{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T21:39:11Z","timestamp":1781732351762,"version":"3.54.5"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T00:00:00Z","timestamp":1738713600000},"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. Med."],"abstract":"<jats:sec><jats:title>Objectives<\/jats:title><jats:p>To explore the mechanism underlying the effect of Fructus Akebiae (FAE) against hepatic fibrosis in mice through combined network pharmacology, liver metabolomics, and 16S rDNA analyses of the gut microbiota.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, we randomly divided mice into the control, model, FAE high-dose, FAE medium-dose, and FAE low-dose groups to analyze the pathological changes in the hepatic fibrosis and levels of the <jats:italic>\u03b1<\/jats:italic>-SMA, collagen 1, Nuclear Factor Kappa B (NF-<jats:italic>\u03ba<\/jats:italic> B), Toll Like Receptor 4 (TLR4). The gut microbiota was analyzed through 16S rDNA sequencing analysis of liver metabolites using liquid chromatography-mass spectrometry. Furthermore, network pharmacology was used to determine the specific molecular regulation mechanism of FAE in hepatic fibrosis treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>FAE treatment markedly improved the pathological changes in the hepatic fibrosis. Analysis revealed that FAE administration reversed the carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>)-induced dysbiosis by increasing the abundance of <jats:italic>Akkermansia<\/jats:italic> and reducing that of <jats:italic>Cyanobacteria<\/jats:italic>. Additionally, metabolomic analysis showed that FAE treatment reversed the CCl<jats:sub>4<\/jats:sub>-induced metabolic disorders by regulating amino and nucleotide sugar metabolism. Furthermore, correlation analysis showed that <jats:italic>Akkermansia<\/jats:italic> and <jats:italic>Verrucomicobiota<\/jats:italic> were closely related to D-tolasaccharide and maltotetraose saccharide. Moreover, network pharmacology indicated that FAE might regulate the signaling pathway through the JUN\/CASP3\/NOS3\/PTGS2\/HSP90AA1 during treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>FAE may be a promising treatment for hepatic fibrosis, and its protective effects are associated with improvements in the microbiome and metabolic disorders.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmed.2024.1492383","type":"journal-article","created":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T07:36:56Z","timestamp":1738741016000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Combined metabolomics and 16S rDNA sequence analyses of the gut microbiome reveal the action mechanism of Fructus Akebiae against hepatic fibrosis"],"prefix":"10.3389","volume":"11","author":[{"given":"Rong-Rong","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duo-Rui","family":"Nie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang-Hui","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Hang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,2,5]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/s41423-023-00983-5","article-title":"Mesenchymal stromal cells in hepatic fibrosis\/cirrhosis: from pathogenesis to treatment","volume":"20","author":"Yang","year":"2023","journal-title":"Cell Mol Immunol"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"155117","DOI":"10.1016\/j.phymed.2023.155117","article-title":"Isovitexin alleviates hepatic fibrosis by regulating miR-21-mediated PI3K\/Akt signaling and glutathione metabolic pathway: based on transcriptomics and metabolomics","volume":"121","author":"Huang","year":"2023","journal-title":"Phytomedicine"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"886","DOI":"10.21037\/atm-22-3593","article-title":"Exploration of new therapeutic targets for viral hepatic fibrosis, alcoholic hepatic fibrosis, and non-alcoholic hepatic fibrosis","volume":"10","author":"Wang","year":"2022","journal-title":"Ann Transl Med"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1625","DOI":"10.1097\/HEP.0000000000000182","article-title":"Hepatic fibrosis: targeting peroxisome proliferator-activated receptor alpha from mechanism to medicines","volume":"78","author":"Gong","year":"2023","journal-title":"Hepatology"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"8355","DOI":"10.3748\/wjg.v23.i47.8355","article-title":"Rifaximin ameliorates hepatic encephalopathy and endotoxemia without affecting the gut microbiome diversity","volume":"23","author":"Kaji","year":"2017","journal-title":"World