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

Figure 3 Natural history of ulcerative colitis. The evidence-based natural history of ulcerative colitis begins with exposure to oxidative stressors (a), which increases colonocyte hydrogen peroxide (H₂O₂) (b). The increase in colonocyte H₂O₂ facilitates extracellular diffusion which overwhelms (oxidizes) local interstitial serum albumin antioxidant defense (60% of serum albumin is interstitial), leading to directed migration of neutrophils (chemotaxis) into the colonic epithelium (c) and mucosal inflammation (d) with subsequent development of ulcerative colitis (e). Large amounts of H₂O₂ are released by neutrophils into the extracellular space (f) with further oxidation of interstitial albumin and exhaustion of tissue antioxidant capacity (c). This worsens colonic inflammation (d) leading to local and systemic reductive depletion (i) as albumin is circulated through the colonic interstitium into tissue lymphatics and back into the systemic circulation. Neutrophil released H₂O₂ “back flows” into colonocytes (g) adding to the already elevated intracellular H₂O₂ levels resulting in mitochondrial DNA damage and mitochondrial heteroplasmy (b, red mtH). Mitochondrial heteroplasmy introduces mutations into the electron transport chain protein subunits, which generate additional H₂O₂ via enhanced electron leakage setting up a vicious cycle of ever increasing colonocyte H₂O₂ (b, red arrows). Increased colonocyte H₂O₂ diffuses into the extracellular space (h) causing disease relapse (c, d, e). The combination of local and systemic reductive depletion along with a ready supply of H₂O₂ from colonocytes and neutrophils (b and d) creates a mucosal inflammation that is self-amplifying, forward propagating, and auto-initiating (relapsing). Elimination of neutrophilic inflammation (d) by any means (i.e., immunosuppressive agents) will not stop relapse from occurring as colonocyte H₂O₂ continues to diffuse into the extracellular space (c, h). Conversely, normalizing colonocyte H₂O₂ alone will not stop the inflammation, which has become self-sustaining. This indicates that simultaneous elimination of all pathological sources contributing H₂O₂ to the inflammatory field must be achieved to ensure long-term remission and normal colonic functionality. Systemic reductive depletion may contribute to other serious health hazards as detailed below. H₂O₂: Hydrogen peroxide.