Gastroenterology

Gastroenterology

Volume 133, Issue 6, December 2007, Pages 1916-1927
Gastroenterology

Basic–Alimentary Tract
Down-Regulation of the Monocarboxylate Transporter 1 Is Involved in Butyrate Deficiency During Intestinal Inflammation

Part of this work was presented in abstract form at the DDW meeting, Chicago, May 17, 2005, and published in abstract form (Gastroenterology 2005;128[Suppl 2]:A497.
https://doi.org/10.1053/j.gastro.2007.08.041Get rights and content

Background & Aims: 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-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). 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 [14C]-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-γ and TNF-α correlated with a decrease in butyrate uptake and subsequent oxidation. IFN-γ and TNF-α 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.

Section snippets

Patients and Biopsies

Colonic biopsy specimens were obtained from inflamed and noninflamed mucosa of 14 patients with CD (9 women, 5 men; mean age, 36 years; range, 21–78 years) and 9 patients with UC (4 women, 5 men; mean age, 46 years; range, 30–62 years). All patients underwent colonoscopy for an active disease. At the time of the study, 9 patients were receiving steroids; 2 patients, 5-aminosalicylic acid; 2 patients, azathioprine; 1 patient, 6-mercaptopurin plus infliximab; 1 patient, cyclosporin; and 8

MCT1 Expression Is Decreased During Intestinal Inflammation

We assessed MCT1 messenger RNA (mRNA) and protein expression in segments of rat colon with DSS-induced colitis and control rats. Western blot analysis of protein lysates showed that MCT1 protein levels were significantly lower in the cecum and proximal and distal colon of rats with DSS-induced colitis in comparison with controls (P < .01) (Figure 1A, i and ii). Similarly, reverse-transcription (RT) PCR analysis showed a significant decrease in MCT1 mRNA expression in these DSS-inflamed colonic

Discussion

Butyrate is essential to the health and integrity of the colonic mucosa, and its oxidation provides 70% of the total energy requirement of colonocytes. Previous studies in active IBD and in experimental DSS-colitis have shown that intestinal inflammation specifically affects butyrate metabolism because glucose and glutamine oxidation rates are not modified.6, 7, 9, 23 The data presented in this paper indicate that inflammation does not induce a general modification in colonocyte metabolism but

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    Supported by grants from the Ligue Nationale de Lutte contre le Cancer; the Biotechnology and Biological Sciences Research Council; and Tenovus, The Cancer Charity.

    We confirm that all of the authors have no conflicts of interest to disclose.

    1

    R.T. and P.d.C. contributed equally to this work.

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