The Role of Leukotriene B4 in Clostridium difficile Toxin A--Induced Ileitis in Rats

Background & Aims: Clostridium difficile toxin A is a potent intestinal inflammatory agent that has been shown to act at least partially by neurogenic mechanisms involving activation of the transient receptor potential vanilloid 1 (TRPV1) (capsaicin) receptor. We tested the hypothesis that leukotriene B 4 (LTB 4 ) mediates the effects of toxin A via activation of the TRPV1 receptor. Methods: Isolated rat ileal segments were pretreated with pharmacologic agents before intraluminal injection of toxin A or LTB 4 . After 3 hours, the treated segments were removed and inflammation was assessed by luminal fluid accumulation, myeloperoxidase activity, and histology. Results: LTB 4 caused ileitis similar to that caused by toxin A and antagonism of TRPV1 receptors but not LTB 4 receptors inhibited LTB 4 -induced inflammation. LTB 4 also stimulated TRPV1-mediated substance P release and pretreatment with a specific substance P-receptor antagonist blocked LTB 4 -induced substance P action and ileitis. Inhibition of the LTB 4 biosynthetic enzyme 5-lipoxygenase inhibited toxin A-induced increases in ileal LTB 4 levels and toxin A- but not LTB 4 -induced ileitis. Conclusions: LTB 4 mediates the inflammatory effects of toxin A via activation of TRPV1 receptors.