Direct evidence of mast cell involvement in Clostridium difficile toxin A-induced enteritis in mice

Background & Aims: The pathogenesis of Clostridium difficile toxin A-induced intestinal inflammation is not completely understood. The aim of this study was to define the contribution of mast cells to the fluid secretion and neutrophil infiltration associated with toxin A-induced enteritis. Methods: Fluid secretion and neutrophil infiltration in toxin A-or buffer-challenged ileal loops were assessed in normal, mast cell-deficient, and mast cell-deficient Kit(W)/Kit(W-v) mice that had undergone selective repair of their mast cell deficiency. The effect of a specific substance P-receptor antagonist was also studied. Results: Intestinal fluid secretion and neutrophil recruitment were significantly diminished in mast cell-deficient Kit(W)/Kit(W-v) and mast cell-deficient Mgf(Sl)/Mgf(Sl-d) mice compared with the respective normal mice. Mast cell-reconstituted Kit(W)/Kit(W-v) mice showed responses similar to the normal congenic mice. Administration of a specific substance P-receptor antagonist (CP-96,345) reduced toxin A-induced intestinal fluid secretion and inhibited neutrophil infiltration in normal, mast cell-deficient Kit(W)/Kit(W-v), and mast cell-reconstituted Kit(W)/Kit(W-v) mice. Conclusions: C. difficile toxin A elicits intestinal fluid secretion and neutrophil infiltration by both mast cell-dependent and -independent pathways, and substance P participates in both pathways.