Ulcerative colitis: Timeline to a cure

Figure 5 Transduction of environmental stimuli increases cellular hydrogen peroxide levels, elevating the risk of ulcerative colitis[27]. Normal energy flux in the colon begins with luminal soluble fiber, which is fermented by bacteria into n-butyrate, a key short-chain fatty acid. Butyrate is absorbed by colonic epithelial cells, where it undergoes beta-oxidation, generating acetyl-CoA. Subsequently, acetyl-CoA enters the Krebs cycle, producing the reducing equivalents NADH, nicotinamide adenine dinucleotide (reduced form) and FADH₂, flavin adenine dinucleotide (reduced form) that drive oxidative phosphorylation to generate ATP, adenosine triphosphate. Panel A: Bioenergetics under oxidative stress. A deficiency in dietary soluble fiber (A1) results in inadequate butyrate production (A3) and reduced acetyl-CoA levels (A5). To offset the energy shortfall, the Krebs cycle engages in anaplerotic metabolism of glutamate (A6)[32,33]. This redirection of glutamate for energy production compromises glutathione synthesis required for hydrogen peroxide (H₂O₂) neutralization leading to elevated cellular H₂O₂ levels (A7). With sufficient accumulation, mitochondrial H₂O₂ can diffuse into the cytoplasm and across the cell membrane into the lamina propria, contributing to the development of ulcerative colitis (UC) (A9). A reduction in acetyl-CoA due to deficiencies in any factors involved in its synthesis, starting with luminal fiber, can lead to elevated cellular H₂O₂ levels, increasing the risk of UC. This is exemplified by a deficiency of vitamin B5, required for the synthesis of coenzyme A, which leads to a colitis in pigs analogous to human UC[34]. Initially, H₂O₂ accumulates within mitochondria, impairing beta oxidation, and is followed by relapse weeks later[21]. This delay reflects the time needed for mitochondrial H₂O₂ to establish a sufficient concentration gradient for cytoplasmic and extracellular diffusion. This explains why butyrate enemas are ineffective in resolving UC as H₂O₂ inhibits beta oxidation (A8)[26]. Sufficient damage to the colonic microbiota (A2) may increase the risk of developing or exacerbating UC. Panel B: The source of H₂O₂ production is influenced by the nature of the environmental stimuli[27]. B1: Disinhibition of the mitochondrial electron transport chain following smoking cessation can result in elevated H₂O₂ production, contributing to the development of ulcerative colitis[35]. B2: A diet rich in fats promotes increased peroxisomal beta-oxidation of long-chain fatty acids, leading to heightened H₂O₂ production, which predisposes individuals to UC. B3: The metabolism of certain drugs, such as nonsteroidal anti-inflammatory drugs, via cytochrome P450 enzymes in the smooth endoplasmic reticulum generates H₂O₂[36], which may contribute to the onset or relapse of UC. B4: Xanthine oxidase metabolizes purines found in red meat, producing significant amounts of H₂O₂[37]. Monoamine oxidase-A metabolizes serotonin released by enterochromaffin cells in the colon under stress, generating significant amounts of H₂O₂[38]. Oxidative stressors are stimuli that increase H₂O₂ in the body. More than one can be present simultaneously and contribute to UC development or relapse. H₂O₂: Hydrogen peroxide; NADH: Nicotinamide adenine dinucleotide (reduced); FADH2: Flavin adenine dinucleotide (reduced); ATP: Adenosine triphosphate; GSH: Glutathione.