Urolithin A Supplementation Increases Acute Exercise Mediated Natural Killer Cell Cytotoxicity

Acute exercise increases the number of natural killer (NK) cells in the blood, resulting in increased cancer cell killing in vitro in healthy adults but less in adults with cancer. This immune dysfunction is partially mediated through impaired immune bioenergetics, particularly mitochondrial function. Urolithin A is a potent mitochondrial enhancer with the potential to enhance immune cell bioenergetics. PURPOSE: Determine whether Urolithin A, a potent mitochondrial enhancer, increases acute exercise-induced cancer cell killing by NK cells. METHODS: Fourteen healthy adults (6F/8M: aged 24 ± 4 years) completed a parallel design, double-blind, randomised, placebo-controlled trial. Supplementation was either 14 days of 500 mg/day Urolithin A [UroA, N = 7 (3F/4M)] or 500 mg/day of a cellulose placebo [CON, N = 7 (3F/4M)]. Participants completed a 30-minute bout of cycling at 75% VO2peak before (T0) and after (T1) supplementation. We assessed the acute-exercise mediated increased (Pre to Post acute-exercise) NK cell killing of K562 cancer cell lines by flow cytometry and lymphocyte mitochondrial function by Seahorse. RESULTS: In all conditions, acute exercise increased the number of blood CD3-/CD56+ NK cells (T0: 1.5 ± 0.5 to 5.2 ± 0.7 x 108 cells/L and T1: 1.7 ± 0.6 to 5.9 ± 0.7 x 108 cells/L; both p < 0.001) resulting in 19.1 ± 5.3% more K562 cell death (p < 0.001) at an effector:target of 100:1. The difference between T0 & T1 Pre to Post K562 cell death increased by 5.0% (95% CI: 3.3, 6.4) for UroA (MeanDiff±SD 19 ± 4.0% v 24 ± 4.0%; p < 0.001) while CON did not change (16.6 ± 5.3% v 15.4 ± 4.7%; p = 0.210). Similarly, the difference between T0 & T1 Pre to Post K562 killing per NK cell increased by 10.5% (95% CI: 2.7, 18.2) for UroA (0.5 ± 9.2% v 11.0 ± 4.5%; p = 0.012) while CON did not change (-2.2 ± 8.3% v -3.8 ± 2.8%; p = 0.706). The difference between T0 & T1 Pre to Post lymphocyte mitochondrial maximal respiration increased by 27.2% (95% CI: 5.0, 49.4) for UroA (6.1 ± 32.4% v 33.3 ± 10.2%; p = 0.021) while CON did not change (3.6 ± 16.1% v 6.0 ± 26.8%; p = 0.847). CONCLUSION: Fourteen days of Urolithin A supplementation enhances NK cell cytotoxicity against K562 cancer cells after acute exercise in part through improved mitochondrial function. Further work is required to determine if Urolithin A supplementation overcomes cancer-related immune dysfunction.