BACKGROUND It is well established that the colonic mucosa is highly dependent upon the luminal presentation of nutrients. This dependence is most marked in the distal colon. The major luminal nutrients are short chain fatty acids (SCFA) that are produced as a by-product of colonic fermentation of carbohydrates. Butyrate appears to be the SCFA that is most avidly metabolized by the colonic mucosa. It has been suggested that ulcerative colitis (UC) is, at least in part, related to an energy deficiency state of the colonic mucosa which may be secondary to impaired SCFA production, uptake, or utilization. OBJECTIVE To determine if butyrate enemas are safe and effective in refractory distal UC. METHODS Ten patients with distal UC, refractory to all other available forms of rectal therapy and to oral sulfasalazine or mesalamine (5-ASA), were treated with nightly butyrate enemas in an open-label study. Enemas consisted of 60 ml of 80 mM sodium butyrate titrated to a pH of 7.0. Patients were assessed clinically and endoscopically at baseline and at 3- to 6-wk intervals, and a disease activity score from 0 to 12 was determined. Response to therapy was determined by changes in the activity score. RESULTS Six of 10 patients responded to therapy. Four of these six had complete responses. The mean disease activity score of all 10 patients fell from 8.0 +/- 2.4 (mean +/- SD) to 4.3 +/- 4.1 at the end of follow-up. Response to therapy could not be predicted based on any of the baseline characteristics analyzed. CONCLUSIONS In this open-label study, patients with distal UC who were refractory to all previous therapy had a 40% complete response rate and an overall 60% response rate. Controlled studies of this promising therapy are indicated.