{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T22:26:59Z","timestamp":1759962419082,"version":"3.41.2"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T00:00:00Z","timestamp":1657152000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2021M702910"],"award-info":[{"award-number":["2021M702910"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>This study aimed to investigate the potential role of gut microbiota in the hepatotoxicity of sodium valproate (SVP) and the protective effect of ginsenoside compound K (G-CK) administration against SVP-induced hepatotoxicity in rats. Measurements of 16S rRNA showed that SVP supplementation led to a 140.749- and 248.900-fold increase in the relative abundance of <jats:italic>Akkermansia muciniphila<\/jats:italic> (<jats:italic>A. muciniphila<\/jats:italic>) and <jats:italic>Bifidobacterium pseudolongum<\/jats:italic> (<jats:italic>B. pseudolongum<\/jats:italic>), respectively (<jats:italic>p<\/jats:italic> &amp;lt; 0.05). The increase in <jats:italic>A. muciniphila<\/jats:italic> was almost completely reversed by G-CK treatment. The relative abundance of <jats:italic>A. muciniphila<\/jats:italic> was strongly positively correlated with aspartate transaminase (AST) and alanine aminotransferase (ALT) levels (<jats:italic>r<\/jats:italic> &amp;gt; 0.78, <jats:italic>p<\/jats:italic> &amp;lt; 0.05). The PICRUSt analysis showed that G-CK could inhibit the changes of seven pathways caused by SVP, of which four pathways, including the fatty acid biosynthesis, lipid biosynthesis, glycolysis\/gluconeogenesis, and pyruvate metabolism, were found to be negatively correlated with AST and ALT levels (<jats:italic>r<\/jats:italic> \u2265 0.70, <jats:italic>p<\/jats:italic> &amp;lt; 0.01 or &amp;lt; 0.05). In addition, the glycolysis\/gluconeogenesis and pyruvate metabolism were negatively correlated with the relative abundance of <jats:italic>A. muciniphila<\/jats:italic> (<jats:italic>r<\/jats:italic> &amp;gt; 0.65, <jats:italic>p<\/jats:italic> &amp;lt; 0.01 or &amp;lt; 0.05). This alteration of the gut microbiota composition that resulted in observed changes to the glycolysis\/gluconeogenesis and pyruvate metabolism may be involved in both the hepatotoxicity of SVP and the protective effect of G-CK administration against SVP-induced hepatotoxicity. Our study provides new evidence linking the gut microbiota with SVP-induced hepatotoxicity.<\/jats:p>","DOI":"10.3389\/fmicb.2022.936585","type":"journal-article","created":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T08:34:15Z","timestamp":1657182855000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Gut Microbiota Modulates the Protective Role of Ginsenoside Compound K Against Sodium Valproate-Induced Hepatotoxicity in Rat"],"prefix":"10.3389","volume":"13","author":[{"given":"Luping","family":"Zhou","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangchang","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianwei","family":"Liao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lulu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongsheng","family":"Ouyang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2","DOI":"10.3354\/ame01753","article-title":"Minor revision to V4 region SSU rRNA 806R gene primer greatly increases detection of SAR11 bacterioplankton","volume":"75","author":"Apprill","year":"2015","journal-title":"Aquatic. Microbial. Ecol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"965","DOI":"10.3389\/fphar.2017.00965","article-title":"Single- and multiple-dose trials to determine the pharmacokinetics, safety, tolerability, and sex effect of oral ginsenoside compound k in healthy chinese volunteers","volume":"8","author":"Chen","year":"","journal-title":"Front. Pharmacol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"636","DOI":"10.3389\/fphar.2017.00636","article-title":"Food and sex-related impacts on the pharmacokinetics of a single-dose of ginsenoside compound K in healthy subjects","volume":"8","author":"Chen","year":"","journal-title":"Front. Pharmacol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1016\/j.scitotenv.2018.10.387","article-title":"Gut microbiota dysbiosis correlates with a low-dose PCB126-induced dyslipidemia and non-alcoholic fatty liver disease","volume":"653","author":"Chi","year":"2019","journal-title":"Sci. Total Environ."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1671","DOI":"10.1007\/s00213-018-5006-5","article-title":"Differential effects of psychotropic drugs on microbiome composition and gastrointestinal function","volume":"236","author":"Cussotto","year":"2019","journal-title":"Psychopharmacology (Berl)"},{"key":"B6","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1139\/y04-096","article-title":"Effects of valproic acid on cardiac metabolism","volume":"82","author":"Daniels","year":"2004","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"145","DOI":"10.2174\/1574892810666150317144511","article-title":"HDAC inhibitors as novel anti-cancer therapeutics","volume":"10","author":"De Souza","year":"2015","journal-title":"Recent. Pat. Anticancer Drug Discov."