ORIGINAL ARTICLE Impaired Butyrate Oxidation in Ulcerative Colitis Is Due to Decreased Butyrate Uptake and a Defect in the Oxidation Pathway Vicky De Preter, PhD,* Ingrid Arijs, PhD,* ,† Karen Windey, MSc,* Wiebe Vanhove, BSc, † Severine Vermeire, MD, PhD,* Frans Schuit, PhD, † Paul Rutgeerts, MD, PhD,* and Kristin Verbeke, PhD* 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 14 C-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 com- pared with controls (P < 0.001 for all). In a subgroup of patients (n ¼ 20), the gene expression was reassessed after infliximab therapy. In res- ponders 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 b-oxidation pathway of butyrate. (Inflamm Bowel Dis 2012;18:1127–1136) Key Words: ulcerative colitis, butyrate, gene expression F ermentative breakdown of undigested dietary and endoge- nous carbohydrates results in the production of short-chain fatty acids (SCFA) comprising acetate, propionate, and butyr- ate. SCFA are essential for the metabolism of colonic epithe- lial cells and for the maintenance of normal colonic function. Particularly, butyrate has important physiological effects on the colonic mucosa, including stimulation of mucous secre- tion, increase of vascular flow, motility, and sodium and water absorption. 1 It also affects gene expression of the colo- nic mucosa 2 and reduces inflammation mainly by inhibition of nuclear factor kappaB (NF-jB) activation. 3 Butyrate is considered the major energy source for the colonic mucosa. It is oxidized through the fatty acid b-oxida- tion and tricarboxylic acid cycle pathways in the mitochon- dria, which provides up to 70% of the energetic needs. 4 Evi- dence from in vitro (isolated colonocytes and biopsies) and in vivo (animal models and human) studies 5–10 indicates that bu- tyrate oxidation is impaired in the colonic mucosa of patients with ulcerative colitis (UC). UC is an inflammatory bowel disease (IBD) of yet unknown etiology, but is likely to result from an inadequate response of the mucosal immune system to the commensal intestinal microbiota in genetically suscepti- ble subjects. Inhibition of butyrate oxidation induces an energy-deficient state ultimately resulting in reduced absorp- tion of sodium, reduced secretion of mucin, and a shorter life of the colonocytes. Additional Supporting Information may be found in the online version of this article. Received for publication August 8, 2011; Accepted August 17, 2011. From the *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. Supported 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. Reprints: Kristin Verbeke, PhD, Translational Research Center for Gastrointestinal Disorders (TARGID), O&N 1, box 701, Herestraat 49, 3000 Leuven, Belgium (e-mail: Kristin.Verbeke@med.kuleuven.be). Copyright V C 2011 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1002/ibd.21894 Published online 10 October 2011 in Wiley Online Library (wileyonlinelibrary. com). Inflamm Bowel Dis  Volume 18, Number 6, June 2012 1127