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Here, metagenomic sequencing was performed on fecal samples (\n                    <jats:italic>n<\/jats:italic>\n                    = 785) from individuals across East, Central, and Northwestern China. Gut microbial dysbiosis in CCA was characterized by depletion of short\u2010chain fatty acids\u2010producing species and enrichment of potential pathobionts (\n                    <jats:italic>Klebsiella aerogenes<\/jats:italic>\n                    ,\n                    <jats:italic>Clostridium symbiosum<\/jats:italic>\n                    ). Diagnostic models built using species\u2010level markers demonstrated superior performance, compared to pathway\u2010based models, achieving area under the curve (AUC) values of 98.63% and 99.42% in the discovery cohort, with robust cross\u2010regional validation (AUC = 80.89% and 80.43%). The model effectively distinguished CCA from hepatocellular carcinoma (AUC = 97.86%) and liver fibrosis (AUC = 98.73%) and nonalcoholic fatty liver disease (mean AUC = 96.86%). Analysis of public datasets encompassing 6847 samples across 31 studies and 11 disease states revealed moderate disease specificity influenced by biomarker overlap across conditions. Mechanistically, depleted\n                    <jats:italic>Bifidobacterium pseudocatenulatum<\/jats:italic>\n                    suppressed CCA progression, associated with inhibition of the PI3K\u2010AKT\u2010mTOR pathway. Collectively, this study supports the potential of fecal metagenomic signatures as a complementary noninvasive aid for CCA detection, and provides functional evidence for a candidate protective microbe.\n                  <\/jats:p>","DOI":"10.1002\/advs.202517658","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T10:56:23Z","timestamp":1773312983000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Multicohort Validation of Gut Microbiome Signatures for Cholangiocarcinoma Diagnosis and Functional Characterization of\n                    <i>Bifidobacterium Pseudocatenulatum<\/i>"],"prefix":"10.1002","volume":"13","author":[{"given":"Benchen","family":"Rao","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases State Key Laboratory of Antiviral Drugs Pingyuan Laboratory the First Affiliated Hospital of Zhengzhou University  Zhengzhou China"},{"name":"Gene 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