{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T21:23:29Z","timestamp":1788989009748,"version":"build-2803163510"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T00:00:00Z","timestamp":1769990400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82470693"],"award-info":[{"award-number":["82470693"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013794","name":"Shanxi Provincial Department of Education","doi-asserted-by":"publisher","award":["2022L138"],"award-info":[{"award-number":["2022L138"]}],"id":[{"id":"10.13039\/501100013794","id-type":"DOI","asserted-by":"publisher"}]},{"name":"First Hospital of Shanxi Medical University Introduction Talent Fund","award":["SYYYRC-2022006"],"award-info":[{"award-number":["SYYYRC-2022006"]}]},{"DOI":"10.13039\/501100013318","name":"Shanxi Provincial Department of Science and Technology","doi-asserted-by":"crossref","award":["202203021221248"],"award-info":[{"award-number":["202203021221248"]}],"id":[{"id":"10.13039\/501100013318","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100013318","name":"Shanxi Provincial Department of Science and Technology","doi-asserted-by":"crossref","award":["202302130501013"],"award-info":[{"award-number":["202302130501013"]}],"id":[{"id":"10.13039\/501100013318","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100013318","name":"Shanxi Provincial Department of Science and Technology","doi-asserted-by":"crossref","award":["202204010931008"],"award-info":[{"award-number":["202204010931008"]}],"id":[{"id":"10.13039\/501100013318","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Natural Science Foundation of Shanxi","award":["202103021224408"],"award-info":[{"award-number":["202103021224408"]}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Hepatocellular carcinoma (HCC) is a prevalent and lethal malignancy worldwide. Gut microbiota play crucial roles in liver disease progression and may offer noninvasive diagnostic value, yet microbial signatures specific to advanced HCC remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Seventy-six participants, including early-stage HCC (HCC12), advanced HCC (HCC34), liver cirrhosis (LC), and healthy controls (CG), were prospectively enrolled. Fecal samples underwent 16S rRNA sequencing to characterize microbial diversity and community composition. Differential taxa were identified using Kruskal\u2013Wallis tests, linear discriminant analysis effect size (LEfSe), and zero-inflated negative binomial regression (ZINB). Machine learning models were constructed using clinical features, representative microbiota, and their combination. External validation was performed using 74 published HCC cases.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Advanced HCC exhibited reduced microbial richness and diversity, accompanied by substantial community structure alterations.\n                      <jats:italic>Enterococcus<\/jats:italic>\n                      ,\n                      <jats:italic>Enterococcaceae<\/jats:italic>\n                      ,\n                      <jats:italic>Enterobacteriaceae<\/jats:italic>\n                      , and\n                      <jats:italic>Escherichia\u2013Shigella<\/jats:italic>\n                      were enriched in HCC34, whereas\n                      <jats:italic>Ruminococcus<\/jats:italic>\n                      and\n                      <jats:italic>Blautia<\/jats:italic>\n                      were depleted. These taxa correlated strongly with liver injury markers and HCC-specific biomarkers. The extreme gradient boosting model showed high diagnostic potential when using either clinical or microbial features alone, while the combined model achieved improved accuracy (AUC\u202f=\u202f1.0 in the primary test set). External validation supported the good generalizability of the model (AUC\u202f=\u202f1.0 in the external cohort). Feature importance analysis identified\n                      <jats:italic>Enterococcus<\/jats:italic>\n                      as the most influential discriminator of advanced HCC.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This study reveals distinct gut microbial signatures associated with advanced HCC and suggests that\n                      <jats:italic>Enterococcus<\/jats:italic>\n                      may serve as a potentially important microbial marker linked to disease severity. Integrating gut microbiota profiling with clinical features may offer a promising noninvasive strategy for the accurate identification of advanced HCC and provides hypothesis-generating insights for microbiome-based therapeutic interventions.