The Hidden Driver of SIBO and Chronic Gut Dysfunction: Bile Acid Malabsorption, Dysbiosis, and the Mitochondrial Cascade — Part III: The Mitochondrial Toxicity Cascade

Unconjugated Primary Bile Acids as Mitochondrial Toxins Primary bile acids (cholic acid, chenodeoxycholic acid) in their unconjugated form are significantly more lipophilic than their conjugated counterparts. At high luminal concentrations&#8212;which occur when secondary bile acid synthesis has failed&#8212;primary bile acids can be absorbed passively across the small intestinal epithelium and delivered to colonocytes, hepatocytes, and other tissues. Inside cells, unconjugated primary bile acids exert direct mitochondrial toxicity through multiple mechanisms: 1. Uncoupling of the Proton Gradient Unconjugated bile acids are amphipathic molecules capable of shuttling protons across the inner mitochondrial membrane, disrupting the proton-motive force that drives ATP synthesis. This is concentration-dependent: at low physiologic concentrations of secondary bile acids (which activate FXR/TGR5 and are tightly regulated), this effect is negligible. But when primary bile acids accumulate, ATP synthesis efficiency falls dramatically. 2. Impairment of Complex I and Complex III Research from multiple groups has demonstrated that unconjugated primary bile acids directly inhibit electron transport chain activity, particularly at Complex I (NADH dehydrogenase) and Complex III (cytochrome bc1 complex). This results in increased reactive oxygen species (ROS) generation and impaired oxidative