We show here that luminal mucus from the colon and the stomach of guinea pigs, mice and humans exhibits substantial carbonic anhydrase (CA) activity, by which the velocity of the CO2 hydration reaction is accelerated 1000-2000-fold, approximately 1/10 of what is found in the red cell. Although this CA shares several properties with CA II, studies with CA II-deficient mice show that gastrointestinal mucus CA is not affected in these animals and thus does not appear to be CA II. We speculate that the mucus layer covering the luminal surface of gastrointestinal epithelium can, due to the presence of CA, maintain a normal tissue pCO(2) in the epithelium, even when the pCO(2) values in the lumen are much higher, as is known for stomach and colon. To test this hypothesis, we have developed a mathematical model which describes (a) diffusion of CO2 and HCO3- across the mucus layer and (b) H+ transport mediated by continuous secretion of mucus, which due to its high H+ buffer capacity transports H+ by convection towards the lumen. The model predicts that continuous transport of the reaction products of CO, towards the lumen, by diffusion and convection, protects the epithelium against high CO2 partial pressures in the lumen. (C) 2003 Elsevier Science Inc. All rights reserved.