{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T04:29:17Z","timestamp":1792384157083,"version":"4.4.0"},"reference-count":42,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2022,6,23]],"date-time":"2022-06-23T00:00:00Z","timestamp":1655942400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>Bile acids are hepatic metabolites and have many properties considered to be relevant to the pathophysiology of NAFLD. Circulating levels of the intestinal microbiome\u2010modified bile acid deoxycholate are increased in cirrhosis.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>To further elucidate the role of bile acids and intestinal microbiota linked to bile acids in progressively severe NAFLD, a multiomic study of feces including 16S rRNA sequencing, microbial transcriptomics and metabolomics was performed in a cohort with varying phenotypes of NAFLD. Several bile acids of microbial origin derived from deoxycholic acid (DCA) (glycodeoxycholate, 7\u2010ketodeoxycholic acid, dehydrocholic acid) increased with disease activity and fibrosis stage. These were linked to increased expression of microbial bile salt hydrolase, bile acid operon (BaiCD) and hydroxysteroid dehydrogenases (hdhA) required for DCA and downstream metabolite synthesis providing a mechanistic basis for altered bile acid profiles with disease progression. <jats:italic toggle=\"yes\">Bacteroidetes<\/jats:italic> and several genera of Lachnospiraceae family containing DCA generating genes increased with increasing disease severity, whereas several potentially beneficial microbes sensitive to antibacterial effects of DCA e.g., Ruminococcaceae were decreased. The clinical relevance of these data was confirmed in an independent cohort enrolled in a clinical trial for NASH where at entry DCA and its conjugates were associated with advanced fibrosis. In patients treated with placebo, DCA declined in those with fibrosis regression and increased in those with fibrosis progression. DCA rose further in those with compensated cirrhosis when they experienced decompensation.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>These findings demonstrate a role for bile acids and the bile acid dependent microbiome in the development and progression of NAFLD and set the stage to leverage these findings for NASH biomarker development and for therapeutics.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.32568","type":"journal-article","created":{"date-parts":[[2022,5,13]],"date-time":"2022-05-13T17:49:15Z","timestamp":1652464155000},"page":"1811-1824","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":134,"title":["Metabolic reprogramming of the intestinal microbiome with functional bile acid changes underlie the development of NAFLD"],"prefix":"10.1097","volume":"76","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9577-4102","authenticated-orcid":false,"given":"Ekaterina","family":"Smirnova","sequence":"first","affiliation":[{"name":"Department of Biostatistics,Virginia Commonwealth University School of Medicine,Richmond,Virginia,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark D.","family":"Muthiah","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,National University Health System,Singapore"},{"name":"Yong Loo Lin School of Medicine,National University of Singapore,Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Narayan","sequence":"additional","affiliation":[{"name":"Second Genome Inc.,South San Francisco,California,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamad S.","family":"Siddiqui","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition,Department of Internal Medicine,Virginia Commonwealth University School of Medicine,Richmond,Virginia,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Puneet","family":"Puri","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition,Department of Internal Medicine,Virginia Commonwealth University School of Medicine,Richmond,Virginia,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Velimir A.","family":"Luketic","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition,Department of Internal Medicine,Virginia Commonwealth University School of Medicine,Richmond,Virginia,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa J.","family":"Contos","sequence":"additional","affiliation":[{"name":"Department of Pathology,Virginia Commonwealth University School of Medicine,Richmond,Virginia,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Idowu","sequence":"additional","affiliation":[{"name":"Department of Pathology,Virginia Commonwealth University School of Medicine,Richmond,Virginia,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jen\u2010Chieh","family":"Chuang","sequence":"additional","affiliation":[{"name":"Gilead Sciences Inc.,Foster City,California,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew N.","family":"Billin","sequence":"additional","affiliation":[{"name":"Gilead Sciences Inc.,Foster City,California,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan S.","family":"Huss","sequence":"additional","affiliation":[{"name":"Gilead Sciences Inc.,Foster City,California,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert P.","family":"Myers","sequence":"additional","affiliation":[{"name":"Gilead Sciences Inc.,Foster City,California,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherry","family":"Boyett","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition,Department of Internal Medicine,Virginia Commonwealth University School of Medicine,Richmond,Virginia,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mulugeta","family":"Seneshaw","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition,Department of Internal Medicine,Virginia Commonwealth University School of Medicine,Richmond,Virginia,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hae\u2010Ki","family":"Min","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition,Department of Internal Medicine,Virginia Commonwealth University School of Medicine,Richmond,Virginia,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faridodin","family":"Mirshahi","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition,Department