Impaired butyrate oxidation in ulcerative colitis is due to decreased butyrate uptake and a defect in the oxidation pathway†
Vicky De Preter PhD
Translational Research Center for Gastrointestinal Disorders (TARGID) and Leuven Food Science and Nutrition Research Centre (LFoRCe), University Hospital Gasthuisberg, K.U. Leuven, Leuven, Belgium
Search for more papers by this authorIngrid Arijs PhD
Translational Research Center for Gastrointestinal Disorders (TARGID) and Leuven Food Science and Nutrition Research Centre (LFoRCe), University Hospital Gasthuisberg, K.U. Leuven, Leuven, Belgium
Gene Expression Unit, Department of Molecular Cell Biology, K.U. Leuven, Leuven, Belgium
Search for more papers by this authorKaren Windey MSc
Translational Research Center for Gastrointestinal Disorders (TARGID) and Leuven Food Science and Nutrition Research Centre (LFoRCe), University Hospital Gasthuisberg, K.U. Leuven, Leuven, Belgium
Search for more papers by this authorWiebe Vanhove BSc
Gene Expression Unit, Department of Molecular Cell Biology, K.U. Leuven, Leuven, Belgium
Search for more papers by this authorSeverine Vermeire MD, PhD
Translational Research Center for Gastrointestinal Disorders (TARGID) and Leuven Food Science and Nutrition Research Centre (LFoRCe), University Hospital Gasthuisberg, K.U. Leuven, Leuven, Belgium
Search for more papers by this authorFrans Schuit PhD
Gene Expression Unit, Department of Molecular Cell Biology, K.U. Leuven, Leuven, Belgium
Search for more papers by this authorPaul Rutgeerts MD, PhD
Translational Research Center for Gastrointestinal Disorders (TARGID) and Leuven Food Science and Nutrition Research Centre (LFoRCe), University Hospital Gasthuisberg, K.U. Leuven, Leuven, Belgium
Search for more papers by this authorCorresponding Author
Kristin Verbeke PhD
Translational Research Center for Gastrointestinal Disorders (TARGID) and Leuven Food Science and Nutrition Research Centre (LFoRCe), University Hospital Gasthuisberg, K.U. Leuven, Leuven, Belgium
Translational Research Center for Gastrointestinal Disorders (TARGID), O&N 1, box 701, Herestraat 49, 3000 Leuven, BelgiumSearch for more papers by this authorVicky De Preter PhD
Translational Research Center for Gastrointestinal Disorders (TARGID) and Leuven Food Science and Nutrition Research Centre (LFoRCe), University Hospital Gasthuisberg, K.U. Leuven, Leuven, Belgium
Search for more papers by this authorIngrid Arijs PhD
Translational Research Center for Gastrointestinal Disorders (TARGID) and Leuven Food Science and Nutrition Research Centre (LFoRCe), University Hospital Gasthuisberg, K.U. Leuven, Leuven, Belgium
Gene Expression Unit, Department of Molecular Cell Biology, K.U. Leuven, Leuven, Belgium
Search for more papers by this authorKaren Windey MSc
Translational Research Center for Gastrointestinal Disorders (TARGID) and Leuven Food Science and Nutrition Research Centre (LFoRCe), University Hospital Gasthuisberg, K.U. Leuven, Leuven, Belgium
Search for more papers by this authorWiebe Vanhove BSc
Gene Expression Unit, Department of Molecular Cell Biology, K.U. Leuven, Leuven, Belgium
Search for more papers by this authorSeverine Vermeire MD, PhD
Translational Research Center for Gastrointestinal Disorders (TARGID) and Leuven Food Science and Nutrition Research Centre (LFoRCe), University Hospital Gasthuisberg, K.U. Leuven, Leuven, Belgium
Search for more papers by this authorFrans Schuit PhD
Gene Expression Unit, Department of Molecular Cell Biology, K.U. Leuven, Leuven, Belgium
Search for more papers by this authorPaul Rutgeerts MD, PhD
Translational Research Center for Gastrointestinal Disorders (TARGID) and Leuven Food Science and Nutrition Research Centre (LFoRCe), University Hospital Gasthuisberg, K.U. Leuven, Leuven, Belgium
Search for more papers by this authorCorresponding Author
Kristin Verbeke PhD
Translational Research Center for Gastrointestinal Disorders (TARGID) and Leuven Food Science and Nutrition Research Centre (LFoRCe), University Hospital Gasthuisberg, K.U. Leuven, Leuven, Belgium
Translational Research Center for Gastrointestinal Disorders (TARGID), O&N 1, box 701, Herestraat 49, 3000 Leuven, BelgiumSearch for more papers by this authorSupported by a grant from the Fund for Scientific Research-Flanders (F.W.O. Vlaanderen) Belgium (FWO project nr. G.0600.09). V.D.P., I.A., and S.V. are postdoctoral fellows from the Fund for Scientific Research – Flanders.