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmicb.2026.1760859","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T17:11:01Z","timestamp":1770052261000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Gut microbial signatures of advanced hepatocellular carcinoma and their potential diagnostic value"],"prefix":"10.3389","volume":"17","author":[{"given":"Yan","family":"Wang","sequence":"first","affiliation":[{"name":"First Clinical Medical College, Shanxi Medical University","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Yang","sequence":"additional","affiliation":[{"name":"First Clinical Medical College, Shanxi Medical University","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuang","family":"Liu","sequence":"additional","affiliation":[{"name":"First Clinical Medical College, Shanxi Medical University","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufeng","family":"Liu","sequence":"additional","affiliation":[{"name":"Microbiological Laboratory of Ophthalmology, Shanxi Eye Hospital","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongyuan","family":"Bai","sequence":"additional","affiliation":[{"name":"Fifth Clinical Medical College, Shanxi Medical University","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wentao","family":"Miao","sequence":"additional","affiliation":[{"name":"First Clinical Medical College, Shanxi Medical University","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiantian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Assisted Reproduction Center, First Hospital of Shanxi Medical University","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery and Liver Transplantation Center, First Hospital of Shanxi Medical University","place":["Taiyuan, China"]},{"name":"Shanxi Provincial Key Laboratory for Digestive Diseases and Organ Transplantation, First Hospital of Shanxi Medical University","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery and Liver Transplantation Center, First Hospital of Shanxi Medical University","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyong","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Biliopancreatic Surgery, First Hospital of Shanxi Medical University","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery and Liver Transplantation Center, First Hospital of Shanxi Medical University","place":["Taiyuan, China"]},{"name":"Shanxi Provincial Key Laboratory for Digestive Diseases and Organ Transplantation, First Hospital of Shanxi Medical University","place":["Taiyuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,2]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1016\/j.cgh.2015.12.042","article-title":"Role of the GALAD and BALAD-2 serologic models in diagnosis of hepatocellular carcinoma and prediction of survival in patients","volume":"14","author":"Berhane","year":"2016","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1296","DOI":"10.1055\/s-0042-119529","article-title":"The GALAD scoring algorithm based on AFP, AFP-L3, and DCP significantly improves detection of BCLC early stage hepatocellular carcinoma","volume":"54","author":"Best","year":"2016","journal-title":"Z. Gastroenterol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"702414","DOI":"10.3389\/fcell.2021.702414","article-title":"Molecular immune mechanism of intestinal microbiota and their metabolites in the occurrence and development of liver cancer","volume":"9","author":"Bi","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1186\/s12943-024-02101-z","article-title":"Biomarkers for diagnosis and therapeutic options in hepatocellular carcinoma","volume":"23","author":"Chan","year":"2024","journal-title":"Mol. Cancer"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1016\/j.ccr.2012.02.007","article-title":"Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4","volume":"21","author":"Dapito","year":"2012","journal-title":"Cancer Cell"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1038\/s41568-023-00594-2","article-title":"Bacteria in cancer initiation, promotion and progression","volume":"23","author":"El Tekle","year":"2023","journal-title":"Nat. Rev. Cancer"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"4875","DOI":"10.3390\/cancers15194875","article-title":"The gut microbiome as a biomarker and therapeutic target in hepatocellular carcinoma","volume":"15","author":"Gok Yavuz","year":"2023","journal-title":"Cancers"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1038\/s41579-023-00904-3","article-title":"The gut-liver axis and gut microbiota in health and liver disease","volume":"21","author":"Hsu","year":"2023","journal-title":"Nat. Rev. Microbiol."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1111\/liv.15082","article-title":"Validation of the GALAD model for early diagnosis and monitoring of hepatocellular carcinoma in Chinese multicenter study","volume":"42","author":"Huang","year":"2022","journal-title":"Liver Int."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1038\/s43018-021-00251-3","article-title":"Chronic liver disease enables gut Enterococcus faecalis colonization to promote liver carcinogenesis","volume":"2","author":"Iida","year":"2021","journal-title":"Nat. Cancer"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1158\/1055-9965.EPI-13-0870","article-title":"The detection of hepatocellular carcinoma using a prospectively developed and validated model based on serological biomarkers","volume":"23","author":"Johnson","year":"2014","journal-title":"Cancer Epidemiol. Biomarkers Prev."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"807648","DOI":"10.3389\/fimmu.2021.807648","article-title":"Potential role of the gut microbiome in colorectal cancer progression","volume":"12","author":"Kim","year":"2021","journal-title":"Front. Immunol."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1038\/nchembio.1535","article-title":"Gut microbiota-generated metabolites in animal health and disease","volume":"10","author":"Lee","year":"2014","journal-title":"Nat. Chem. Biol."