Down-regulation of the monocarboxylate transporter 1 is involved in butyrate deficiency during intestinal inflammation.
OBJECTIVE
Butyrate oxidation is impaired in intestinal mucosa of patients with inflammatory bowel diseases (IBD). Butyrate uptake by colonocytes involves the monocarboxylate transporter (MCT) 1. We aimed to investigate the role of MCT1 in butyrate oxidation deficiency during colonic inflammation.


METHODS
Colonic tissues were collected from patients with IBD or healthy controls and from rats with dextran sulfate sodium (DSS)-induced colitis. The intestinal epithelial cell line HT-29 was treated with interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). MCT1 expression was analyzed by real-time reverse-transcription polymerase chain reaction, Western blot, and immunofluorescence. Butyrate uptake and oxidation in HT-29 cells was assessed using [(14)C]-butyrate. The mechanism of MCT1 gene regulation was analyzed by nuclear run-on and reporter gene assays.


RESULTS
MCT1 messenger RNA (mRNA) and protein levels were markedly decreased in inflamed colonic mucosa of IBD patients and rats. In HT-29 cells, down-regulation of MCT1 mRNA and protein abundance by IFN-gamma and TNF-alpha correlated with a decrease in butyrate uptake and subsequent oxidation. IFN-gamma and TNF-alpha did not affect MCT1 mRNA stability but rather down-regulated gene transcription. We demonstrate that the cytokine response element is located in the proximal -111/+213 core region of the MCT1 promoter.


CONCLUSIONS
The data suggest that butyrate oxidation deficiency in intestinal inflammation is a consequence of reduction in MCT1-mediated butyrate uptake. This reinforces the proposition that butyrate oxidation deficiency in IBD is not a primary defect.
Thibault
Ronan
R
UMR 1280 Physiologie des Adaptations Nutritionnelles, INRA, Université de Nantes, Nantes, France.
De Coppet
Pierre
P
Daly
Kristian
K
Bourreille
Arnaud
A
Cuff
Mark
M
Bonnet
Christian
C
Mosnier
Jean-François
JF
Galmiche
Jean-Paul
JP
Shirazi-Beechey
Soraya
S
Segain
Jean-Pierre
JP
D000328:Adult; D000368:Aged; D000818:Animals; D002087:Butyrates / Q000378:metabolism*; D002478:Cells, Cultured; D003092:Colitis / Q000276:immunology; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D015870:Gene Expression; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology; D008297:Male; D008875:Middle Aged; D027501:Monocarboxylic Acid Transporters / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology*; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D027981:Symporters / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology*; D000099233:Monocarboxylate Transport Protein 1
D002087:Butyrates; D027501:Monocarboxylic Acid Transporters; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1