Abstract
Background:
In ulcerative colitis (UC) butyrate metabolism is impaired due to a defect in the butyrate oxidation pathway and/or transport. In the present study we correlated butyrate uptake and oxidation to the gene expression of the butyrate transporter SLC16A1 and the enzymes involved in butyrate oxidation (ACSM3, ACADS, ECHS1, HSD17B10, and ACAT2) in UC and controls.
Methods:
Colonic mucosal biopsies were collected during endoscopy of 88 UC patients and 20 controls with normal colonoscopy. Butyrate uptake and oxidation was measured by incubating biopsies with 14C-labeled Na-butyrate. To assess gene expression, total RNA from biopsies was used for quantitative reverse-transcription polymerase chain reaction (qRT-PCR). In 20 UC patients, gene expression was reassessed after treatment with infliximab.
Results:
Butyrate uptake and oxidation were significantly decreased in UC versus controls (P < 0.001 for both). Butyrate oxidation remained significantly reduced in UC after correction for butyrate uptake (P < 0.001), suggesting that the butyrate oxidation pathway itself is also affected. Also, the mucosal gene expression of SLC16A1, ACSM3, ACADS, ECHS1, HSD17B10, and ACAT2 was significantly decreased in UC as compared with controls (P < 0.001 for all). In a subgroup of patients (n = 20), the gene expression was reassessed after infliximab therapy. In responders to therapy, a significant increase in gene expression was observed. Nevertheless, only ACSM3 mRNA levels returned to control values after therapy in the responders groups.
Conclusions:
The deficiency in the colonic butyrate metabolism in UC is initiated at the gene expression level and is the result of a decreased expression of SLC16A1 and enzymes in the β-oxidation pathway of butyrate. (Inflamm Bowel Dis 2012;)
Supporting Information
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REFERENCES
- 1 Mortensen PB, Clausen MR. Short-chain fatty acids in the human colon: relation to gastrointestinal health and disease. Scand J Gastroenterol Suppl. 1996; 216: 132–148.
- 2 Vanhoutvin SA, Troost FJ, Hamer HM, et al. Butyrate-induced transcriptional changes in human colonic mucosa. PLoS One. 2009; 4: e6759.
- 3 Segain JP, de la Bletiere DR, Bourreille A, et al. Butyrate inhibits inflammatory responses through NF kappa B inhibition: implications for Crohn's disease. Gut. 2000; 47: 397–403.
- 4 Roediger WEW. Role of anaerobic-bacteria in the metabolic welfare of the colonic mucosa in Man. Gut. 1980; 21: 793–798.
- 5 Ahmad MS, Krishnan S, Ramakrishna BS, et al. Butyrate and glucose metabolism by colonocytes in experimental colitis in mice. Gut. 2000; 46: 493–499.
- 6 De Preter V, Bulteel V, Suenaert P, et al. Pouchitis, similar to active ulcerative colitis, is associated with impaired butyrate oxidation by intestinal mucosa. Inflamm Bowel Dis. 2009; 15: 335–340.
- 7 Den Hond E, Hiele M, Evenepoel P, et al. In vivo butyrate metabolism and colonic permeability in extensive ulcerative colitis. Gastroenterology. 1998; 115: 584–590.
