Heavy exercise causes gut symptoms and, in extreme cases, "heat stroke" partially due to increased intestinal permeability of luminal toxins. We examined bovine colostrum, a natural source of growth factors, as a potential moderator of such effects. Twelve volunteers completed a double-blind, placebo-controlled, crossover protocol (14 days colostrum/placebo) prior to standardized exercise. Gut permeability utilized 5 h urinary lactulose-to-rhamnose ratios. In vitro studies (T84, HT29, NCM460 human colon cell lines) examined colostrum effects on temperature-induced apoptosis (active caspase-3 and 9, Baxα, Bcl-2), heat shock protein 70 (HSP70) expression and epithelial electrical resistance. In both study arms, exercise increased blood lactate, heart rate, core temperature (mean 1.4°C rise) by similar amounts. Gut hormone profiles were similar in both arms although GLP-1 levels rose following exercise in the placebo but not the colostrum arm (P = 0.026). Intestinal permeability in the placebo arm increased 2.5-fold following exercise (0.38 ± 0.012 baseline, to 0.92 ± 0.014, P < 0.01), whereas colostrum truncated rise by 80% (0.38 ± 0.012 baseline to 0.49 ± 0.017) following exercise. In vitro apoptosis increased by 47-65% in response to increasing temperature by 2°C. This effect was truncated by 60% if colostrum was present (all P < 0.01). Similar results were obtained examining epithelial resistance (colostrum truncated temperature-induced fall in resistance by 64%, P < 0.01). Colostrum increased HSP70 expression at both 37 and 39°C (P < 0.001) and was truncated by addition of an EGF receptor-neutralizing antibody. Temperature-induced increase in Baxα and reduction in Bcl-2 was partially reversed by presence of colostrum. Colostrum may have value in enhancing athletic performance and preventing heat stroke.