{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T16:21:51Z","timestamp":1790785311866,"version":"4.1.0"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2021,8,28]],"date-time":"2021-08-28T00:00:00Z","timestamp":1630108800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:p>Alcohol\u2010associated liver disease (ALD) is a significant clinical problem for which the most effective therapy is alcohol abstinence. The two aims of this study were, first, to identify the liver transcriptome, fecal microbiome, and portal serum metabolome at peak injury and during early and late resolution from ALD; and second, to integrate their interactions and understand better the pathogenesis of ALD. To provoke alcohol\u2010induced liver injury, female and male wild\u2010type mice were fed the control or ethanol Lieber\u2010DeCarli diets for 6\u00a0weeks. To study early and late resolution, alcohol was withdrawn from the diet and mice were sacrificed after 3 and 14\u00a0days, respectively. At peak injury, there was increased signal transducer and activator of transcription (<jats:italic toggle=\"yes\">Stat3<\/jats:italic>), <jats:italic toggle=\"yes\">Rho\u2010GTPases<\/jats:italic>, <jats:italic toggle=\"yes\">Tec kinase<\/jats:italic> and glycoprotein VI (<jats:italic toggle=\"yes\">Gp6<\/jats:italic>), and decreased peroxisome proliferator\u2013activated receptor signaling. During resolution from ALD, there was up\u2010regulation of vitamin D receptor\/retinoid X receptor, toll\u2010like receptor, <jats:italic toggle=\"yes\">p38<\/jats:italic> and <jats:italic toggle=\"yes\">Stat3<\/jats:italic>, and down\u2010regulation of liver X receptor signaling. Females showed significant changes in catabolic pathways, whereas males increased cellular stress, injury, and immune\u2010response pathways that decreased during resolution. The bacterial genus <jats:italic toggle=\"yes\">Alistipes<\/jats:italic> and the metabolite dipeptide glycyl\u2010L\u2010leucine increased at peak but decreased during resolution from ALD in both genders. Hepatic induction of mitogen\u2010activated protein kinase (<jats:italic toggle=\"yes\">Map3k1<\/jats:italic>) correlated with changes in the microbiome and metabolome at peak but was restored during ALD resolution. Inhibition of MAP3K1 protected from ALD in mice. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> Alcohol abstinence restores the liver transcriptome, fecal microbiome, and portal serum metabolome in a gender\u2010specific manner. Integration of multiomics data identified <jats:italic toggle=\"yes\">Map3k1<\/jats:italic> as a key gene driving pathogenesis and resolution from ALD.<\/jats:p>","DOI":"10.1002\/hep4.1793","type":"journal-article","created":{"date-parts":[[2021,8,28]],"date-time":"2021-08-28T07:38:11Z","timestamp":1630136291000},"page":"133-160","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":17,"title":["The Integrated \u201cMultiomics\u201d Landscape at Peak Injury and Resolution From Alcohol\u2010Associated Liver Disease"],"prefix":"10.1097","volume":"6","author":[{"given":"Sukanta","family":"Das","sequence":"first","affiliation":[{"name":"Department of Pathology,University of Illinois at Chicago,Chicago,IL,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodong","family":"Ge","sequence":"additional","affiliation":[{"name":"Department of Pathology,University of Illinois at Chicago,Chicago,IL,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Pathology,University of Illinois at Chicago,Chicago,IL,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romain","family":"Desert","sequence":"additional","affiliation":[{"name":"Department of Pathology,University of Illinois at Chicago,Chicago,IL,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5101-3950","authenticated-orcid":false,"given":"Zhuolun","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Pathology,University of Illinois at Chicago,Chicago,IL,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dipti","family":"Athavale","sequence":"additional","affiliation":[{"name":"Department of Pathology,University of Illinois at Chicago,Chicago,IL,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pathology,University of Illinois at Chicago,Chicago,IL,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harriet","family":"Gaskell","sequence":"additional","affiliation":[{"name":"Department of Pathology,University of Illinois at Chicago,Chicago,IL,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Lantvit","sequence":"additional","affiliation":[{"name":"Department of Pathology,University of Illinois at Chicago,Chicago,IL,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace","family":"Guzman","sequence":"additional","affiliation":[{"name":"Department