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

Figure 4 Normal vs low-fiber colonocyte bioenergetics. A: The normal vectorial bioenergetic flux beginning with soluble dietary fiber that is converted to short-chain fatty acids (i.e., butyrate) by bacteria in the colonic lumen. Butyrate is rapidly absorbed by colonic epithelial cells (colonocytes). Once inside the colonocyte, butyrate undergoes mitochondrial beta-oxidation to generate acetyl-coenzyme A (CoA), which is processed by the Krebs cycle that produces NADH and FADH2. The high-energy electrons present in NADH and FADH2 are used to drive oxidative phosphorylation (Oxphos) resulting in the biosynthesis of ATP, which fuels most of the cell’s energy needs; B: Low fiber intake decreases available butyrate needed for acetyl-CoA production. Under these energy-restricted conditions, glutamate is diverted into the Krebs cycle and away from the synthesis of glutathione (GSH). Diversion of glutamate into the Krebs cycle is called anapleurotic metabolism (red curved arrow) and is needed to replenish depleted Krebs cycle intermediary metabolites that would otherwise be supplied by dietary soluble fiber, which can no longer perform this role due to a low fiber diet. Since glutamate is needed for the synthesis of GSH, the sequestration of glutamate as a replacement energy source restricts the amount of glutathione the cell is able to synthesize. GSH is the principal reducing equivalent required to neutralize cellular hydrogen peroxide (H₂O₂). Insufficient glutathione will cause cellular H₂O₂ to increase, which upon extracellular diffusion may initiate neutrophil chemotaxis into the colonic epithelium and de novo ulcerative colitis or disease relapse. Interruption of colonocyte bioenergetic flux anywhere along the pathway from the microbiome to acetyl CoA will increase colonocyte anapleurotic metabolism and cellular H₂O₂, which can lead to ulcerative colitis. H₂O₂: Hydrogen peroxide; CoA: Coenzyme A.