{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T16:12:17Z","timestamp":1789661537956,"version":"4.0.1"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,15]],"date-time":"2022-06-15T00:00:00Z","timestamp":1655251200000},"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":["31772450"],"award-info":[{"award-number":["31772450"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, whose etiology is poorly understood. Accumulating evidence indicates that gut microbiota plays an important role in the occurrence and progression of various human diseases, including NAFLD. In this study, NAFLD mouse models were established by feeding a high-fat diet (HFD). Baicalein, a natural flavonoid with multiple biological activities, was administered by gavage, and its protective effect on NAFLD was analyzed by histopathological and blood factor analysis. Gut microbiota analysis demonstrated that baicalein could remodel the overall structure of the gut microbiota from NAFLD model mice, especially <jats:italic>Anaerotruncus<\/jats:italic>, <jats:italic>Lachnoclostridium,<\/jats:italic> and <jats:italic>Mucispirillum.<\/jats:italic> Transcriptomic analysis showed baicalein restored the expressions of numerous genes that were upregulated in hepatocytes of NAFLD mice, such as <jats:italic>Apoa4<\/jats:italic>, <jats:italic>Pla2g12a<\/jats:italic>, <jats:italic>Elovl7<\/jats:italic>, <jats:italic>Slc27a4<\/jats:italic>, <jats:italic>Hilpda<\/jats:italic>, <jats:italic>Fabp4<\/jats:italic>, <jats:italic>Vldlr<\/jats:italic>, <jats:italic>Gpld1<\/jats:italic>, and <jats:italic>Apom<\/jats:italic>. Metabolomics analysis proved that baicalein mainly regulated the processes associated with lipid metabolism, such as alpha-Linolenic acid, 2-Oxocarboxylic acid, Pantothenate and CoA biosynthesis, and bile secretion. Multi-omics analysis revealed that numerous genes regulated by baicalein were significantly correlated with pathways related to lipid metabolism and biosynthesis and secrection of bile acid, and baicalein might affect lipid metabolism in liver <jats:italic>via<\/jats:italic> regulating the ecological structure of gut microbiota in NAFLD mice. Our results elucidated the correlated network among diet, gut microbiota, metabolomic, and transcriptional profiling in the liver. This knowledge may help explore novel therapeutic approaches against NAFLD.<\/jats:p>","DOI":"10.3389\/fphar.2022.925349","type":"journal-article","created":{"date-parts":[[2022,6,15]],"date-time":"2022-06-15T04:43:57Z","timestamp":1655268237000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":22,"title":["Multi-Omics Reveals Inhibitory Effect of Baicalein on Non-Alcoholic Fatty Liver Disease in Mice"],"prefix":"10.3389","volume":"13","author":[{"given":"Ping","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianran","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmei","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baofeng","family":"Chai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2713","DOI":"10.1002\/jcb.27635","article-title":"Interaction of Gut Microbiota with Dysregulation of Bile Acids in the Pathogenesis of Nonalcoholic Fatty Liver Disease and Potential Therapeutic Implications of Probiotics","volume":"120","author":"Chen","year":"2019","journal-title":"J. Cell Biochem."},{"key":"B2","doi-asserted-by":"publisher","first-page":"153693","DOI":"10.1016\/j.phymed.2021.153693","article-title":"A Botanical Dietary Supplement from White Peony and Licorice Attenuates Nonalcoholic Fatty Liver Disease by Modulating Gut Microbiota and Reducing Inflammation","volume":"91","author":"Chen","year":"2021","journal-title":"Phytomedicine"},{"key":"B3","doi-asserted-by":"publisher","first-page":"2119","DOI":"10.3390\/cells10082119","article-title":"High-Fat Diet Alters the Retinal Transcriptome in the Absence of Gut Microbiota","volume":"10","author":"Dao","year":"2021","journal-title":"Cells"},{"key":"B4","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1016\/j.metabol.2017.03.013","article-title":"Non-alcoholic Fatty Liver Disease: An Update with Special Focus on the Role of Gut Microbiota","volume":"71","author":"Doulberis","year":"2012","journal-title":"Metabolism"},{"key":"B5","doi-asserted-by":"publisher","first-page":"812293","DOI":"10.3389\/fimmu.2022.812293","article-title":"Multi-Omics Analysis Reveals Aberrant Gut-Metabolome-Immune Network in Schizophrenia","volume":"13","author":"Fan","year":"2022","journal-title":"Front. Immunol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"2974","DOI":"10.3748\/wjg.v24.i27.2974","article-title":"Pathogenesis of Non-alcoholic Fatty Liver Disease in Children and Adolescence: From \"two Hit Theory\" to \"multiple Hit Model\"","volume":"24","author":"Fang","year":"2018","journal-title":"World J. Gastroenterol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1746","DOI":"10.3748\/wjg.v20.i7.1746","article-title":"Modulation of Hepatic Steatosis by Dietary Fatty Acids","volume":"20","author":"Ferramosca","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1016\/s1499-3872(15)60026-1","article-title":"Gut Microbiota and Non-alcoholic Fatty Liver Disease","volume":"14","author":"Gkolfakis","year":"2015","journal-title":"Hepatobiliary Pancreat. Dis. Int."