Butyrate Inhibits Deoxycholic-Acid-Resistant Colonic Cell Proliferation via Cell Cycle Arrest and Apoptosis: A Potential Pathway Linking Dietary Fiber to Cancer Prevention

Abstract

Scope: Butyrate, an intestinal microbiota metabolite of dietary fiber, exhibits colon cancer preventive effects. In contrast, a high fat intake increases fecal secondary bile acids, such as deoxycholic acid (DCA, a potential cancer promoter), which selectively enrich mutant epithelial cells with an abnormally high resistance to DCA-induced apoptosis in the colon. This study is conducted to test the hypothesis that physiological concentrations of butyrate inhibit DCA-resistant colonic cell proliferation.

Methods and results: With human HCT-116 cells as parental colonic cells, a human DCA-resistant colonic cell line (DCA-RCL) is developed. DCA treatment increases apoptosis and intracellular reactive oxygen species (an apoptotic trigger) at a rate threefold greater in HCT-116 cells than in DCA-RCL cells. Subsequently, 41 apoptosis related genes (including signaling pathways) with greater than onefold (mRNA) change in DCA-RCL cells are identified compared with HCT-116 cells. Moreover, butyrate treatment inhibits DCA-RCL cell proliferation with similar efficacy when compared with HCT116 cells via cellular myelocytomatosis oncogene (c-Myc)/p38 mitogen-activated protein kinase pathway.

Conclusion: It is demonstrated that butyrate inhibits DCA-RCL cell proliferation at the cellular and molecular level. These data provide a proof of concept that butyrate can protect against colon carcinogenesis through a specific targeting of DCA-resistant colonic cells.

Keywords: apoptosis; butyrate; cell cycle; colon cancer; deoxycholic acid.