of Pathology,University of Illinois at Chicago,Chicago,IL,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7941-6804","authenticated-orcid":false,"given":"Natalia","family":"Nieto","sequence":"additional","affiliation":[{"name":"Department of Pathology,University of Illinois at Chicago,Chicago,IL,USA"},{"name":"Department of Medicine,Division of Gastroenterology and Hepatology,University of Illinois at Chicago,Chicago,IL,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2021,8,28]]},"reference":[{"key":"hep41793-bib-0001-20241114","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1053\/j.gastro.2011.09.002","article-title":"Alcoholic liver disease: pathogenesis and new therapeutic targets","volume":"141","year":"2011","journal-title":"Gastroenterology"},{"key":"hep41793-bib-0002-20241114","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/nrgastro.2015.35","article-title":"Alcoholic liver disease: mechanisms of injury and targeted treatment","volume":"12","year":"2015","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"hep41793-bib-0003-20241114","first-page":"147","article-title":"Alcoholic liver disease: pathogenesis and current management","volume":"38","year":"2017","journal-title":"Alcohol Res"},{"key":"hep41793-bib-0004-20241114","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1111\/j.1530-0277.2011.01677.x","article-title":"Chronic alcohol exposure alters gene expression in HepG2 cells","volume":"36","year":"2012","journal-title":"Alcohol Clin Exp Res"},{"key":"hep41793-bib-0005-20241114","doi-asserted-by":"crossref","first-page":"2303","DOI":"10.1016\/S0002-9440(10)63587-0","article-title":"Gene expression profiling of alcoholic liver disease in the baboon (Papio hamadryas) and human liver","volume":"163","year":"2003","journal-title":"Am J Pathol"},{"key":"hep41793-bib-0006-20241114","doi-asserted-by":"crossref","first-page":"6816","DOI":"10.1038\/s41598-017-07161-4","article-title":"Pre\u2010therapy liver transcriptome landscape in Indian and French patients with severe alcoholic hepatitis and steroid responsiveness","volume":"7","year":"2017","journal-title":"Sci Rep"},{"key":"hep41793-bib-0007-20241114","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1016\/j.jhep.2009.03.007","article-title":"Signalling pathways in alcohol\u2010induced liver inflammation","volume":"50","year":"2009","journal-title":"J Hepatol"},{"key":"hep41793-bib-0008-20241114","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1093\/alcalc\/agx025","article-title":"Gut\u2010liver axis and sterile signals in the development of alcoholic liver disease","volume":"52","year":"2017","journal-title":"Alcohol Alcohol"},{"key":"hep41793-bib-0009-20241114","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.jhep.2018.10.023","article-title":"Inflammatory pathways in alcoholic steatohepatitis","volume":"70","year":"2019","journal-title":"J Hepatol"},{"key":"hep41793-bib-0010-20241114","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1053\/j.gastro.2014.01.020","article-title":"Interactions between the intestinal microbiome and liver diseases","volume":"146","year":"2014","journal-title":"Gastroenterology"},{"key":"hep41793-bib-0011-20241114","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1053\/j.gastro.2016.02.073","article-title":"Changes in the intestinal microbiome and alcoholic and nonalcoholic liver diseases: causes or effects?","volume":"150","year":"2016","journal-title":"Gastroenterology"},{"key":"hep41793-bib-0012-20241114","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1111\/acer.12704","article-title":"Alcoholic liver disease: the gut microbiome and liver cross talk","volume":"39","year":"2015","journal-title":"Alcohol Clin Exp Res"},{"key":"hep41793-bib-0013-20241114","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.jhep.2018.10.019","article-title":"Microbiome as a therapeutic target in alcohol\u2010related liver disease","volume":"70","year":"2019","journal-title":"J Hepatol"},{"key":"hep41793-bib-0014-20241114","doi-asserted-by":"crossref","first-page":"514","DOI":"10.4291\/wjgp.v5.i4.514","article-title":"Alterations of the gut microbiome and metabolome in alcoholic liver disease","volume":"5","year":"2014","journal-title":"World J Gastrointest Pathophysiol"},{"key":"hep41793-bib-0015-20241114","doi-asserted-by":"crossref","first-page":"22672","DOI":"10.1074\/jbc.M114.552141","article-title":"High mobility group box\u20101 (HMGB1) participates in the pathogenesis of alcoholic liver disease (ALD)","volume":"289","year":"2014","journal-title":"J Biol Chem"},{"key":"hep41793-bib-0016-20241114","doi-asserted-by":"crossref","first-page":"2380","DOI":"10.1002\/hep.30093","article-title":"High