Why Butyrate Supplementation Makes Chronic Gut Dysfunction Worse: The Data They Don't Show You — How Butyrate Gets Oxidized (When It Works)

Under optimal conditions, here&#8217;s the pathway: Butyrate enters colonocytes via MCT1 (monocarboxylate transporter 1). Activated to butyryl-CoA by acyl-CoA synthetases (ACS). Fed into beta-oxidation in mitochondria, generating acetyl-CoA. Acetyl-CoA enters the TCA cycle (citric acid cycle), feeding Complex I, II, III, and IV. Electron transport chain oxidizes NADH and FADH&#8322; , pumping protons and generating the proton gradient. ATP synthase harnesses this gradient , producing ATP. The efficiency is high. One mole of butyrate generates ~20 moles of ATP under aerobic conditions. But this entire pathway assumes: Intact colonocyte mitochondria Functioning beta-oxidation enzymes (CPT1, CPT2, FADH&#8322; dehydrogenase, 3-ketoacyl-CoA thiolase) Adequate electron transport chain components Sufficient NAD&#8314;, CoQ10, and other cofactors Adequate oxygen availability In chronic gut dysfunction? None of these are guaranteed.