Bile–Pancreas–Gut Axis Dysfunction as a Potential Contributor to Oxidative Stress and Endothelial Glycocalyx Injury in Cardiometabolic Disease

Background: Cardiometabolic disease (CMD) is traditionally attributed to dyslipidemia, insulin resistance, and chronic inflammation. However, early endothelial dysfunction frequently occurs in individuals with normal conventional biomarkers, suggesting unrecognized upstream drivers of vascular vulnerability. Hypothesis: We propose that dysfunction of the bile–pancreas–gut axis represents a previously underrecognized upstream driver of mitochondrial oxidative stress and endothelial glycocalyx injury. Early disturbances in bile flow and pancreatic ductal dynamics may generate a biochemical phenotype characterized by pancreatic enzyme levels in the upper quartile of the normal range, upper-normal alkaline phosphatase (ALP), and preserved gamma-glutamyl transferase (GGT). This profile may reflect functional biliary stasis and ductal stress rather than overt disease. Mechanisms: Functional biliary stasis may increase circulating hydrophobic bile acids (e.g., deoxycholic acid, lithocholic acid), which at low micromolar concentrations impair mitochondrial oxidative phosphorylation and promote electron leakage at complexes I and III, generating superoxide and hydrogen peroxide. Mitochondrial reactive oxygen species (ROS) activate NADPH oxidases (NOX1/NOX2/NOX4), establishing a feed-forward "ROS-induced ROS release" loop. Concurrent gut-derived lipopolysaccharide (LPS) translocation and pancreatic stress signals further amplify redox signaling. This oxidative environment promotes activation of matrix metalloproteinase-9 (MMP-9), ADAM17, and heparanase, leading to enzymatic shedding of the endothelial glycocalyx. Simultaneous oxidative depletion of tetrahydrobiopterin (BH₄) promotes endothelial nitric oxide synthase (eNOS) uncoupling, reducing nitric oxide bioavailability and increasing superoxide generation. These processes collectively contribute to a permissive state for low-density lipoprotein (LDL) retention, oxidation, and atherogenesis. Implications: This hypothesis positions mitochondrial and NOX-derived ROS as central integrators linking subclinical hepatobiliary dysfunction to vascular injury. It is testable using routine biomarkers (lipase, amylase, ALP, GGT) alongside redox markers (F2-isoprostanes, oxidized LDL, 8-OHdG). Validation may enable earlier risk stratification and targeted redox-modulating interventions.