Abstract
BACKGROUND: Cholangiocarcinoma (CCA) is an aggressive cancer with a poor prognosis. Histopathology evaluation of brushings and biopsies obtained during endoscopic retrograde cholangiopancreatography (ERCP) currently remains the main method of diagnosis, which has limited sensitivity for malignancy detection. Our study aimed to identify human bile-derived biomarkers to improve CCA diagnosis. Bile samples were collected from patients during ERCP for primary sclerosing cholangitis, CCA, or benign biliary disease. METHODS: Bile samples were collected from patients undergoing ERCP for biliary obstruction due to primary sclerosing cholangitis, newly identified malignant strictures concerning for CCA, or benign biliary disease. Using 16S sequencing, metabolomics, and bile acid quantification, we aimed to identify distinctive microbial and metabolite signatures associated with CCA. RESULTS: Multi-omics analyses revealed distinct microbial and metabolite signatures associated with CCA. From these findings, we identified and validated microbial and metabolite markers capable of accurately detecting CCA with improved sensitivity and specificity for malignancy detection compared to current cytology-based methods. CONCLUSIONS: These findings highlight the potential of multi-omics bile-based diagnostic panels to enhance endoscopic detection of biliary malignancies, offering a promising tool for evaluating indeterminate biliary strictures and advancing precision in ERCP diagnostics.