Microbiota in cholestatic diseases: crosstalk among bile composition, the biliary microbiome, and host immunity

Cholestatic liver diseases are a heterogeneous group of hepatobiliary disorders caused by impaired bile formation, secretion, or excretion, leading to hepatocyte injury, biliary inflammation, fibrosis, and eventually cirrhosis. Traditional studies have largely focused on isolated mechanisms, including bile acid toxicity, immune dysregulation, and genetic susceptibility. However, recent advances in metagenomics, metabolomics, and immunology have highlighted the critical role of the gut and biliary microbiota in disease pathogenesis. This review proposes the core concept of a "tripartite interplay among bile composition, biliary microbiome, and host immunity," integrating the dynamic crosstalk among these three axes in cholestatic liver diseases. Bile composition shapes microbial communities and modulates immune responses through receptors such as FXR and TGR5. In turn, the biliary microbiome regulates bile acid metabolism and immune activity through microbial metabolites. Meanwhile, the host immune system senses microbial signals via pattern-recognition receptors, triggering inflammatory pathways and influencing microbial colonization and metabolism. These reciprocal interactions form complex feedback loops that drive disease progression from early inflammation to chronic fibrosis and cirrhosis. Based on this framework, emerging diagnostic approaches combine microbial signatures, bile acid profiles, and immune markers into multidimensional biomarker systems. Therapeutically, integrated strategies targeting the microbiome, bile acid metabolism, and immune pathways may offer synergistic benefits. Despite challenges including sampling difficulty, interindividual variability, and limitations of current models, future technologies such as single-cell sequencing, spatial transcriptomics, and multi-omics integration may enable precision diagnosis and targeted therapy.