{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T10:02:59Z","timestamp":1788256979849,"version":"build-2803163510"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,8,19]],"date-time":"2021-08-19T00:00:00Z","timestamp":1629331200000},"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":["81770634"],"award-info":[{"award-number":["81770634"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>There is increasing appreciation for the roles of the gut-liver axis in liver and gall diseases. Specific gut microbes are associated with susceptibility to gallstone diseases, while the relationship between intestinal flora and liver metabolism in the formation of gallstones remains unclear. In this study, an experimental group of model mice was given a lithogenic diet, and a control group was given a normal diet. Both groups were fed for 8 weeks. Integrating 16S rRNA gene sequencing and non-targeted metabolomics to explore the impact of the lithogenic diet on intestinal flora and liver metabolism, Spearman correlation analysis reveals the network of relationships between the intestine and liver. Our findings showed that the gut microbiome and liver metabolome compositions of the test group were significantly changed compared with those of the normal group. Through our research, biomarkers of gallstones were identified at the phylum (5), class (5), order (5), family (7), and genus levels. We predicted the function of the differential flora. We analyzed the liver metabolism of mice with gallstones paired with their flora, and the results showed that there were 138 different metabolites between the two groups. The metabolic pathways enriched by these differential metabolites are highly consistent with the functions of the disordered flora. We focused on an analysis of the relationship between deoxycholic acid, asymmetric dimethylarginine, glucosamine, tauroursodeoxycholic acid, and the disordered flora. This provides a basis for the establishment of the intestine-liver axis in gallstone disease. This research provides a theoretical basis for the research and development of probiotics and prebiotics.<\/jats:p>","DOI":"10.3389\/fphys.2021.716654","type":"journal-article","created":{"date-parts":[[2021,8,19]],"date-time":"2021-08-19T09:51:42Z","timestamp":1629366702000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Changes and Correlations of the Intestinal Flora and Liver Metabolite Profiles in Mice With Gallstones"],"prefix":"10.3389","volume":"12","author":[{"given":"Yang","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqi","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biao","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongbo","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenjun","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,8,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1016\/j.femsre.2004.09.003","article-title":"The interaction between bacteria and bile.","volume":"29","author":"Begley","year":"2005","journal-title":"FEMS Microbiol. Rev."},{"key":"B2","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1016\/S0016-5085(96)70024-0","article-title":"7 alpha-dehydroxylating bacteria enhance deoxycholic acid input and cholesterol saturation of bile in patients with gallstones.","volume":"111","author":"Berr","year":"1996","journal-title":"Gastroenterology"},{"key":"B3","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1038\/nm1785","article-title":"Hepatic insulin resistance directly promotes formation of cholesterol gallstones.","volume":"14","author":"Biddinger","year":"2008","journal-title":"Nat. Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"764","DOI":"10.1002\/hep.28356","article-title":"The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota.","volume":"63","author":"Boursier","year":"2016","journal-title":"Hepatology (Baltimore MD)"},{"key":"B5","doi-asserted-by":"publisher","first-page":"644","DOI":"10.3346\/jkms.2008.23.4.644","article-title":"Insulin resistance is associated with gallstones even in non-obese, non-diabetic Korean men.","volume":"23","author":"Chang","year":"2008","journal-title":"J. Korean Med. Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"550","DOI":"10.3390\/cancers12030550","article-title":"The effect of cholecystectomy on the risk of colorectal cancer in patients with gallbladder stones.","volume":"12","author":"Chen","year":"2020","journal-title":"Cancers"},{"key":"B7","doi-asserted-by":"publisher","first-page":"930","DOI":"10.1016\/s0016-5085(97)70189-6","article-title":"Gallbladder relaxation in patients with pigment and cholesterol stones.","volume":"113","author":"Chen","year":"1997","journal-title":"Gastroenterology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"2576","DOI":"10.1016\/j.bbadis.2019.06.016","article-title":"FMO3 and its metabolite TMAO contribute to the formation of gallstones.","volume":"1865","author":"Chen","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"B9","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1007\/s00535-013-0846-6","article-title":"Cancer risk in patients with cholelithiasis and after cholecystectomy: a nationwide cohort study.","volume":"49","author":"Chen","year":"2014","journal-title":"J. Gastroenterol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"e13066","DOI":"10.1111\/eci.13066","article-title":"Gastrointestinal defects in gallstone and cholecystectomized patients.","volume":"49","author":"Di Ciaula","year":"2019","journal-title":"Eur. J. Clin. Invest."