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1093\/jn\/nxy084","article-title":"The hepatotoxicity of palmitic acid in zebrafish involves the intestinal microbiota","volume":"148","author":"Ding","year":"2018","journal-title":"J. Nutr."},{"key":"B9","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.jhep.2018.02.024","article-title":"Gut microbiota mediates diurnal variation of acetaminophen induced acute liver injury in mice","volume":"69","author":"Gong","year":"2018","journal-title":"J. Hepatol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1002\/npr2.12196","article-title":"Neuropharmacology of antiseizure drugs","volume":"41","author":"Hakami","year":"2021","journal-title":"Neuropsychopharmacol. Rep."},{"key":"B11","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.jchromb.2014.08.011","article-title":"An effective assessment of valproate sodium-induced hepatotoxicity with UPLC-MS and (1)HNMR-based metabonomics approach","volume":"969","author":"Huo","year":"2014","journal-title":"J. Chromatogr. B Anal. Technol. Biomed. Life Sci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"10038","DOI":"10.1073\/pnas.1507645112","article-title":"Gut microbiota facilitates dietary heme-induced epithelial hyperproliferation by opening the mucus barrier in colon","volume":"112","author":"Ijssennagger","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"B13","doi-asserted-by":"publisher","first-page":"114844","DOI":"10.1016\/j.envpol.2020.114844","article-title":"Effects of difenoconazole on hepatotoxicity, lipid metabolism and gut microbiota in zebrafish (Danio rerio)","volume":"265","author":"Jiang","year":"2020","journal-title":"Environ. Pollut."},{"key":"B14","doi-asserted-by":"publisher","first-page":"451","DOI":"10.5142\/jgr.2013.37.451","article-title":"Pharmacokinetics of ginsenoside Rb1 and its metabolite compound K after oral administration of Korean Red Ginseng extract","volume":"37","author":"Kim","year":"2013","journal-title":"J. Ginseng. Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"9","DOI":"10.3390\/ijms18091912","article-title":"Mitochondrial liver toxicity of valproic acid and its acid derivatives is related to inhibition of and#945;-lipoamide dehydrogenase","volume":"18","author":"Kudin","year":"2017","journal-title":"Int. J. Mol. Sci."},{"key":"B16","doi-asserted-by":"publisher","first-page":"114624","DOI":"10.1016\/j.taap.2019.114624","article-title":"Role of intestinal microbiota-mediated genipin dialdehyde intermediate formation in geniposide-induced hepatotoxicity in rats","volume":"377","author":"Li","year":"2019","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"129572","DOI":"10.1016\/j.chemosphere.2021.129572","article-title":"The hepatotoxicity of altrazine exposure in mice involves the intestinal microbiota","volume":"272","author":"Liu","year":"2021","journal-title":"Chemosphere"},{"key":"B18","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1186\/s13229-018-0251-3","article-title":"The valproic acid rat model of autism presents with gut bacterial dysbiosis similar to that in human autism","volume":"9","author":"Liu","year":"2018","journal-title":"Mol. Autism"},{"key":"B19","doi-asserted-by":"publisher","first-page":"234","DOI":"10.21037\/atm-22-501","article-title":"A narrative review of the pharmacology of ginsenoside compound K","volume":"10","author":"Liu","year":"2022","journal-title":"Ann. Transl. Med"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1457","DOI":"10.3390\/nu10101457","article-title":"Gut microbiota's relationship with liver disease and role in hepatoprotection by dietary natural products and probiotics","volume":"10","author":"Meng","year":"2018","journal-title":"Nutrients"},{"key":"B21","doi-asserted-by":"publisher","first-page":"104","DOI":"10.3390\/molecules27010104","article-title":"Insights into structural modifications of valproic acid and their pharmacological profile","volume":"27","author":"Mishra","year":"2021","journal-title":"Molecules"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1323","DOI":"10.1016\/j.clinbiochem.2013.06.012","article-title":"Adverse drug reactions induced by valproic acid","volume":"46","author":"Nanau","year":"2013","journal-title":"Clin. Biochem."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1403","DOI":"10.1111\/1462-2920.13023","article-title":"Every base matters: assessing small subunit rRNA primers for marine microbiomes with mock communities, time series and global field samples","volume":"18","author":"Parada","year":"2016","journal-title":"Environ. Microbiol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"9300","DOI":"10.1038\/s41598-020-66251-y","article-title":"An anticonvulsive drug, valproic acid (valproate), has effects on the biosynthesis of fatty acids and polyketides in microorganisms","volume":"10","author":"Poolchanuan","year":"2020","journal-title":"Sci. Rep."},{"key":"B25","doi-asserted-by":"publisher","first-page":"75","DOI":"10.18053\/jctres.04.201801.005","article-title":"Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives","volume":"4","author":"Ramachandran","year":"2018","journal-title":"J. Clin. Transl. Res."