Immunobiology of bile and cholangiocytes.

The biliary tract is now recognized as an immune organ, and within the biliary tract, both bile and cholangiocytes play a key role in maintaining immune defense and homeostasis. First, immunoreactive proteins such as secretory IgA provide local antimicrobial effects. Second, bile acids (BAs) protect the biliary tree from immune-related injury through receptor signaling, mainly via the membrane-bound receptor TGR5 on cholangiocytes. Third, the biliary microbiota, similar to the intestinal microbiota, contributes to sustaining a stable physiobiological microenvironment. Fourth, cholangiocytes actively modulate the expression/release of adhesion molecules and cytokines/chemokines and are involved in antigen presentation; additionally, cholangiocyte senescence and apoptosis also influence immune responses. Conversely, aberrant bile composition, altered BA profiles, imbalances in the biliary microbiota, and cholangiocyte dysfunction are associated with immune-mediated cholangiopathies, including primary biliary cholangitis, primary sclerosing cholangitis, and biliary atresia. While current therapeutic agents that modulate BA homeostasis and receptor signaling have shown promise in preclinical and clinical studies, future research on biliary/intestinal microbiota and cholangiocyte function should focus on developing novel therapeutic strategies for treating cholangiopathies.