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

Resta-Lenert, Silvia, Francis Truong, Kim E. Barrett, and Lars Eckmann. Inhibition of epithelial chloride secretion by butyrate: role of reduced adenylyl cyclase expression and activity. Am J Physiol Cell Physiol 281: C1837-C1849, 2001.--Butyrate and other short-chain fatty acids (SCFAs) are found at high concentrations in the colonic lumen and affect multiple epithelial cell functions. To better understand how SCFAs regulate ion transport, we investigated the effects of SCFAs on [Cl.sup.-] secretion in human colonic epithelial cell line [T.sub.84] Butyrate inhibited [Cl.sup.-] secretory responses to prostaglandin [E.sub.2], forskolin, and cholera toxin. Other SCFAs were less effective or inactive. Reduced secretion was associated with decreased synthesis of the second messenger cAMP rather than increased degradation. Expression and activity of adenylyl cyclase were decreased by butyrate, whereas phosphodiesterase activity was unaffected and phosphodiesterase inhibition did not reverse the effects of butyrate on [Cl.sub.-] secretion. Furthermore, butyrate decreased expression of the basolateral Na-K-2C1 cotrans-porter indicating that it might modulate the secretory capacity of the cells. However, butyrate did not affect secretory responses to the calcium-dependent secretagogue carbachol, cAMP analogs, or uroguanylin, indicating that normal secretory responses to adequate levels of second messengers in butyrate-treated [T.sup.84] cells are possible. These results show that butyrate affects several aspects of epithelial [Cl.sup.-] secretion, including second messenger generation and expression of key ion transporters. However, these effects may not all be equally important in determining [Cl.sup.-] secretion in response to physiologically relevant secretagogues. intestinal epithelial cells; short-chain fatty acids, ion transport Received 21 September 2000; accepted in final form 15 August 2001