Acute time course and magnitude of the inflammatory and hepcidin responses to exercise in the heat

Iron homeostasis is modulated by many factors (biological sex, diet, contraceptive use, etc.), but a key regulator is the hormone hepcidin. Hepcidin blocks the only known cellular iron exporting channel leading to reduced iron availability in the circulation. Reduced iron availability can negatively impact the development of new red blood cells, a process that is critical to adaptations during training to enhance performance. While previous literature shows that the interleukin-6 (IL-6) cytokine response to exercise results in elevated hepcidin production, there is no current literature quantifying circulating endotoxins effect on augmenting hepcidin production during exercise in hot environmental conditions. Endotoxins permeate through the gut into the circulation during sustained endurance exercise or when body core temperature is greatly elevated. The purpose of this study is to examine the time course and magnitude of the inflammatory and hepcidin responses to circulatory endotoxins evoked by exercise under hot environmental conditions in female athletes. We hypothesize that endotoxins in the circulation may contribute additional inflammatory insult on exercising athletes, leading to increased inflammatory signaling (such as IL-6) and therefore increased hepcidin production. These results will inform how hot environmental exercise may impact iron balance and provide insight into the impact of endotoxin-associated gut permeability as a new aspect of maintaining proper iron status in athletes. In a randomized cross-over study design, fourteen endurance trained female athletes (age 28.2 (range: 36) years; body mass index 23.2 (21.8, 24.6) kg·m -2 ; VO 2 max 56.2 (51.1, 61.4) ml·kg -1 ·min -1 ) completed two exercise sessions on a treadmill at 70% VO 2 max in hot (35°C and 40% relative humidity) and cool (11°C and 40% relative humidity) environmental conditions. Body core temperature was measured throughout the duration of exercise. Blood samples were collected pre-exercise, post-exercise, and serially every hour for 3-h after exercise for analysis of lipopolysaccharide (LPS), tumor necrosis factor alpha (TNFa), interleukin-6 (IL-6), and hepcidin. Results were compared using a mixed model; values are presented mean±95% CI. End-exercise body core temperature was significantly elevated in the hot exercise condition compared to the cool (hot: D1.87°C; cool: D0.93 °C, p = 0.012). There were no changes in LPS concentrations at any time point. TNFa was similarly elevated in both hot and cold exercise conditions. IL-6 concentrations were elevated in both conditions immediately post-exercise, but the hot condition had a greater rise in IL-6 concentration (hot: D1.15 (1.4, 0.90; cool: D0.73 (0.90, 0.56), p = 0.01). Hepcidin concentrations were similarly elevated in both conditions after exercise, except at 3-h post-exercise, where the rise in hepcidin was greater in the hot exercise condition (hot: D7.74 ng/mL (11.78, 3.71); cool: D3.14 ng/mL (5.40, 0.88); p = 0.004). These data suggest that exercise in a hot environment evokes elevated IL-6 production, and elevated peak hepcidin concentration 3-h post-exercise compared to a cool exercise condition. Additionally, these data indicate that LPS did not change with exercise and likely does not contribute to the elevated inflammation seen post-exercise in the hot condition. Funded by the Wu Tsai Human Performance Alliance and the Joe and Clara Tsai Foundation. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.