Elevated circulating bile acids alleviate acute pancreatitis by restoring mitochondrial function via acinar cell uptake

Acute pancreatitis (AP) is commonly linked to bile acid (BA) dyshomeostasis, yet the causal role of elevated circulating BAs and the functional significance of their uptake by pancreatic acinar cells in AP progression remain unclear and controversial. A cerulein (CER)-induced rat model of AP was established, and pathological elevation of circulating BAs was achieved via intraperitoneal injection of sodium taurocholate (Na-TC, 50 mg/kg). Targeted metabolomics was used to quantify BA profiles in serum and pancreatic tissue. In vitro experiments on pancreatic acinar cells were conducted to assess BA uptake and its effects on cell survival. Mitochondrial function was evaluated via confocal microscopy, RNA-sequencing, and biochemical assays for membrane potential, adenosine triphosphate (ATP), and reactive oxygen species. Systemic Na‑TC administration increased serum and pancreatic total BA levels to concentrations comparable to biliary pancreatitis. Under these clinically relevant BA elevations, Na‑TC treatment significantly attenuated CER-induced pancreatic histopathological damage, inflammation, and oxidative stress. In vitro, Na‑TC (10–200 μM) reduced CER-induced acinar cell apoptosis/necrosis, but this protection was abrogated by the BA transporter inhibitor rifamycin sodium salt. RNA-sequencing and functional analyses revealed that BA uptake upregulated mitochondrial electron transport chain subunits, enhanced oxidative phosphorylation, restored mitochondrial membrane potential, and increased ATP production. These findings challenge the traditional view of circulating BA toxicity in AP and indicate that, at levels comparable to those observed in biliary pancreatitis, uptake of a certain amount of BAs by pancreatic acinar cells is beneficial rather than harmful.