Butyrate Increases GLUT2 mRNA Abundance by Initiating Transcription in Caco2-BBe Cells

Background: Glucose transporter 2 (GLUT2) is a high-capacity, facilitative intestinal monosaccharide transporter, known to be upregulated by short-chain fatty acids (SCFAs) derived from the intestinal microbiota during fermentation. Understanding the mechanisms regulating intestinal function is important to optimize therapies for patients with intestinal failure and ultimately reduce their dependence on parenteral nutrition. Objective: The objective was to examine the mechanism regulating the underlying response of GLUT2 to the SCFA butyrate. Methods: GLUT2 messenger RNA (mRNA) abundance was measured in differentiated Caco2-BBe monolayers treated for 0.5-24 hours with 0-20 mM butyrate using quantitative reverse transcription–polymerase chain reaction. Activation of the human GLUT2 promoter was measured using luciferase reporting in transiently transfected Caco2-BBe monolayers. Results: GLUT2 mRNA abundance was higher (P < .0001) with 1-4 hours of exposure to 2.5, 7.5, and 10 mM butyrate. Butyrate induced (P < .0001) promoter activity in a dose-dependent fashion. Analysis of the GLUT2 promoter indicated that regions– 282/+522, –216/+522, and –145/+522 had a heightened (P < .05) response to butyrate compared with 1135/+522 and 564/+522. Conclusions: Butyrate upregulates GLUT2 mRNA abundance in Caco2-BBe monolayers by activating specific regions within the human GLUT2 promoter. These results identify a cellular mechanism wherein butyrate upregulates intestinal absorption that may be relevant to patients with reduced function. Additional work is necessary to understand cellular targets of butyrate therapy and define clinically appropriate means of providing such strategies, such as consuming prebiotics and probiotics.