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

Figure 1 Ulcerative colitis: Evidence-based pathogenesis and relapse. A: Pre-inflammatory; B: Active inflammation; C: Relapse. Hydrogen peroxide (H₂O₂) is produced by all cells of the body, mainly as a toxic by-product of cellular metabolism and must be immediately neutralized to prevent cell damage. If produced in excess by colonocytes (colonic epithelial cells), H₂O₂ easily diffuses through the cell membrane; 1: To the extracellular space where its unique properties of long life, potent oxidizing power, and the ability to attract neutrophils (neutrophilic chemotaxis) combine to promote oxidative damage of colonocyte tight junctions; 2: While attracting neutrophils into the colonic epithelium; 3: Continued H₂O₂ exposure leads to oxidative disintegration of tight junctional proteins and increased colonic epithelial paracellular permeability; 4: Increased paracellular permeability promotes bacterial translocation into the sterile lamina propria; 5: And facilitates neutrophil migration up the H₂O₂ concentration gradient into the crypts of Lieberkühn; 6: Both of which lead to colonic inflammation and eventual ulcerative colitis. Neutrophils exposed to bacteria in the crypts become activated and produce large amounts of H₂O₂ that diffuses into colonic epithelial cells; 7: Which adds to the already high colonocyte H₂O₂ load. The increased colonocyte H₂O₂ oxidizes mitochondrial DNA (mtDNA) introducing genetic mutations that miscode when transcribing for electron transport chain (ETC) proteins; 8: Faulty ETC proteins exhibit additional electron leakage leading to greater H₂O₂ production creating a vicious cycle of mtDNA damage and ever greater H₂O₂ production, which contributes to and increases the frequency and severity of relapse; 9: This amounts to a “hard-wired” genetic reprogramming that promotes colonic inflammation as discussed below. H₂O₂: Hydrogen peroxide; mtDNA: Mitochondrial DNA.