Abstract 26: Deletion of Slc5a8 in mice promotes metabolic syndrome, colonic inflammation, and colon cancer: A phenomenon dependent on dietary fiber content

Abstract

Abstract SLC5A8 is a candidate tumor suppressor that is silenced in colon cancer. It is a transporter that mediates concentrative entry of short-chain fatty acids (SCFAs: acetate, propionate, and butyrate) into colon cells. SCFAs are produced at high concentrations in colon by bacterial fermentation of dietary fiber (acetate, ∼60 mM; propionate, ∼20 mM; butyrate, ∼10 mM). Among SCFAs, propionate and butyrate are inhibitors of histone deacetylases (HDACs). These HDAC inhibitors induce differentiation in normal colon cells but cause apoptosis in colon cancer cells. They also suppress colonic inflammation. We postulate that the transporter is silenced in colon cancer to prevent the entry of these HDAC inhibitors into tumor cells. We have demonstrated the tumor-suppressive function of SLC5A8 in vitro in colon cancer cells and hence hypothesized that deletion of Slc5a8 in mice would promote inflammation and cancer in colon. Surprisingly however, there was no difference between wild type (WT) mice and Slc5a8-null (KO) mice in progression of colonic inflammation and colon cancer in experimental model systems when mice were fed optimal dietary fiber. SLC5A8 transports butyrate and propionate with a Michaelis constant of ∼0.05 mM; under in vivo conditions where butyrate and propionate are present at >10 mM in colon, the transporter plays only a minor role in the entry of these compounds into colon cells. At high concentrations, they diffuse into cells bypassing the transporter. As such we postulated that Slc5a8-null mice would have enhanced colonic inflammation and colon cancer only under low-fiber dietary conditions where butyrate/propionate concentrations in colon are low enough that the transporter is obligatory for their entry into colon cells. To test this hypothesis, we maintained WT and KO mice with a low-fiber diet starting at 4-weeks of age. We found that, under these conditions, the KO mice gained more weight than WT mice, became obese with increased abdominal fat, and exhibited hyperglycemia. When dextran sulfate sodium was administered in drinking water (2% for 1 week), KO mice died from severe colonic inflammation whereas WT mice were able to withstand the treatment and did not die. We then examined the incidence of colon cancer in these mice by crossing them with ApcMin/+ mouse. Under optimal dietary fiber conditions, there was no difference between Slc5a8+/+/ApcMin/+ mice and Slc5a8-/-/ApcMin/+ mice in the incidence of colon cancer. But, under low-fiber dietary conditions, the incidence of colon cancer was much higher in Slc5a8-/-/ApcMin/+ mice than in Slc5a8+/+/ApcMin/+ mice. These studies show that Slc5a8 indeed functions as a tumor suppressor in colon in vivo, but only if dietary fiber content is low. In addition, under these dietary conditions, Slc5a8 also protects against metabolic syndrome and colonic inflammation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 26. doi:1538-7445.AM2012-26