Impact of dietary berberine supplementation on heat shock, inflammatory, and apoptotic responses to exercise-heat stress

Prolonged work or exercise in hot ambient conditions increases core temperature and reduces total body water, causing cardiovascular strain that promotes hepatosplanchnic shunting and gastrointestinal barrier damage. This allows gram-negative bacteria to translocate from the gut into circulation, increasing circulating concentrations of lipopolysaccharide (LPS) and activating NF-κB mediated pro-inflammatory cascades that increase the likelihood of exertional heat illness. Berberine is a plant-derived isoquinoline quaternary alkaloid that has been shown to improve gastrointestinal barrier function and inhibit the lipopolysaccharide (LPS) mediated pro-inflammatory cytokine response across multiple animal models. PURPOSE: To determine if one week of 1.5g/day dietary berberine supplementation alters heat shock, inflammatory, and apoptotic responses in peripheral blood mononuclear cells (PBMC) during prolonged exercise-heat stress. To do so, we tested the hypothesis that berberine would reduce the heat shock and inflammatory responses to exercise stress in human subjects, as has been shown previously during passive heat exposure in animal models. METHODS: Eight recreationally active participants (6 men and 2 women; Age: 23±3 years, Stature: 1.75±0.03 m, Mass: 71.8±2.7 kg, VO2max: 57.5±2.1 mL/kg FFM/min) ingested 1.5 g of Berberine or Placebo for 7d prior to a 1hr treadmill run (60% VO2max) in hot (35°C) and moderately humid (39% RH) conditions. Blood samples were collected before (Pre), immediately after (Post), 1h after (1-Post), and 3h after (3-Post) exercise. Heat shock proteins (HSP90, HSP70, HSP60, HSP32) and protein markers of inflammatory capacity (TLR4, IκBα, pNF-κB, NF-κB, pNF-κB/NF-κB Granzyme K) and apoptosis (BAX, BCL-2, BAX/BCL-2) were measured in PBMC. RESULTS: There was an interaction effect for HSP90 wherein HSP90 was reduced at Post in Berberine (-31%; p=0.03) but had returned to Pre values by 1-Post exercise. Whereas in PLACEBO HSP90 content was reduced at 1-Post (-34%; p= 0.013) and remained lower at 3-Post exercise (-32%; p= 0.017). There was a significant main effect of time for HSP60 where HSP60 was reduced below Pre at Post (-43%; p=0.001) and 3-Post exercise (-39%; p=0.003). There was a significant main effect of time for NF-κB which was reduced at Post exercise (-33%; p=0.007). There was an interaction effect for IκBα wherein IκBα was reduced at Post (-29%; p=0.02) and 1-Post-exercise in Berberine (-49%; p=0.04). Whereas in PLACEBO IκBα content was elevated above Pre at 3-Post exercise (+48%; p= 0.013). There was a significant main effect of time for Granzyme K, where Granzyme K was reduced below Pre at 1-Post exercise (-48%; p=0.008). There was a significant main effect of Condition for BCL-2, which was 27% lower with Berberine supplementation (p = 0.044). There was a significant main effect of time for BAX/BCL-2, wherein BAX/BCL-2, was elevated above Pre at 1-Post exercise (+160%; p< 0.001). There were no main or interaction effects for HSP70, HSP32, TLR-4, pNF-κB, or BAX. CONCLUSION: One week of 1.5g/day dietary berberine supplementation increased HSP90 and reduced IκBα and BCL-2 content in PBMC. These data suggest berberine does not reduce stress responses in PBMC during challenging exercise in the heat. This abstract was presented at the American Physiology Summit 2026 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.