of Internal Medicine,Virginia Commonwealth University School of Medicine,Richmond,Virginia,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arun J.","family":"Sanyal","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition,Department of Internal Medicine,Virginia Commonwealth University School of Medicine,Richmond,Virginia,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2022,6,23]]},"reference":[{"key":"hep32568-bib-0001-20250415","article-title":"Gene\u2010environmental interactions as metabolic drivers of nonalcoholic steatohepatitis","volume":"12","year":"2021","journal-title":"Front Endocrinol"},{"issue":"1","key":"hep32568-bib-0002-20250415","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1002\/hep.29367","article-title":"The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases","volume":"67","year":"2018","journal-title":"Hepatology"},{"issue":"4","key":"hep32568-bib-0003-20250415","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1016\/j.cgh.2018.06.011","article-title":"Rates of and factors associated with placebo response in trials of pharmacotherapies for nonalcoholic steatohepatitis: systematic review and meta\u2010analysis","volume":"17","year":"2019","journal-title":"Clin Gastroenterol Hepatol"},{"issue":"4","key":"hep32568-bib-0004-20250415","article-title":"Drug discovery and treatment paradigms in nonalcoholic steatohepatitis","volume":"3","year":"2020","journal-title":"Endocrinol Diabetes Metab"},{"issue":"7402","key":"hep32568-bib-0005-20250415","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/nature11234","article-title":"Structure, function and diversity of the healthy human microbiome","volume":"486","year":"2012","journal-title":"Nature"},{"issue":"3","key":"hep32568-bib-0006-20250415","doi-asserted-by":"crossref","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","year":"2020","journal-title":"Gastroenterology"},{"issue":"3","key":"hep32568-bib-0007-20250415","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1002\/hep.29892","article-title":"Link between gut\u2010microbiome derived metabolite and shared gene\u2010effects with hepatic steatosis and fibrosis in NAFLD","volume":"68","year":"2018","journal-title":"Hepatology"},{"issue":"5","key":"hep32568-bib-0008-20250415","article-title":"A universal gut\u2010microbiome\u2010derived signature predicts cirrhosis","volume":"32","year":"2020","journal-title":"Cell Metab"},{"issue":"12","key":"hep32568-bib-0009-20250415","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/s41574-019-0266-7","article-title":"Bile acids in glucose metabolism and insulin signalling\u2014mechanisms and research needs","volume":"15","year":"2019","journal-title":"Nat Rev Endocrinol"},{"issue":"2","key":"hep32568-bib-0010-20250415","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1002\/hep.29359","article-title":"The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids","volume":"67","year":"2018","journal-title":"Hepatology"},{"issue":"5","key":"hep32568-bib-0011-20250415","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1053\/gast.2002.36572","article-title":"AGA technical review on nonalcoholic fatty liver disease","volume":"123","year":"2002","journal-title":"Gastroenterology"},{"issue":"10","key":"hep32568-bib-0012-20250415","article-title":"Association of histologic disease activity with progression of nonalcoholic fatty liver disease","volume":"2","year":"2019","journal-title":"JAMA Netw Open"},{"issue":"6","key":"hep32568-bib-0013-20250415","doi-asserted-by":"crossref","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","year":"2005","journal-title":"Hepatology"},{"issue":"5","key":"hep32568-bib-0014-20250415","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1002\/cbdv.200900322","article-title":"Quantitative assessment of the human gut microbiome using multitag pyrosequencing","volume":"7","year":"2010","journal-title":"Chem Biodivers"},{"issue":"1","key":"hep32568-bib-0015-20250415","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1002\/hep.31178","article-title":"Fecal microbiome distinguishes alcohol consumption from alcoholic hepatitis but does not discriminate disease severity","volume":"72","year":"2020","journal-title":"Hepatology"},{"issue":"2","key":"hep32568-bib-0016-20250415","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1002\/hep.29514","article-title":"The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial","volume":"67","year":"2018","journal-title":"Hepatology"},{"issue":"4","key":"hep32568-bib-0017-20250415","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1053\/j.gastro.2018.07.006","article-title":"Simtuzumab is ineffective for patients with bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis","volume":"155","year":"2018","journal-title":"Gastroenterology"},{"issue":"2","key":"hep32568-bib-0018-20250415","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1002\/hep.31622","article-title":"Combination therapies including Cilofexor and Firsocostat for bridging fibrosis and cirrhosis attributable to NASH","volume":"73","year":"2021","journal-title":"Hepatology"},{"issue":"1","key":"hep32568-bib-0020-20250415","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1890\/0012-9658(2001)082[0290:FMMTCD]2.0.CO;2","article-title":"Fitting multivariate models to community data: a comment on distance\u2010based redundancy analysis","volume":"82","year":"2001","journal-title":"Ecology"},{"issue":"6","key":"hep32568-bib-0021-20250415","doi-asserted-by":"crossref","first-page":"R60","DOI":"10.1186\/gb-2011-12-6-r60","article-title":"Metagenomic biomarker discovery and explanation","volume":"12","year":"2011","journal-title":"Genome Biol"},{"issue":"3","key":"hep32568-bib-0022-20250415","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1111\/1467-9868.00346","article-title":"A direct approach to false discovery rates","volume":"64","year":"2002","journal-title":"J R Stat Soc Ser B Stat Methodol"},{"issue":"1","key":"hep32568-bib-0023-20250415","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1111\/j.1467-9868.2004.00439.x","article-title":"Strong control, conservative point estimation and simultaneous conservative