Short-chain fatty acids (SCFA), acetate, propionate, and butyrate, are produced by bacterial fermentation in the colon and stimulate Na+ and Cl- absorption. We have studied the effects of SCFA on fluid and electrolyte absorption during cholera toxin (CT) -induced colonic secretion in rabbit, using a steady-state perfusion technique with marker (PEG) dilution. Perfusion with SCFA significantly (P < 0.01) reduced colonic water secretion. Butyrate reduced water secretion the most (95%), followed by propionate (90%), and acetate (80%). Butyrate significantly (P < 0.001) reduced secretions of Na+ (95.5%), K+ (75.2%), and Cl-(80.7%) ions but not HCO3- ions. Propionate similarly reduced secretion of HCO3-(45.3%). Acetate significantly (P < 0.001) inhibited Na+ (76.4%) and Cl- (75.7%) secretion, but the inhibitions of K+ (23.6%) and HCO3 (28.8%) were not significantly different from the controls. We conclude that SCFA reduce CT-induced water and electrolyte secretion in the rabbit proximal colon, and its potential as an antidiarrheal agent should be further evaluated.