{"doi":"10.1016/j.jhepr.2025.101467","title":"Blood and tissue dysregulated bile acids and short-chain fatty acids in cholangiocarcinoma","abstract":"Background & Aims Cholangiocarcinoma (CCA) is subclassified into intrahepatic (iCCA) and extrahepatic (eCCA), with distinct epidemiology and pathogenesis. Dysregulated bile acid (BA) homeostasis has been implicated in the initiation and progression of CCA. This study aimed to investigate the roles of circulating and tumor BAs, oxysterols, short-chain fatty acids (SCFAs), transcriptomic changes, and stool microbiota composition in CCA, and their potential diagnostic and therapeutic implications. Methods We used ultra-performance liquid chromatography-tandem mass spectrometry to quantify BAs , oxysterols, and SCFAs in serum from patients with benign focal nodular hyperplasia (FNH; n=27), primary sclerosing cholangitis (PSC; n=20), iCCA (n=29), and eCCA (n=35), and in tumor and adjacent non-tumor iCCA (n=30) and eCCA (n=26) tissues. Open-source liver transcriptome and gut microbiome datasets were analyzed for the activity of BA metabolic pathways and associated gene expression. Results Total primary conjugated BA levels and taurine-to-glycine ratio of conjugated BAs were significantly elevated in the serum of PSC and CCA patients compared to FNH controls ( p <0.05). Transcriptomic analysis revealed a significant downregulation of GLYAT and BAAT, key genes involved in glycine and taurine conjugation, in PSC and CCA ( p <0.05). Hepatic oxysterol levels were increased concomitantly with BAs in CCA patients. Among SCFAs, butyric acid was positively correlated with conjugated BAs in the serum of iCCA patients; whereas acetic acid was negatively correlated with BAs in the serum of non-PSC-eCCA patients ( p < 0.05). Conjugated BAs were positively correlated with CA19-9 levels in both iCCA and non-PSC-eCCA patients. Conclusions There are profound changes in serum and tissue primary and taurine-conjugated BAs during cholangiocarcinogenesis. Elucidating the potential mechanisms regulating BAs and oxysterols in CCA patients may advance the diagnosis and treatment of CCA. Impact and implications Cholangiocarcinomas (CCAs) are aggressive malignancies with limited treatment options. Although CCA cells exhibit distinctive metabolic profiles, studying their metabolic regulatory mechanisms via the enterohepatic axis remains challenging. Using targeted metabolomics, this study analyzed bile acid (BA) profiles in serum and liver tissue, serum short-chain fatty acids (SCFAs), and liver oxysterol levels in intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA) patients, compared to focal nodular hyperplasia (FNH) and primary sclerosing cholangitis (PSC) controls. Liver transcriptome analysis identified differentially expressed genes in BA metabolism pathways in PSC and CCA patients. Additionally, correlations were assessed between BAs, oxysterols, SCFAs, and clinical characteristics, along with microbiome components linked to CCA development. These findings shed light on the BA landscape in CCA patients and provide a foundation for identifying novel diagnostic biomarkers and therapeutic targets.","journal":"JHEP Reports","year":2025,"id":532451,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9639,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1413612,"name":"Hind Hassan","orcid":"0000-0001-7726-0327","position":1,"is_corresponding":false},{"id":1413613,"name":"Tayla Rashanaye Brooks","orcid":"0000-0001-7586-3351","position":2,"is_corresponding":false},{"id":776287,"name":"Caitlin J. VanLith","orcid":"0000-0002-3929-6561","position":3,"is_corresponding":false},{"id":1055304,"name":"Matthew A. Cooley","orcid":"0000-0003-1855-7651","position":4,"is_corresponding":false},{"id":1414005,"name":"Mohamad Elgozair","orcid":null,"position":5,"is_corresponding":false},{"id":680659,"name":"Fowsiyo Ahmed","orcid":"0000-0002-0201-6706","position":6,"is_corresponding":false},{"id":13487,"name":"Nasra H. Giama","orcid":null,"position":7,"is_corresponding":false},{"id":387887,"name":"Nellie A. Campbell","orcid":"0000-0002-3812-6747","position":8,"is_corresponding":false},{"id":639694,"name":"Lianyong Su","orcid":null,"position":9,"is_corresponding":false},{"id":650700,"name":"Yunling Tai","orcid":null,"position":10,"is_corresponding":false},{"id":1413614,"name":"Jianlin Ren","orcid":"0000-0002-4973-7076","position":11,"is_corresponding":false},{"id":268726,"name":"Huiping Zhou","orcid":"0000-0002-0050-372X","position":12,"is_corresponding":false},{"id":13968,"name":"Lewis R. Roberts","orcid":"0000-0001-7885-8574","position":13,"is_corresponding":false},{"id":1414004,"name":"Yaming Liu","orcid":null,"position":0,"is_corresponding":true}],"reference_count":39,"raw_metadata":null,"created_at":"2026-07-19T02:51:23.237536Z","pmid":"41281446","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}