Creatine supplementation enhances immunological function of neutrophils by increasing cellular adenosine triphosphate

Suguru Saito; Duo-Yao Cao; Alato Okuno; Xiaomo Li; Zhenzi Peng; Musin Kelel; Noriko M Tsuji

doi:10.12938/bmfh.2022-018

Creatine supplementation enhances immunological function of neutrophils by increasing cellular adenosine triphosphate

Biosci Microbiota Food Health. 2022;41(4):185-194. doi: 10.12938/bmfh.2022-018. Epub 2022 Jun 17.

Authors

Suguru Saito^{1

2

3}, Duo-Yao Cao^{4

5}, Alato Okuno⁶, Xiaomo Li⁷, Zhenzi Peng⁸, Musin Kelel⁹, Noriko M Tsuji^{10

11}

Affiliations

¹ Division of Virology, Department of Infection and Immunology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0431, Japan.
² Biofluid Biomarker Center, Graduate School of Medical and Dental Sciences, Niigata University, 757 Ichiban-cho, Ashahimachi-dori, Nishi-ku, Niigata, Niigata 951-8510, Japan.
³ Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2R7, Canada.
⁴ College of Animal Science and Technology, Northwest A&F University, Taicheng Rd, Yangling District, Xianyang, Shaanxi 712100, China.
⁵ Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁶ Department of Health and Nutrition, Faculty of Human Design, Shibata Gakuen University, Aomori 036-8530, Japan.
⁷ Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁸ Institute of Medical Sciences, Xiangya Hospital, Central South University, 139 Renmin Middle Rd, Yuan Jia Ling Shang Quan, Furong District, Changsha, Hunan 410083, China.
⁹ Department of Biotechnology, College of Biological and Chemical Engineering, Addis Ababa Science and Technology University, Addis Ababa, Ethiopia.
¹⁰ Division of Microbiology, Department of Pathology and Microbiology, Nihon University School of Medicine, 30-1 Oyaguchi-Kamimachi, Itabashi, Tokyo 173-8610, Japan.
¹¹ Department of Food Science, Jumonji University, 2-1-28 Sugasawa, Niiza, Saitama 352-8510, Japan.

Abstract

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.

Keywords: adenosine triphosphate (ATP); antibacterial immunity; creatine; neutrophil extracellular traps (NETs); neutrophils; reactive oxygen species (ROS); sepsis.