The role of volume-sensitive CI channels in the stimulation of chloride absorption by short-chain fatty acids in the rat colon

The short-chain fatty acids acetate, propionate and butyrate induced a concentration-dependent decrease in short-circuit current (I_sc) of the rat colon in vitro. The decrease in I_sc, being more pronounced in the distal than in the proximal colon, was dependent on the presence of CI^- ions and partly on the presence of HCO^-₃. In the distal colon, the fall in I_sc could be inhibited by amiloride, indicating that the activity of the Na⁺/H⁺ exchanger is necessary for the induction of this response. The decrease in I_sc was diminished by the CI^- channel blocker, 5-nitro-2-(3-phenylpropylamino)-benzoate, and the lipoxygenase inhibitor, nordihydroguaiaretic acid. In contrast, inhibitors of the leukotriene pathway or a CI^- channel blocker did not affect the I_sc response in the proximal colon. Measurements of unidirectional fluxes revealed that butyrate caused a stimulation of the mucosa to serosa fluxes (J_ms) of Na⁺ and CI^- in the distal, but only of j_ms^Na in the proximal colon. Unidirectional Rb⁺ fluxes were not altered. The stimulation of j_ms^cl correlated with the degree of metabolism of the short-chain fatty acid. The increase in j_ms^cl was most pronounced for butyrate, smaller for acetate and not observed with the poorly metabolizable short-chain fatty acid, isobutyrate. Consequently, two factors seem to be responsible for the stimulation of CI^- absorption by short-chain fatty acids in the distal colon: (1) the intracellular production of HCO^-₃ during the oxidation of short-chain fatty acids as substrate for the apical Cr/HCO^-₃ exchanger, and (2) the activation of volume-sensitive basolateral CI^- channels.