The Role of Leukotriene B 4 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 B4 (LTB4) 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 LTB4. After 3 hours, the treated segments were removed and inflammation was assessed by luminal fluid accumulation, myeloperoxidase activity, and histology. Results: LTB4 caused ileitis similar to that caused by toxin A and antagonism of TRPV1 receptors but not LTB4 receptors inhibited LTB4-induced inflammation. LTB4 also stimulated TRPV1-mediated substance P release and pretreatment with a specific substance P–receptor antagonist blocked LTB4-induced substance P action and ileitis. Inhibition of the LTB4 biosynthetic enzyme 5-lipoxygenase inhibited toxin A–induced increases in ileal LTB4 levels and toxin A– but not LTB4-induced ileitis. Conclusions: LTB4 mediates the inflammatory effects of toxin A via activation of TRPV1 receptors.