J Gastroenterol"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"530","DOI":"10.3390\/metabo13040530","article-title":"Deciphering gut microbiome responses upon microplastic exposure via integrating metagenomics and activity-based metabolomics","volume":"13","author":"Tu","year":"2023","journal-title":"Meta"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"1347120","DOI":"10.3389\/fphar.2024.1347120","article-title":"Gut microbes combined with metabolomics reveal the protective effects of Qijia Rougan decoction against CCl4-induced hepatic fibrosis","volume":"15","author":"Li","year":"2024","journal-title":"Front Pharmacol"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1053\/j.gastro.2020.04.077","article-title":"Contribution of the intestinal microbiome and gut barrier to hepatic disorders","volume":"159","author":"Chopyk","year":"2020","journal-title":"Gastroenterology"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"2155018","DOI":"10.1080\/19490976.2022.2155018","article-title":"Alterations in gut microbiome and metabolomics in chronic hepatitis B infection-associated liver disease and their impact on peripheral immune response","volume":"15","author":"Shen","year":"2022","journal-title":"Gut Microbes"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"1284742","DOI":"10.3389\/fphar.2023.1284742","article-title":"The regulatory role and mechanism of exosomes in hepatic fibrosis","volume":"14","author":"Yao","year":"2023","journal-title":"Front Pharmacol"},{"key":"ref11","author":"Zhang","year":"2023"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"e34353","DOI":"10.1097\/MD.0000000000034353","article-title":"Mechanisms of main components in Curcuma longa L. on hepatic fibrosis based on network pharmacology and molecular docking: A review","volume":"102","author":"Han","year":"2023","journal-title":"Medicine"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"114073","DOI":"10.1016\/j.jpba.2021.114073","article-title":"Investigation of the therapeutic effect of Yinchen Wuling powder on CCl4-induced hepatic fibrosis in rats by 1H NMR and MS-based metabolomics analysis","volume":"200","author":"Zhang","year":"2021","journal-title":"J Pharm Biomed Anal"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"3253","DOI":"10.3390\/cimb44070224","article-title":"Identification of gut microbiome metabolites via network pharmacology analysis in treating alcoholic liver disease","volume":"44","author":"Oh","year":"2022","journal-title":"Curr Issues Mol Biol"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"671","DOI":"10.3892\/etm.2014.1775","article-title":"Effects of Fructus Akebiae on learning and memory impairment in a scopolamine-induced animal model of dementia","volume":"8","author":"Wang","year":"2014","journal-title":"Exp Ther Med"},{"key":"ref16","first-page":"433","article-title":"Clinical effect of the extract of TCM Fructus akebiae combined with ursodeoxycholic acid on nonalcoholic fatty liver disease","volume":"32","author":"Jin","year":"2019","journal-title":"Pak J Pharm Sci"},{"key":"ref17","volume-title":"Pharmacopoeia of People's Public of China. Part 1 ed","year":"2020"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"651","DOI":"10.3892\/mmr.2020.11134","article-title":"TLR4 mediates inflammation and hepatic fibrosis induced by chronic intermittent hypoxia in rats","volume":"22","author":"Lin","year":"2020","journal-title":"Mol Med Rep"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"113204","DOI":"10.1016\/j.biopha.2022.113204","article-title":"Gut microbiota combined with metabolomics reveal the mechanism of curcumol on liver fibrosis in mice","volume":"152","author":"Zheng","year":"2022","journal-title":"Biomed Pharmacother"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"187","DOI":"10.3389\/fphar.2018.00187","article-title":"Exploring the mechanism of Dangguiliuhuang decoction against hepatic fibrosis by network pharmacology and experimental validation","volume":"9","author":"Cao","year":"2018","journal-title":"Front Pharmacol"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"946628","DOI":"10.3389\/fimmu.2022.946628","article-title":"The gut\u2013liver axis in immune remodeling of hepatic cirrhosis","volume":"13","author":"Guan","year":"2022","journal-title":"Front Immunol"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1016\/j.cca.2021.10.014","article-title":"Gut microbiome and metabolic response in non-alcoholic fatty liver disease","volume":"523","author":"Abuwani","year":"2021","journal-title":"Clin