Cholestasis is a known complication of inflammatory bowel disease, yet its pathogenesis is unknown. Kawaguchi et al. used trinitrobenzene sulfonic acid (TNB) to produce colitis and cholestasis in the rat and examined the role of endotoxin and changes in junctional proteins in its pathogenesis. Twenty-four hours after colonic instillation of TNB, bile salts in serum were elevated, bile flow was reduced, and paracellular routes of entry of horseradish peroxidase into bile were increased compared with control studies. Tight junction-associated proteins, Z01 and 7H6, were assessed by confocal microscopy. Z01 bordered the bile canaliculus membrane as in the controls but appeared discontinuous, whereas 7H6, which is involved in maintenance of paracellular permeability, was diminished and relocated to the submembranous cytoplasm. Portal blood contained endotoxin but not increased levels of IL-1โค, IL-6, and interferon gamma. Polymyxin B, which binds and neutralizes endotoxin, but not penicillin or metronidazole, completely prevented the cholestasis. These findings suggest that endotoxin was the cause of the cholestasis in this TNB colitis model and that polymyxin B might be an effective therapy in some cholestatic inflammatory bowel disease patients. (Page 1285.