The intracellular target of butyrate's actions: HDAC or HDON'T?

The intracellular target of butyrate's actions: HDAC or HDON'T? Butyrate, the four-carbon short chain fatty acid, has special significance for clinicians and scientists interested in large bowel physiology. It is normally present in the colonic lumen at millimolar concentrations as a product of bacterial fermentation of luminal carbohydrates and is readily taken up by the colonic epithelium to be used as a major energy source via-oxidation. Butyrate aVects key functions of the colonic epithelium in vivo or at least in vitro in models of the colonic epithelium. These functions include promotion of sodium and water absorption, improvement of tight junction permeability, and acceleration of epithelial restitution. Thus, butyrate plays an important role in the maintenance of colonic mucosal health. Butyrate has also been implicated in the pathogenesis of colonic diseases, especially colorectal cancer and ulcerative colitis. Butyrate's role in the pathogenesis of ulcerative colitis has been a fascinating saga. In 1981, Roediger first reported that epithelial cells isolated from the rectum of patients with ulcerative colitis exhibited impaired-oxidation of butyrate. 1 His " energy-deficiency " hypothesis created more attention when diversion colitis, which may histologically resemble ulcerative colitis, was shown to be largely caused by a deficient supply of short chain fatty acids in the lumen. 2 Whether a defect in-oxidation has specificity for ulcerative colitis and indeed whether it is more than an in vitro artefact have been questioned, but attempts to resolve these issues have not really succeeded. The report by Ahmad et al (see page 493), in which deficient-oxidation of colonic epithelial cells identical to that in ulcerative colitis was shown also to occur in dextran sulphate induced colitis in mice, rekindles debate about this issue. The recent profusion of models of colitis in animals deficient in key immune molecules has tended to draw attention away from the potential primary role of the colonic epithelium in ulcerative colitis. In none of these models, however, do the alterations in crypt architecture at all resemble those that characterise ulcerative colitis. Only models induced by epithelial injury, especially dextran sul-phate induced colitis, mimic the shortened and branched crypts of ulcerative colitis, in contrast to the hypertrophic, straight crypts observed in the immune models. We now need information about the metabolic characteristics of the colonic epithelial cells in immune based models of colitis to determine whether the metabolic abnormalities in epithe-lial cells are indeed secondary to inflammation itself or are specific …