Creatine is an organic compound which is utilized in biological activities, especially
for adenosine triphosphate (ATP) production in the phosphocreatine system. This is a
well-known biochemical reaction that is generally recognized as being mainly driven in
specific parts of the body, such as the skeletal muscle and brain. However, our report
shows a novel aspect of creatine utilization and ATP synthesis in innate immune cells.
Creatine supplementation enhanced immune responses in neutrophils, such as cytokine
production, reactive oxygen species (ROS) production, phagocytosis, and NETosis, which
were characterized as antibacterial activities. This creatine-induced functional
upregulation of neutrophils provided a protective effect in a murine bacterial sepsis
model. The mortality rate in mice challenged with
Escherichia coli
K-12
was decreased by creatine supplementation compared with the control treatment.
Corresponding to this decrease in mortality, we found that creatine supplementation
decreased blood pro-inflammatory cytokine levels and bacterial colonization in organs.
Creatine supplementation significantly increased the cellular ATP level in neutrophils
compared with the control treatment. This ATP increase was due to the phosphocreatine
system in the creatine-treated neutrophils. In addition, extracellular creatine was used
in this ATP synthesis, as inhibition of creatine uptake abolished the increase in ATP in
the creatine-treated neutrophils. Thus, creatine is an effective nutrient for modifying
the immunological function of neutrophils, which contributes to enhancement of
antibacterial immunity.