{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T01:52:15Z","timestamp":1790905935925,"version":"4.1.0"},"reference-count":73,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T00:00:00Z","timestamp":1769385600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Nutr."],"abstract":"<jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>Ursodeoxycholic acid (UDCA), a naturally occurring bile acid with established hepatoprotective properties, has garnered attention for its potential role in metabolic health. This study provides scientific validation for these traditional uses by demonstrating UDCA\u2019s protective mechanisms against non-alcoholic fatty liver disease (NAFLD) through gut microbiota modulation and metabolic regulation. This study elucidates the therapeutic mechanisms of UDCA against high-fat diet-induced NAFLD through integrated microbiota-metabolomics analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using a 12-week murine NAFLD model, oral UDCA (15\u202fmg\/kg\/day and 30\u202fmg\/kg\/day) was administered to evaluate its hepatoprotective effects. Hepatic steatosis and injury were assessed via serum ALT\/AST levels, lipid profiles, and histopathology. Ultra-performance liquid chromatography\u2013tandem mass spectrometry (UPLC-MS\/MS) quantified bile acid metabolites, while 16S rRNA sequencing analyzed gut microbiota composition. Serum metabolomics and network pharmacology were employed to identify metabolic pathways and mechanistic targets, respectively. Molecular analyses (qPCR\/Western blot) assessed PPAR\u03b3\/Nrf2\/NF-\u03baB signaling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      UDCA treatment significantly ameliorated high-fat diet-induced NAFLD, as demonstrated by improved serum ALT\/AST levels, attenuated hepatic steatosis, and reduced histopathological damage. UPLC-MS\/MS analysis revealed a marked reorganization of bile acid metabolism, characterized by elevated non-12\u03b1-hydroxylated bile acids (UDCA, TUDCA) and enhanced alternative synthesis\n                      <jats:italic>via<\/jats:italic>\n                      CYP27A1 upregulation. 16S rRNA sequencing identified UDCA-driven restructuring of the gut microbiota, with specific enrichment of short-chain fatty acid-producing\n                      <jats:italic>Muribaculum<\/jats:italic>\n                      spp. and suppression of pro-inflammatory\n                      <jats:italic>Prevotella<\/jats:italic>\n                      (\n                      <jats:italic>CAG-485<\/jats:italic>\n                      ). Serum metabolomics further confirmed these benefits, showing increased eicosapentaenoic acid (anti-inflammatory) and decreased long-chain acylcarnitines (lipid peroxidation markers). At the molecular level, UDCA activated PPAR\u03b3\/Nrf2 antioxidative signaling while inhibiting NF-\u03baB-mediated inflammation, and network pharmacology analysis identified 225 potential targets (including TNF-\n                      <jats:italic>\u03b1<\/jats:italic>\n                      , IL6, and NF-\u03baB) within lipid\/atherosclerosis pathways, collectively underscoring UDCA\u2019s multimodal protective mechanisms against NAFLD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      These findings validate UDCA\u2019s multifaceted hepatoprotection\n                      <jats:italic>via<\/jats:italic>\n                      microbiota-bile acid crosstalk and metabolic-inflammatory modulation. The study provides a mechanistic basis for UDCA\u2019s traditional use in hepatobiliary disorders by integrating microbial, metabolic, and molecular evidence.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnut.2026.1714100","type":"journal-article","created":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T05:41:12Z","timestamp":1769406072000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Ursodeoxycholic acid alleviates high-fat diet-induced liver injury by modulating gut microbiota-mediated bile acid metabolism: an integrated microbiota-metabolomics analysis"],"prefix":"10.3389","volume":"13","author":[{"given":"Xueyun","family":"Dong","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, School of Medicine, Jiangsu University","place":["Zhenjiang, China"]},{"name":"Department of Laboratory Medicine, Yancheng First Hospital Affiliated of Nanjing University Medical School, The Yancheng Clinical College of Xuzhou Medical University, The First People\u2019s Hospital of Yancheng","place":["Yancheng, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Sun","sequence":"additional","affiliation":[{"name":"Critical Care Medicine, Jurong Hospital Affiliated to Jiangsu University","place":["Zhenjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, School of Medicine, Jiangsu University","place":["Zhenjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunhan","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, School of Medicine, Jiangsu University","place":["Zhenjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayuan","family":"He","sequence":"additional","affiliation":[{"name":"Health Testing Center, Zhenjiang Center for Disease Control and Prevention","place":["Zhenjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuehui","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Yancheng First Hospital Affiliated of Nanjing University Medical School, The Yancheng Clinical College of Xuzhou Medical University, The First People\u2019s Hospital of Yancheng","place":["Yancheng, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Yancheng First Hospital Affiliated of Nanjing University Medical School, The Yancheng Clinical College of Xuzhou Medical University, The First People\u2019s Hospital of Yancheng","place":["Yancheng, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asmaa","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, School of Medicine, Jiangsu University","place":["Zhenjiang, China"]},{"name":"Department of Pulmonary Medicine, Abbassia Chest Hospital, EMOH","place":["Cairo, Egypt"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Chen","sequence":"additional","affiliation":[{"name":"Public Experiment and Service Center, Jiangsu University","place":["Zhenjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leilei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, School of Medicine, Jiangsu University","place":["Zhenjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, School of Medicine, Jiangsu University","place":["Zhenjiang, China"]},{"name":"Department of Laboratory Medicine, Yancheng First Hospital Affiliated of Nanjing University Medical School, The Yancheng Clinical College of Xuzhou Medical University, The First People\u2019s Hospital of Yancheng","place":["Yancheng, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keke","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Yancheng First Hospital Affiliated of Nanjing University Medical School, The Yancheng Clinical College of Xuzhou Medical University, The First People\u2019s Hospital of Yancheng","place":["Yancheng, China"]},{"name":"Molecular Medical Research Center, Yancheng Clinical Medical College of Jiangsu University","place":["Yancheng, 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