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"350","DOI":"10.3350\/cmh.2024.0857","article-title":"Gut microbiota-mediated gut-liver axis: a breakthrough point for understanding and treating liver cancer","volume":"31","author":"Li","year":"2025","journal-title":"Clin. Mol. Hepatol."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"6533628","DOI":"10.1155\/2022\/6533628","article-title":"Relationship between intestinal microflora and hepatocellular cancer based on gut-liver axis theory","volume":"2022","author":"Li","year":"2022","journal-title":"Contrast Media Mol. Imaging"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13099-018-0281-6","article-title":"Alteration in gut microbiota associated with hepatitis B and non-hepatitis virus related hepatocellular carcinoma","volume":"11","author":"Liu","year":"2019","journal-title":"Gut Pathog."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"1140126","DOI":"10.3389\/fcimb.2023.1140126","article-title":"Intestinal flora plays a role in the progression of hepatitis-cirrhosis-liver cancer","volume":"13","author":"Liu","year":"2023","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1038\/s41398-021-01620-3","article-title":"Gut microbiota link dietary fiber intake and short-chain fatty acid metabolism with eating behavior","volume":"11","author":"Medawar","year":"2021","journal-title":"Transl. Psychiatry"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1002\/hep.30036","article-title":"Hepatocellular carcinoma is associated with gut microbiota profile and inflammation in nonalcoholic fatty liver disease","volume":"69","author":"Ponziani","year":"2019","journal-title":"Hepatology"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1919","DOI":"10.1093\/annonc\/mdu106","article-title":"The efficacy and safety of probiotics in people with cancer: a systematic review","volume":"25","author":"Redman","year":"2014","journal-title":"Ann. Oncol."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.1038\/s41586-024-07754-w","article-title":"Gut microbiota carcinogen metabolism causes distal tissue tumours","volume":"632","author":"Roje","year":"2024","journal-title":"Nature"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.ejca.2021.11.023","article-title":"Global, regional and national burden of primary liver cancer by subtype","volume":"161","author":"Rumgay","year":"2022","journal-title":"Eur. J. Cancer"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1016\/j.jhep.2019.08.016","article-title":"Gut microbiome in HCC\u2014mechanisms, diagnosis and therapy","volume":"72","author":"Schwabe","year":"2020","journal-title":"J. Hepatol."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1324","DOI":"10.1038\/nm1663","article-title":"TLR4 enhances TGF-beta signaling and hepatic fibrosis","volume":"13","author":"Seki","year":"2007","journal-title":"Nat. Med."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1016\/j.cgh.2022.01.047","article-title":"The performance of AFP, AFP-3, DCP as biomarkers for detection of hepatocellular carcinoma (HCC): a phase 3 biomarker study in the United States","volume":"21","author":"Tayob","year":"2023","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"S67","DOI":"10.1016\/j.jhep.2020.11.013","article-title":"The microbiota in cirrhosis and its role in hepatic decompensation","volume":"75","author":"Trebicka","year":"2021","journal-title":"J. Hepatol."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1038\/s41575-018-0011-z","article-title":"The gut-liver axis and the intersection with the microbiome","volume":"15","author":"Tripathi","year":"2018","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1038\/nrgastro.2017.72","article-title":"The gut microbiome and liver cancer: mechanisms and clinical translation","volume":"14","author":"Yu","year":"2017","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"4973589","DOI":"10.1155\/2021\/4973589","article-title":"Dysbiosis of gut microbiota promotes hepatocellular carcinoma progression by regulating the immune response","volume":"2021","author":"Zhang","year":"2021","journal-title":"J. Immunol. Res."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/s41392-019-0074-5","article-title":"Demystifying the manipulation of host immunity, metabolism, and extraintestinal tumors by the gut microbiome","volume":"4","author":"Zhang","year":"2019","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1159\/000546574","article-title":"China liver cancer guidelines for the diagnosis and treatment of hepatocellular carcinoma (2024 edition)","volume":"14","author":"Zhou","year":"2025","journal-title":"Liver Cancer"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1016\/j.trecan.2021.01.010","article-title":"Gut microbiota in cancer immune response and immunotherapy","volume":"7","author":"Zhou","year":"2021","journal-title":"Trends Cancer"}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2026.1760859\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T17:11:03Z","timestamp":1770052263000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2026.1760859\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,2]]},"references-count":33,"alternative-id":["10.3389\/fmicb.2026.1760859"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2026.1760859","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,2]]},"article-number":"1760859"}}