mobility group box\u20101 drives fibrosis progression signaling via the receptor for advanced glycation end products in mice","volume":"68","year":"2018","journal-title":"Hepatology"},{"key":"hep41793-bib-0017-20241114","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1136\/gutjnl-2015-310752","article-title":"Signalling via the osteopontin and high mobility group box\u20101 axis drives the fibrogenic response to liver injury","volume":"66","year":"2017","journal-title":"Gut"},{"key":"hep41793-bib-0018-20241114","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1002\/hep.26931","article-title":"Osteopontin binding to lipopolysaccharide lowers tumor necrosis factor\u2010alpha and prevents early alcohol\u2010induced liver injury in mice","volume":"59","year":"2014","journal-title":"Hepatology"},{"key":"hep41793-bib-0019-20241114","doi-asserted-by":"crossref","first-page":"G228","DOI":"10.1152\/ajpgi.00465.2011","article-title":"Arachidonic acid stimulates TNFalpha production in Kupffer cells via a reactive oxygen species\u2010pERK1\/2\u2010Egr1\u2010dependent mechanism","volume":"303","year":"2012","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"hep41793-bib-0020-20241114","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1002\/hep.21427","article-title":"Oxidative\u2010stress and IL\u20106 mediate the fibrogenic effects of [corrected] Kupffer cells on stellate cells","volume":"44","year":"2006","journal-title":"Hepatology"},{"key":"hep41793-bib-0021-20241114","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1111\/j.1530-0277.1982.tb05017.x","article-title":"The feeding of alcohol in liquid diets: two decades of applications and 1982 update","volume":"6","year":"1982","journal-title":"Alcohol Clin Exp Res"},{"key":"hep41793-bib-0022-20241114","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1186\/1471-2407-7-183","article-title":"The isothiocyanate class of bioactive nutrients covalently inhibit the MEKK1 protein kinase","volume":"7","year":"2007","journal-title":"BMC Cancer"},{"key":"hep41793-bib-0023-20241114","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1016\/j.jhep.2020.07.016","article-title":"Inhibition of IRAK4 kinase activity improves ethanol\u2010induced liver injury in mice","volume":"73","year":"2020","journal-title":"J Hepatol"},{"key":"hep41793-bib-0024-20241114","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1111\/j.1872-034X.2007.00032.x","article-title":"Protection of estrogens against the progression of chronic liver disease","volume":"37","year":"2007","journal-title":"Hepatol Res"},{"key":"hep41793-bib-0025-20241114","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/S0168-8278(01)00050-2","article-title":"The antiestrogen toremifene protects against alcoholic liver injury in female rats","volume":"35","year":"2001","journal-title":"J Hepatol"},{"key":"hep41793-bib-0026-20241114","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1016\/j.jhep.2011.05.015","article-title":"Pathways of liver injury in alcoholic liver disease","volume":"55","year":"2011","journal-title":"J Hepatol"},{"key":"hep41793-bib-0027-20241114","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1053\/j.gastro.2008.01.016","article-title":"Cell type\u2010dependent pro\u2010 and anti\u2010inflammatory role of signal transducer and activator of transcription 3 in alcoholic liver injury","volume":"134","year":"2008","journal-title":"Gastroenterology"},{"key":"hep41793-bib-0028-20241114","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1002\/hep4.1440","article-title":"Hyperoxidized albumin modulates platelets and promotes inflammation through CD36 receptor in severe alcoholic hepatitis","volume":"4","year":"2020","journal-title":"Hepatol Commun"},{"key":"hep41793-bib-0029-20241114","doi-asserted-by":"crossref","first-page":"748174","DOI":"10.1155\/2009\/748174","article-title":"Peroxisome proliferator\u2010activated receptor and retinoic X receptor in alcoholic liver disease","volume":"2009","year":"2009","journal-title":"PPAR Res"},{"key":"hep41793-bib-0030-20241114","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1124\/jpet.106.108175","article-title":"The role of retinoid X receptor alpha in regulating alcohol metabolism","volume":"319","year":"2006","journal-title":"J Pharmacol Exp Ther"},{"key":"hep41793-bib-0031-20241114","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1124\/jpet.107.132258","article-title":"Hepatocyte retinoid X receptor alpha\u2010dependent regulation of lipid homeostasis and inflammatory cytokine expression contributes to alcohol\u2010induced liver injury","volume":"324","year":"2008","journal-title":"J Pharmacol Exp