staphylococcus aureus, did not (15). To our knowledge, this is the first report of the isolation and identification of ATP-secreting bacteria from the feces of SPF mice. However, whether other enterococcal species sec...