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Despite considerable advances in our understanding of the inflammatory bowel diseases, the aetiology of ulcerative colitis remains unclear. Crohn's disease, which is characterised by transmural inflammation involving the small bowel and/or colon, is believed to result from defective innate immune recognition of luminal bacteria in a genetically predisposed individual. 1 In ulcerative colitis, where inflammation is restricted to the mucosa of the colon, it has been suggested that a primary defect in the colonic epithelium resulting in the increased absorption of pro-inflammatory molecules from the colonic lumen may underlie the development of disease. 2 3 Defective colonic epithelial oxidation of butyrate in ulcerative colitis, first demonstrated by Roediger 4 and confirmed by other investigators, 5 6 has been implicated in the pathogenesis of ulcerative colitis. Butyrate, a short-chain fatty acid, is formed from the bacterial fermentation of unabsorbed carbohydrates in the colonic lumen. It undergoes oxidative metabolism in the mitochondria of colonic epithelial cells to CO 2 and ketone bodies and is the major source of energy, providing >70% of the energy requirements 7 for the colonic epithelium, which cannot effectively utilise glucose as energy substrate. 4 Colonocyte butyrate metabolism was defective in an animal model of colitis. 8 Inhibition of butyrate oxidation in experimental animals resulted in mucosal inflammation similar to ulcerative colitis. 9 Decreased ATP levels are evident in mucosa from ulcerative colitis patients. 10 Diversion colitis occurring in the colon surgically excluded from the faecal stream, and therefore a model of butyrate deficiency, is successfully treated by the rectal infusion of butyrate and other short-chain fatty acids. 11 Thus, impaired butyrate oxidation is associated with the development of colitis in a variety of situations.
Oxidation of butyrate is carried out in mitochondria by a series of five enzymes ( fig 1 ). An earlier study, which examined all these enzymes, failed to demonstrate any significant alteration in these enzymes in quiescent ulcerative colitis. 12 Mitochondrial acetoacetyl coenzyme A (CoA) thiolase (EC 2.3.1.9) catalyses the last step in butyrate oxidation to acetyl CoA. In addition to being present in mitochondria, there is a second isoform of this enzyme in the cytosol, which is principally involved in cholesterol biosynthesis as well as ketone body synthesis. 13 The two isoforms can be distinguished biochemically...