Evidence-based pathogenesis and treatment of ulcerative colitis: A causal role for colonic epithelial hydrogen peroxide

In this comprehensive evidence-based analysis of ulcerative colitis (UC), a causal role is identified for colonic epithelial hydrogen peroxide (H(2)O(2)) in both the pathogenesis and relapse of this debilitating inflammatory bowel disease. Studies have shown that H(2)O(2) production is significantly increased in the non-inflamed colonic epithelium of individuals with UC. H(2)O(2) is a powerful neutrophilic chemotactic agent that can diffuse through colonic epithelial cell membranes creating an interstitial chemotactic molecular “trail” that attracts adjacent intravascular neutrophils into the colonic epithelium leading to mucosal inflammation and UC. A novel therapy aimed at removing the inappropriate H(2)O(2) mediated chemotactic signal has been highly effective in achieving complete histologic resolution of colitis in patients experiencing refractory disease with at least one (biopsy-proven) histologic remission lasting 14 years to date. The evidence implies that therapeutic intervention to prevent the re-establishment of a pathologic H(2)O(2) mediated chemotactic signaling gradient will indefinitely preclude neutrophilic migration into the colonic epithelium constituting a functional cure for this disease. Cumulative data indicate that individuals with UC have normal immune systems and current treatment guidelines calling for the suppression of the immune response based on the belief that UC is caused by an underlying immune dysfunction are not supported by the evidence and may cause serious adverse effects. It is the aim of this paper to present experimental and clinical evidence that identifies H(2)O(2) produced by the colonic epithelium as the causal agent in the pathogenesis of UC. A detailed explanation of a novel therapeutic intervention to normalize colonic H(2)O(2), its rationale, components, and formulation is also provided.