- 8 Kato K, Ishii Y, Mizuno S, et al. Usefulness of rectally administering [1(_13)C]-butyrate for breath test in patients with active and quiescent ulcerative colitis. Scand J Gastroenterol. 2007; 42: 207–214.
- 9 Chapman MAS, Grahn MF, Boyle MA, et al. Butyrate oxidation is impaired in the colonic mucosa of sufferers of quiescent ulcerative-colitis. Gut. 1994; 35: 73–76.
- 10 Duffy MM, Regan MC, Ravichandran P, et al. Mucosal metabolism in ulcerative colitis and Crohn's disease. Dis Colon Rectum. 1998; 41: 1399–1405.
- 11 Thibault R, Blachier F, Darcy-Vrillon B, et al. Butyrate utilization by the colonic mucosa in inflammatory bowel diseases: a transport deficiency. Inflamm Bowel Dis. 2010; 16: 684–695.
- 12 Vernia P, Caprilli R, Latella G, et al. Fecal lactate and ulcerative-colitis. Gastroenterology. 1988; 95: 1564–1568.
- 13 Hove H, Mortensen PB. Influence of intestinal inflammation (IBD) and small and large bowel length on fecal short-chain fatty acids and lactate. Dig Dis Sci. 1995; 40: 1372–1380.
- 14 Thibault R, De Coppet P, Daly K, et al. Down-regulation of the monocarboxylate transporter 1 is involved in butyrate deficiency during intestinal inflammation. Gastroenterology. 2007; 133: 1916–1927.
- 15 Santhanam S, Venkatraman A, Ramakrishna BS. Impairment of mitochondrial acetoacetyl CoA thiolase activity in the colonic mucosa of patients with ulcerative colitis. Gut. 2007; 56: 1543–1549.
- 16 Allan ES, Winter S, Light AM, et al. Mucosal enzyme activity for butyrate oxidation; no defect in patients with ulcerative colitis. Gut. 1996; 38: 886–893.
- 17 Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative-colitis—a randomized study. N Engl J Med. 1987; 317: 1625–1629.
- 18 Geboes K, Riddell R, Ost A, et al. A reproducible grading scale for histological assessment of inflammation in ulcerative colitis. Gut. 2000; 47: 404–409.
- 19 Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005; 353: 2462–2476.
- 20 Arijs I, Li K, Toedter G, et al. Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis. Gut. 2009; 58: 1612–1619.
- 21 Finnie IA, Taylor BA, Rhodes JM. Ileal and colonic epithelial metabolism in quiescent ulcerative-colitis — increased glutamine-metabolism in distal colon but no defect in butyrate metabolism. Gut. 1993; 34: 1552–1558.
- 22 Hadjiagapiou C, Schmidt L, Dudeja PK, et al. Mechanism(s) of butyrate transport in Caco-2 cells: role of monocarboxylate transporter 1. Am J Physiol Gastrointest Liver Physiol. 2000; 279: G775–G780.
- 23
Franke E-R,
Weniger JH.
Der Stickstoff, Kohlenstoff, und Energiegehalt des Fleisches und der Warmewert des Fettes verschiedener Nutztierarten.
Arch Tierernähr.
1958;
8:
81–94.
10.1080/17450395809424770 Google Scholar
- 24 Zilbauer M, Jenke A, Wenzel G, et al. Intestinal alpha-defensin expression in pediatric inflammatory bowel disease. Inflamm Bowel Dis. 2010;.
- 25 Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001; 29: e45.
- 26 Hamer HM, Jonkers D, Venema K, et al. Review article: the role of butyrate on colonic function. Aliment Pharmacol Ther. 2008; 27: 104–119.
- 27 Davie JR. Inhibition of histone deacetylase activity by butyrate. J Nutr. 2003; 133: 2485S–2493S.
- 28 Place RF, Noonan EJ, Giardina C. HDAC inhibition prevents NF-kappa B activation by suppressing proteasome activity: down-regulation of proteasome subunit expression stabilizes I kappa B alpha. Biochem Pharmacol. 2005; 70: 394–406.