consistency of false discovery rates: a unified approach","volume":"66","year":"2004","journal-title":"J R Stat Soc Ser B Stat Methodol"},{"issue":"12","key":"hep32568-bib-0024-20250415","article-title":"Moderated estimation of fold change and dispersion for RNA\u2010seq data with DESeq2","volume":"15","year":"2014","journal-title":"Genome Biol"},{"issue":"5","key":"hep32568-bib-0025-20250415","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1002\/hep.29085","article-title":"Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta\u2010analysis","volume":"65","year":"2017","journal-title":"Hepatology"},{"key":"hep32568-bib-0026-20250415","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1002\/hep4.1885","article-title":"Development of alcohol\u2010associated hepatitis is associated with specific changes in gut\u2010modified bile acids","volume":"6","year":"2022","journal-title":"Hepatol Commun"},{"issue":"1","key":"hep32568-bib-0027-20250415","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1080\/19490976.2015.1127483","article-title":"Consequences of bile salt biotransformations by intestinal bacteria","volume":"7","year":"2016","journal-title":"Gut Microbes"},{"issue":"1","key":"hep32568-bib-0028-20250415","article-title":"Systematic assessment of secondary bile acid metabolism in gut microbes reveals distinct metabolic capabilities in inflammatory bowel disease","volume":"7","year":"2019","journal-title":"Microbiome"},{"key":"hep32568-bib-0029-20250415","article-title":"Interactions between bacteria and bile salts in the gastrointestinal and hepatobiliary tracts","volume":"4","year":"2017","journal-title":"Front Med"},{"issue":"4","key":"hep32568-bib-0030-20250415","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/j.femsre.2004.09.003","article-title":"The interaction between bacteria and bile","volume":"29","year":"2005","journal-title":"FEMS Microbiol Rev"},{"key":"hep32568-bib-0031-20250415","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.cct.2016.02.012","article-title":"Efficacy and safety study of cenicriviroc for the treatment of non\u2010alcoholic steatohepatitis in adult subjects with liver fibrosis: CENTAUR Phase 2b study design","volume":"47","year":"2016","journal-title":"Contemp Clin Trials"},{"issue":"5","key":"hep32568-bib-0032-20250415","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1002\/hep.29477","article-title":"A randomized, placebo\u2010controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis","volume":"67","year":"2018","journal-title":"Hepatology"},{"key":"hep32568-bib-0033-20250415","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1002\/hep.32315","article-title":"Placebo effect on progression and regression in NASH: evidence from a meta\u2010analysis","volume":"75","year":"2022","journal-title":"Hepatology"},{"issue":"10","key":"hep32568-bib-0034-20250415","article-title":"Secondary unconjugated bile acids induce hepatic stellate cell activation","volume":"19","year":"2018","journal-title":"Int J Mol Sci"},{"issue":"11","key":"hep32568-bib-0035-20250415","doi-asserted-by":"crossref","first-page":"2158","DOI":"10.1194\/jlr.M062653","article-title":"Deoxycholic acid modulates cell death signaling through changes in mitochondrial membrane properties","volume":"56","year":"2015","journal-title":"J Lipid Res"},{"issue":"5","key":"hep32568-bib-0036-20250415","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1053\/gast.2001.23256","article-title":"Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities","volume":"120","year":"2001","journal-title":"Gastroenterology"},{"issue":"1","key":"hep32568-bib-0037-20250415","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mito.2005.10.004","article-title":"Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it","volume":"6","year":"2006","journal-title":"Mitochondrion"},{"issue":"6","key":"hep32568-bib-0038-20250415","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1016\/j.jhep.2005.03.004","article-title":"NASH: a mitochondrial disease","volume":"42","year":"2005","journal-title":"J Hepatol"},{"issue":"3","key":"hep32568-bib-0039-20250415","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1007\/s10545-016-9927-z","article-title":"Mitochondrial dysfunction in liver failure requiring transplantation","volume":"39","year":"2016","journal-title":"J Inherit Metab Dis"},{"issue":"1","key":"hep32568-bib-0040-20250415","article-title":"Inhibition of NF\u2010\u03baB by deoxycholic acid induces miR\u201021\/PDCD4\u2010dependent hepatocellular apoptosis","volume":"5","year":"2015","journal-title":"Sci Rep"},{"issue":"1","key":"hep32568-bib-0041-20250415","article-title":"Gut microbiota associations with metabolic syndrome and relevance of its study in pediatric subjects","volume":"13","year":"2021","journal-title":"Gut Microbes"},{"issue":"1","key":"hep32568-bib-0042-20250415","article-title":"Antibiotic\u2010induced alterations of the gut microbiota alter secondary bile acid production and allow for Clostridium difficile spore germination and outgrowth in the large intestine","volume":"1","year":"2016","journal-title":"mSphere"},{"issue":"1","key":"hep32568-bib-0043-20250415","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1172\/JCI4414","article-title":"Increasing dietary cholesterol induces different regulation of classic and alternative bile acid synthesis","volume":"103","year":"1999","journal-title":"J Clin Invest"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hep.32568","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/hep.32568","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.32568","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T16:44:37Z","timestamp":1744735477000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.32568"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,23]]},"references-count":42,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2022]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.32568","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,23]]},"assertion":[{"value":"2021-12-03","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-05-03","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}