},{"key":"B9","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1016\/j.jhep.2021.05.022","article-title":"Burden of Non-alcoholic Fatty Liver Disease in Asia, the Middle East and North Africa: Data from Global Burden of Disease 2009-2019","volume":"75","author":"Golabi","year":"2021","journal-title":"J. Hepatol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"6818","DOI":"10.1039\/d0fo00436g","article-title":"Ganoderic Acid A from Ganoderma Lucidum Ameliorates Lipid Metabolism and Alters Gut Microbiota Composition in Hyperlipidemic Mice Fed a High-Fat Diet","volume":"11","author":"Guo","year":"2020","journal-title":"Food Funct."},{"key":"B11","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1007\/s12602-018-9419-6","article-title":"Are Probiotics Effective in Targeting Alcoholic Liver Diseases?","volume":"11","author":"Hong","year":"2019","journal-title":"Probiotics Antimicrob. Proteins"},{"key":"B12","doi-asserted-by":"publisher","first-page":"2091","DOI":"10.1016\/j.ajpath.2021.08.006","article-title":"Microbial Reconstitution Improves Aging-Driven Lacrimal Gland Circadian Dysfunction","volume":"191","author":"Jiao","year":"2021","journal-title":"Am. J. Pathol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"482","DOI":"10.3390\/metabo11080482","article-title":"Gut Microbiome and Metabolome Profiles Associated with High-Fat Diet in Mice","volume":"11","author":"Jo","year":"2021","journal-title":"Metabolites"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1016\/j.metabol.2016.05.003","article-title":"Non-alcoholic Fatty Liver Disease and Dyslipidemia: An Update","volume":"65","author":"Katsiki","year":"2016","journal-title":"Metabolism"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1313","DOI":"10.1002\/hep.20701","article-title":"Design and Validation of a Histological Scoring System for Nonalcoholic Fatty Liver Disease","volume":"41","author":"Kleiner","year":"2005","journal-title":"Hepatology"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.3389\/fimmu.2017.01159","article-title":"Fructose: A Dietary Sugar in Crosstalk with Microbiota Contributing to the Development and Progression of Non-alcoholic Liver Disease","volume":"8","author":"Lambertz","year":"2017","journal-title":"Front. Immunol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1787","DOI":"10.1136\/gutjnl-2012-303816","article-title":"Intestinal Microbiota Determines Development of Non-alcoholic Fatty Liver Disease in Mice","volume":"62","author":"Le Roy","year":"2013","journal-title":"Gut"},{"key":"B18","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1016\/j.jff.2017.12.036","article-title":"Serum Metabolomics Analysis for Biomarker of Lactobacillus Plantarum NCU116 on Hyperlipidaemic Rat Model Feed by High Fat Diet","volume":"42","author":"Li","year":"2018","journal-title":"J. Funct. Foods"},{"key":"B19","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1016\/j.bbrc.2020.07.045","article-title":"Baicalein Enhanced Cisplatin Sensitivity of Gastric Cancer Cells by Inducing Cell Apoptosis and Autophagy via Akt\/mTOR and Nrf2\/Keap 1 Pathway","volume":"531","author":"Li","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B20","doi-asserted-by":"publisher","first-page":"9732","DOI":"10.18632\/aging.202728","article-title":"Comprehensive Multiomics Analysis of the Effect of Ginsenoside Rb1 on Hyperlipidemia","volume":"13","author":"Lianqun","year":"2021","journal-title":"Aging (Albany NY)"},{"key":"B21","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.jnutbio.2019.03.005","article-title":"Fish Oil Alleviates Circadian Bile Composition Dysregulation in Male Mice with NAFLD","volume":"69","author":"Liu","year":"2019","journal-title":"J. Nutr. Biochem."},{"key":"B22","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.coph.2021.09.007","article-title":"Non-alcoholic Fatty Liver Disease: Current Therapeutic Options","volume":"61","author":"Majumdar","year":"2021","journal-title":"Curr. Opin. Pharmacol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"2416","DOI":"10.1096\/fj.07-102723","article-title":"Gut Microbiota Modulation with Norfloxacin and Ampicillin Enhances Glucose Tolerance in Mice","volume":"22","author":"Membrez","year":"2008","journal-title":"FASEB J."},{"key":"B24","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/j.plipres.2012.11.002","article-title":"Cholesterol Metabolism and the Pathogenesis of Non-alcoholic Steatohepatitis","volume":"52","author":"Musso","year":"2013","journal-title":"Prog. Lipid Res."},{"key":"B25","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1152\/physiolgenomics.00012.2017","article-title":"Microbiome and NAFLD: Potential Influence of Aerobic Fitness and Lifestyle Modification","volume":"49","author":"Panasevich","year":"2017","journal-title":"Physiol. Genomics"},{"key":"B26","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1136\/gutjnl-2015-310283","article-title":"Microbiota-induced Obesity Requires Farnesoid X Receptor","volume":"66","author":"Pars\u00e9us","year":"2017","journal-title":"Gut"},{"key":"B27","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1016\/j.mce.2012.06.002","article-title":"Baicalein, a Natural Product, Selectively Activating AMPK\u03b1(2) and Ameliorates Metabolic Disorder in Diet-Induced Mice","volume":"362","author":"Pu","year":"2012","journal-title":"Mol. Cell. Endocrinol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1506","DOI":"10.1161\/CIRCRESAHA.113.300512","article-title":"Platelets as Cellular Effectors of Inflammation in Vascular Diseases","volume":"112","author":"Rondina","year":"2013","journal-title":"Circ. Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"2847","DOI":"10.2337\/db14-1916","article-title":"Dietary Polyphenols Promote Growth of the Gut Bacterium Akkermansia Muciniphila and Attenuate High-Fat Diet-Induced Metabolic Syndrome","volume":"64","author":"Roopchand","year":"2015","journal-title":"Diabetes"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1926","DOI":"10.1111\/jgh.12643","article-title":"Clinical Association between Non-alcoholic Fatty Liver Disease and the Development of Hypertension","volume":"29","author":"Ryoo","year":"2014","journal-title":"J. Gastroenterol. Hepatol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"2764","DOI":"10.3390\/ijms23052764","article-title":"Natural Compounds for Counteracting Nonalcoholic Fatty Liver Disease (NAFLD): Advantages and Limitations of the Suggested Candidates","volume":"23","author":"Salvoza","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B32","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1016\/j.tem.2019.08.008","article-title":"NAFLD and Atherosclerosis: Two Sides of the Same Dysmetabolic Coin?","volume":"30","author":"Stols-Gon\u00e7alves","year":"2019","journal-title":"Trends Endocrinol. Metab."},{"key":"B33","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1080\/17474124.2019.1569513","article-title":"Gut Microbiota: Novel Therapeutic Target for Nonalcoholic Fatty Liver Disease","volume":"13","author":"Suk","year":"2019","journal-title":"Expert. Rev. Gastroenterol. Hepatol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1039\/c9fo02237f","article-title":"Baicalein Reduces Hepatic Fat Accumulation by Activating AMPK in Oleic Acid-Induced HepG2 Cells and High-Fat Diet-Induced Non-insulin-resistant Mice","volume":"11","author":"Sun","year":"2020","journal-title":"Food Funct."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1293","DOI":"10.1016\/j.bbalip.2019.05.016","article-title":"Turnover of Bile Acids in Liver, Serum and Caecal Content by High-Fat Diet Feeding Affects Hepatic Steatosis in Rats","volume":"1864","author":"Tang","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Cell Biol. Lipids"},{"key":"B36","doi-asserted-by":"publisher","first-page":"454","DOI":"10.14218\/JCTH.2020.00012","article-title":"Chronic Liver Disease and Silymarin: A Biochemical and Clinical Review","volume":"8","author":"Tighe","year":"2020","journal-title":"J. Clin. Transl. Hepatol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"700058","DOI":"10.3389\/fnut.2021.700058","article-title":"Role of the Gut Microbiota in Regulating Non-alcoholic Fatty Liver Disease in Children and Adolescents","volume":"8","author":"Tokuhara","year":"2021","journal-title":"Front. Nutr."},{"key":"B38","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1002\/hep.22603","article-title":"Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis: Selected Practical Issues in Their Evaluation and Management","volume":"49","author":"Vuppalanchi","year":"2009","journal-title":"Hepatology"},{"key":"B39","doi-asserted-by":"publisher","first-page":"600","DOI":"10.3389\/fmicb.2020.00600","article-title":"Supplemental Clostridium Butyricum Modulates Lipid Metabolism through Shaping Gut Microbiota and Bile Acid Profile of Aged Laying Hens","volume":"11","author":"Wang","year":"2020","journal-title":"Front. Microbiol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1186\/s12859-017-1579-y","article-title":"metaX: a Flexible and Comprehensive Software for Processing Metabolomics Data","volume":"18","author":"Wen","year":"2017","journal-title":"BMC Bioinforma."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1172","DOI":"10.1016\/j.cmet.2019.11.006","article-title":"Fatty Liver Disease Caused by High-Alcohol-Producing Klebsiella pneumoniae","volume":"30","author":"Yuan","year":"2019","journal-title":"Cell Metab."},{"key":"B42","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1136\/gutjnl-2019-319664","article-title":"Dietary Cholesterol Drives Fatty Liver-Associated Liver Cancer by Modulating Gut Microbiota and Metabolites","volume":"70","author":"Zhang","year":"2021","journal-title":"Gut"},{"key":"B43","doi-asserted-by":"publisher","first-page":"110990","DOI":"10.1016\/j.fct.2019.110990","article-title":"Baicalein Attenuates Impairment of Hepatic Lysosomal Acidification Induced by High Fat Diet via Maintaining V-ATPase Assembly","volume":"136","author":"Zhu","year":"2020","journal-title":"Food Chem. Toxicol."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.925349\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,15]],"date-time":"2022-06-15T04:44:03Z","timestamp":1655268243000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.925349\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,15]]},"references-count":43,"alternative-id":["10.3389\/fphar.2022.925349"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2022.925349","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,15]]},"article-number":"925349"}}