A condition known as diversion colitis frequently develops in segments of the colorectum after surgical diversion of the fecal stream; it persists indefinitely unless the excluded segment is reanastomosed. The disease is characterized by bleeding from inflamed colonic mucosa that mimics the bleeding of idiopathic inflammatory bowel disease, and it may culminate in stricture formation. We hypothesized that this condition is caused by the absence of luminal short-chain fatty acids, the preferred metabolic substrates of colonic epithelium. We studied four patients with diversion colitis, none of whom had evidence of Crohn's, idiopathic ulcerative, or infectious colitis. The excluded segment of the rectosigmoid contained negligible concentrations of short-chain fatty acids. When D-glucose was instilled, it did not undergo appreciable anaerobic fermentation. Instillation of a solution containing short-chain fatty acids twice daily resulted in the disappearance of symptoms and the inflammatory changes observed at endoscopy, over a period of four to six weeks. Remission has been maintained for up to 14 months (in one patient) by instillation daily to twice weekly. Administering enemas containing isotonic saline, or omitting treatment for periods of two to four weeks during the regimen, by contrast, did not produce any improvement or rapid relapse of the colitis. Histologic observation revealed a distinctive type of mucosal inflammation that resolved more slowly and less completely than the gross appearance of the inflamed mucosa. From these preliminary studies we infer that diversion colitis may represent an inflammatory state resulting from a nutritional deficiency in the lumen of the colonic epithelium, which is effectively treated by local application of short-chain fatty acids, the missing nutrients.