Chim Acta"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2014\/192749","article-title":"Akebia trifoliate (Thunb.) KoidzSeed extract inhibits the proliferation of human hepatocellular carcinoma cell lines via inducing endoplasmic reticulum stress","volume":"2014","author":"Lu","year":"2014","journal-title":"Evid Based Complement Alternat Med"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"27(1)","DOI":"10.3390\/molecules27010324","article-title":"Glutathione in brain disorders and aging","volume":"27","author":"Iskusnykh","year":"2022","journal-title":"Molecules"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"199","DOI":"10.3390\/ijms22010199","article-title":"The role of the gut microbiome in liver cirrhosis treatment","volume":"22","author":"Lee","year":"2020","journal-title":"Int J Mol Sci"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"101600","DOI":"10.1016\/j.redox.2020.101600","article-title":"Curcumin blunts epithelial-mesenchymal transition of hepatocytes to alleviate hepatic fibrosis through regulating oxidative stress and autophagy","volume":"36","author":"Kong","year":"2020","journal-title":"Redox Biol"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"4172","DOI":"10.1038\/s41598-023-30582-3","article-title":"Mangiferin relieves CCl4-induced liver fibrosis in mice","volume":"13","author":"Zhang","year":"2023","journal-title":"Sci Rep"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"102274","DOI":"10.1016\/j.redox.2022.102274","article-title":"Mulberrin confers protection against hepatic fibrosis by Trim31\/Nrf2 signaling","volume":"51","author":"Ge","year":"2022","journal-title":"Redox Biol"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"10","DOI":"10.3389\/fcimb.2020.00018","article-title":"Gut microbial Dysbiosis is associated with Profibrotic factors in liver fibrosis mice. Frontiers in cellular and infection","volume":"10","author":"Wan","year":"2020","journal-title":"Microbiology"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"110959","DOI":"10.1016\/j.nut.2020.110959","article-title":"Dietary fiber regulates intestinal flora and suppresses liver and systemic inflammation to alleviate liver fibrosis in mice","volume":"81","author":"Li","year":"2021","journal-title":"Nutrition"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"3900","DOI":"10.3390\/ijms24043900","article-title":"Akkermansia muciniphila as a next-generation probiotic in modulating human metabolic homeostasis and disease progression: A role mediated by gut\u2013liver\u2013brain axes?","volume":"24","author":"Jian","year":"2023","journal-title":"Int J Mol Sci"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"451","DOI":"10.3969\/j.issn.1673-7202.2023.04.002","article-title":"Mechanism of Huoxue Qushi Fomula in treating fatty liver based on network pharmacology and pharmacological experiments","volume":"18","author":"Tingyu","year":"2023","journal-title":"World Chin Med"},{"key":"ref33","first-page":"537","article-title":"Investigation of the mechanism of urolithin A in the treatment of renal fibrosis based on network pharma\u2043cology and experimental verification","volume":"44","author":"Chen","year":"2024","journal-title":"Chin J Hosp Pharm"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"35","DOI":"10.19879\/j.cnki.1005-5304.202312018","article-title":"Study on the prescription and syndrome law of TCM in the treatment of non-alcoholic fatty liver disease based on latent structure model and association rules","volume":"31","author":"Xuanzi","year":"2024","journal-title":"Chin J Inf TCM"},{"key":"ref35","first-page":"1201","article-title":"Role of JNK\/c-Jun in liver stress and injury","volume":"34","author":"Li","year":"2013","journal-title":"Acad J Chin PLA Med Sch"},{"key":"ref36","first-page":"353","article-title":"Protective effect of ursolic acid on hepatic ischemia\/reperfusion injury in mice by regulating PTGS2","volume":"10","author":"Wen","year":"2022","journal-title":"Pract J Organ Transplant"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2024.1492383\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T07:37:02Z","timestamp":1738741022000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2024.1492383\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,5]]},"references-count":36,"alternative-id":["10.3389\/fmed.2024.1492383"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2024.1492383","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,5]]},"article-number":"1492383"}}