- 29 Sartor RB. Microbial influences in inflammatory bowel diseases. Gastroenterology. 2008; 134: 577–594.
- 30 Marchesi JR, Holmes E, Khan F, et al. Rapid and noninvasive metabonomic characterization of inflammatory bowel disease. J Proteome Res. 2007; 6: 546–551.
- 31 Sokol H, Seksik P, Furet JP, et al. Low counts of Faecalibacterium prausnitzii in colitis microbiota. Inflamm Bowel Dis. 2009; 15: 1183–1189.
- 32 De Preter V, Geboes KP, Bulteel V, et al. Kinetics of butyrate metabolism in the normal colon and in ulcerative colitis: the effects of substrate concentration and carnitine on the beta-oxidation pathway. Aliment Pharmacol Ther. 2011; 34: 526–532.
- 33 Harig JM, Soergel KH, Komorowski RA, et al. Treatment of diversion colitis with short-chain-fatty acid irrigation. N Engl J Med. 1989; 320: 23–28.
- 34 Jorgensen J, Mortensen PB. Substrate utilization by intestinal mucosal tissue strips from patients with inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol. 2001; 281: G405–G411.
- 35 Simpson EJ, Chapman MAS, Dawson J, et al. In vivo measurement of colonic butyrate metabolism in patients with quiescent ulcerative colitis. Gut. 2000; 46: 73–77.
- 36 Roediger WEW. The colonic epithelium in ulcerative-colitis — an energy-deficiency disease. Lancet. 1980; 2: 712–715.
- 37 Reimund JM, Wittersheim C, Dumont S, et al. Increased production of tumour necrosis factor-alpha interleukin-1 beta, and interleukin-6 by morphologically normal intestinal biopsies from patients with Crohn's disease. Gut. 1996; 39: 684–689.
- 38 Thibault R, Blachier F, Darcy-Vrillon B, et al. Butyrate utilization by the colonic mucosa in inflammatory bowel diseases: a transport deficiency. Inflamm Bowel Dis. 2010; 16: 684–695.
- 39 Nancey S, Moussata D, Graber I, et al. Tumor necrosis factor alpha reduces butyrate oxidation in vitro in human colonic mucosa: a link from inflammatory process to mucosal damage? Inflamm Bowel Dis. 2005; 11: 559–566.
- 40 Danese S. Mechanisms of action of infliximab in inflammatory bowel disease: an anti-inflammatory multitasker. Dig Liver Dis. 2008; 40( Suppl 2): S225–S228.
- 41 Izutani R, Loh EY, Reinecker HC, et al. Increased expression of interleukin-8 mRNA in ulcerative colitis and Crohn's disease mucosa and epithelial cells. Inflamm Bowel Dis. 1995; 1: 37–47.
- 42 Arijs I, De Hertogh G., Machiels K, et al. Mucosal gene expression of cell adhesion molecules, chemokines, and chemokine receptors in patients with inflammatory bowel disease before and after infliximab treatment. Am J Gastroenterol. 2011; 106: 748–761.
- 43 Banks C, Bateman A, Payne R, et al. Chemokine expression in IBD. Mucosal chemokine expression is unselectively increased in both ulcerative colitis and Crohn's disease. J Pathol. 2003; 199: 28–35.
- 44 Arijs I, De Hertogh G., Lemaire K, et al. Mucosal gene expression of antimicrobial peptides in inflammatory bowel disease before and after first infliximab treatment. PLoS One. 2009; 4: e7984.
- 45 Barnett MP, McNabb WC, Cookson AL, et al. Changes in colon gene expression associated with increased colon inflammation in interleukin-10 gene-deficient mice inoculated with Enterococcus species. BMC Immunol. 2010; 11: 39.
- 46 Hansen JJ, Holt L, Sartor RB. Gene expression patterns in experimental colitis in IL-10-deficient mice. Inflamm Bowel Dis. 2009; 15: 890–899.