},{"key":"B26","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1016\/j.celrep.2017.03.080","article-title":"NLRP6 Protects Il10(-\/-) mice from colitis by limiting colonization of akkermansia muciniphila","volume":"19","author":"Seregin","year":"2017","journal-title":"Cell Rep."},{"key":"B27","doi-asserted-by":"publisher","first-page":"408","DOI":"10.21037\/atm-22-793","article-title":"Effects of ginsenoside compound K on colitis-associated colorectal cancer and gut microbiota profiles in mice","volume":"10","author":"Shao","year":"2022","journal-title":"Ann. Transl. Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1007\/s10545-014-9787-3","article-title":"The spectrum of pyruvate oxidation defects in the diagnosis of mitochondrial disorders","volume":"38","author":"Sperl","year":"2015","journal-title":"J. Inherit. Metab. Dis."},{"key":"B29","doi-asserted-by":"publisher","first-page":"962","DOI":"10.3390\/biomedicines10050962","article-title":"SARS-CoV-2 infection, sex-related differences, and a possible personalized treatment approach with valproic acid: a review","volume":"10","author":"Stakisaitis","year":"2022","journal-title":"Biomedicines"},{"key":"B30","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.pediatrneurol.2017.09.013","article-title":"Antiepileptic drugs and liver disease","volume":"77","author":"Vidaurre","year":"2017","journal-title":"Pediatr. Neurol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"5707","DOI":"10.1021\/acs.jafc.9b08313","article-title":"High l-carnitine ingestion impairs liver function by disordering gut bacteria composition in mice","volume":"68","author":"Wu","year":"2020","journal-title":"J. Agric. Food Chem."},{"key":"B32","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1002\/hep.24018","article-title":"Enteric dysbiosis associated with a mouse model of alcoholic liver disease","volume":"53","author":"Yan","year":"2011","journal-title":"Hepatology"},{"key":"B33","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1016\/j.fitote.2014.11.019","article-title":"A review of biotransformation and pharmacology of ginsenoside compound K","volume":"100","author":"Yang","year":"2015","journal-title":"Fitoterapia"},{"key":"B34","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1186\/s13020-021-00470-x","article-title":"Herbal therapy for ameliorating non-alcoholic fatty liver disease via rebuilding the intestinal microecology","volume":"16","author":"Yang","year":"2021","journal-title":"Chin. Med."},{"key":"B35","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1002\/hep.29327","article-title":"The liver-gut microbiota axis modulates hepatotoxicity of tacrine in the rat","volume":"67","author":"Yip","year":"2018","journal-title":"Hepatology"},{"key":"B36","doi-asserted-by":"publisher","first-page":"3227","DOI":"10.1080\/10408398.2018.1517725","article-title":"A next generation probiotic, Akkermansia muciniphila","volume":"59","author":"Zhai","year":"2019","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"B37","doi-asserted-by":"publisher","first-page":"241","DOI":"10.2131\/jts.42.241","article-title":"Alteration of gut microbial community after N,N-Dimethylformamide exposure","volume":"42","author":"Zhang","year":"2017","journal-title":"J. Toxicol. Sci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1111\/1751-7915.13410","article-title":"Akkermansia muciniphila is a promising probiotic","volume":"12","author":"Zhang","year":"2019","journal-title":"Microb. Biotechnol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"114829","DOI":"10.1016\/j.taap.2019.114829","article-title":"Ginsenoside compound K alleviates sodium valproate-induced hepatotoxicity in rats via antioxidant effect, regulation of peroxisome pathway and iron homeostasis","volume":"386","author":"Zhou","year":"","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"115555","DOI":"10.1016\/j.taap.2021.115555","article-title":"Evaluating the protective effects of individual or combined ginsenoside compound K and the downregulation of soluble epoxide hydrolase expression against sodium valproate-induced liver cell damage","volume":"422","author":"Zhou","year":"2021","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"10149","DOI":"10.1021\/acs.est.0c01543","article-title":"Oral exposure to 1,4-dioxane induces hepatic inflammation in mice: the potential promoting effect of the gut microbiome","volume":"54","author":"Zhou","year":"","journal-title":"Environ. Sci. Technol."}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2022.936585\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T08:34:20Z","timestamp":1657182860000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2022.936585\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,7]]},"references-count":41,"alternative-id":["10.3389\/fmicb.2022.936585"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2022.936585","relation":{},"ISSN":["1664-302X"],"issn-type":[{"type":"electronic","value":"1664-302X"}],"subject":[],"published":{"date-parts":[[2022,7,7]]},"article-number":"936585"}}