Inhibition of epithelial chloride secretion by butyrate: role of reduced adenylyl cyclase expression and activity

Butyrate andother short-chain fatty acids (SCFAs) are found at high concentrationsin the colonic lumen and affect multiple epithelial cell functions. Tobetter understand how SCFAs regulate ion transport, we investigated theeffects of SCFAs on Cl secretion in human colonicepithelial cell line T₈₄. Butyrate inhibitedCl secretory responses to prostaglandin E₂,forskolin, and cholera toxin. Other SCFAs were less effective orinactive. Reduced secretion was associated with decreased synthesis ofthe second messenger cAMP rather than increased degradation. Expressionand activity of adenylyl cyclase were decreased by butyrate, whereasphosphodiesterase activity was unaffected and phosphodiesteraseinhibition did not reverse the effects of butyrate on Clsecretion. Furthermore, butyrate decreased expression of the basolateral Na-K-2Cl cotransporter, indicating that it might modulate the secretory capacity of the cells. However, butyrate did not affectsecretory responses to the calcium-dependent secretagogue carbachol,cAMP analogs, or uroguanylin, indicating that normal secretoryresponses to adequate levels of second messengers in butyrate-treatedT₈₄ cells are possible. These results show that butyrateaffects several aspects of epithelial Cl secretion,including second messenger generation and expression of key iontransporters. However, these effects may not all be equally importantin determining Cl secretion in response tophysiologically relevant secretagogues.