Ther"},{"key":"hep41793-bib-0032-20241114","doi-asserted-by":"crossref","first-page":"906","DOI":"10.3389\/fimmu.2020.00906","article-title":"The genus Alistipes: gut bacteria with emerging implications to inflammation, cancer, and mental health","volume":"11","year":"2020","journal-title":"Front Immunol"},{"key":"hep41793-bib-0033-20241114","first-page":"163","article-title":"Alcohol and gut\u2010derived inflammation","volume":"38","year":"2017","journal-title":"Alcohol Res"},{"key":"hep41793-bib-0034-20241114","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1042\/cs0570521","article-title":"Interaction of amino acids with glycyl\u2010L\u2010leucine hydrolysis and transport in monkey small intestine","volume":"57","year":"1979","journal-title":"Clin Sci"},{"key":"hep41793-bib-0035-20241114","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1177\/1947601913513950","article-title":"MAP3K1: genomic alterations in cancer and function in promoting cell survival or apoptosis","volume":"4","year":"2013","journal-title":"Genes Cancer"},{"key":"hep41793-bib-0036-20241114","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1038\/cdd.2014.239","article-title":"A RING to rule them all? Insights into the Map3k1 PHD motif provide a new mechanistic understanding into the diverse roles of Map3k1","volume":"22","year":"2015","journal-title":"Cell Death Differ"},{"key":"hep41793-bib-0037-20241114","first-page":"1249","article-title":"Mechanisms and cell signaling in alcoholic liver disease","volume":"391","year":"2010","journal-title":"Biol Chem"},{"key":"hep41793-bib-0038-20241114","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1136\/gutjnl-2011-301146","article-title":"Transcriptome analysis identifies TNF superfamily receptors as potential therapeutic targets in alcoholic hepatitis","volume":"62","year":"2013","journal-title":"Gut"},{"key":"hep41793-bib-0039-20241114","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1172\/JCI132691","article-title":"Epithelial splicing regulatory protein 2\u2010mediated alternative splicing reprograms hepatocytes in severe alcoholic hepatitis","volume":"130","year":"2020","journal-title":"J Clin Invest"},{"key":"hep41793-bib-0040-20241114","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1111\/apt.14949","article-title":"Bile acid homeostasis and intestinal dysbiosis in alcoholic hepatitis","volume":"48","year":"2018","journal-title":"Aliment Pharmacol Ther"},{"key":"hep41793-bib-0041-20241114","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1016\/j.jhep.2018.03.031","article-title":"Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis","volume":"69","year":"2018","journal-title":"J Hepatol"},{"key":"hep41793-bib-0042-20241114","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1631\/jzus.B1900073","article-title":"Regulation of bile acid metabolism\u2010related signaling pathways by gut microbiota in diseases","volume":"20","year":"2019","journal-title":"J Zhejiang Univ Sci B"},{"key":"hep41793-bib-0043-20241114","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1146\/annurev.biochem.72.121801.161712","article-title":"The enzymes, regulation, and genetics of bile acid synthesis","volume":"72","year":"2003","journal-title":"Annu Rev Biochem"},{"key":"hep41793-bib-0044-20241114","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.ymeth.2018.04.028","article-title":"Functional microbiomics: evaluation of gut microbiota\u2010bile acid metabolism interactions in health and disease","volume":"149","year":"2018","journal-title":"Methods"}],"updated-by":[{"DOI":"10.1002\/hep4.1985","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T00:00:00Z","timestamp":1669852800000}}],"container-title":["Hepatology Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hep4.1793","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/hep4.1793","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/10.1002\/hep4.1793","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,14]],"date-time":"2024-11-14T11:02:05Z","timestamp":1731582125000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1002\/hep4.1793"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,28]]},"references-count":44,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022]]}},"URL":"https:\/\/doi.org\/10.1002\/hep4.1793","relation":{"correction":[{"id-type":"doi","id":"10.1002\/hep4.1985","asserted-by":"object"}]},"ISSN":["2471-254X","2471-254X"],"issn-type":[{"value":"2471-254X","type":"print"},{"value":"2471-254X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,28]]},"assertion":[{"value":"2021-02-05","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-07-07","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}