},{"key":"B11","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1097\/MOG.0000000000000423","article-title":"An update on the pathogenesis of cholesterol gallstone disease.","volume":"34","author":"Di Ciaula","year":"2018","journal-title":"Curr. Opin. Gastroenterol."},{"key":"B12","first-page":"631","article-title":"Mucin glycoproteins as tumor markers.","volume":"53","author":"Feller","year":"1990","journal-title":"Immunol. Ser."},{"key":"B13","doi-asserted-by":"publisher","first-page":"e70657","DOI":"10.1371\/journal.pone.0070657","article-title":"An analysis of the role of the indigenous microbiota in cholesterol gallstone pathogenesis.","volume":"8","author":"Fremont-Rahl","year":"2013","journal-title":"PLoS One"},{"key":"B14","doi-asserted-by":"publisher","first-page":"835","DOI":"10.3390\/microorganisms8060835","article-title":"Gallstone disease and microbiome.","volume":"8","author":"Grigor\u2019eva","year":"2020","journal-title":"Microorganisms"},{"key":"B15","doi-asserted-by":"publisher","first-page":"2054","DOI":"10.3389\/fimmu.2020.02054","article-title":"Mucins in intestinal mucosal defense and inflammation: learning from clinical and experimental studies.","volume":"11","author":"Grondin","year":"2020","journal-title":"Front. Immunol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1046\/j.1365-2036.2000.014s2009.x","article-title":"Review article: epidemiology of gall-bladder disease\u2013role of intestinal transit.","author":"Heaton","year":"2000","journal-title":"Aliment. Pharmacol. Ther."},{"key":"B17","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/j.hbpd.2020.12.002","article-title":"Biliary microbiota and mucin 4 impact the calcification of cholesterol gallstones.","volume":"20","author":"Hu","year":"2021","journal-title":"Hepatobiliary Pancreat. Dis. Int."},{"key":"B18","doi-asserted-by":"publisher","first-page":"e0247378","DOI":"10.1371\/journal.pone.0247378","article-title":"Stool metabolome-microbiota evaluation among children and adolescents with obesity, overweight, and normal-weight using 1H NMR and 16S rRNA gene profiling.","volume":"16","author":"Jaimes","year":"2021","journal-title":"PloS One"},{"key":"B19","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1002\/hep.30852","article-title":"Characterization of gut microbiota, bile acid metabolism, and cytokines in intrahepatic cholangiocarcinoma.","volume":"71","author":"Jia","year":"2019","journal-title":"Hepatology"},{"key":"B20","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1517\/14712598.2013.758706","article-title":"Cholesterol lowering with bile salt hydrolase-active probiotic bacteria, mechanism of action, clinical evidence, and future direction for heart health applications.","volume":"13","author":"Jones","year":"2013","journal-title":"Expert Opin. Biol. Ther."},{"key":"B21","doi-asserted-by":"publisher","first-page":"16024","DOI":"10.1038\/nrdp.2016.24","article-title":"Gallstones.","volume":"2","author":"Lammert","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1785251","DOI":"10.1080\/19490976.2020.1785251","article-title":"Changes in the fecal bacterial microbiota associated with disease severity in alcoholic hepatitis patients.","volume":"12","author":"Lang","year":"2020","journal-title":"Gut Microbes"},{"key":"B23","doi-asserted-by":"publisher","first-page":"100289","DOI":"10.1016\/j.aohep.2020.100289","article-title":"The effect of Tauroursodeoxycholic acid (TUDCA) and gut microbiota on murine gallbladder stone formation.","volume":"23","author":"Lu","year":"2020","journal-title":"Ann. Hepatol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"eaan5931","DOI":"10.1126\/science.aan5931","article-title":"Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells.","volume":"360","author":"Ma","year":"2018","journal-title":"Science (New York N. Y.)"},{"key":"B25","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1186\/s12933-019-0906-1","article-title":"A functional variant of the dimethylarginine dimethylaminohydrolase-2 gene is associated with myocardial infarction in type 2 diabetic patients.","volume":"18","author":"Mannino","year":"2019","journal-title":"Cardiovasc. Diabetol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1186\/s40168-019-0712-8","article-title":"The human gallbladder microbiome is related to the physiological state and the biliary metabolic profile.","volume":"7","author":"Molinero","year":"2019","journal-title":"Microbiome"},{"key":"B27","doi-asserted-by":"publisher","first-page":"2232","DOI":"10.1136\/gutjnl-2020-322260","article-title":"Mucus barrier, mucins and gut microbiota: the expected slimy partners?","volume":"69","author":"Paone","year":"2020","journal-title":"Gut"},{"key":"B28","doi-asserted-by":"publisher","first-page":"277","DOI":"10.3389\/fimmu.2019.00277","article-title":"Short Chain Fatty Acids (SCFAs)-mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases.","volume":"10","author":"Parada Venegas","year":"2019","journal-title":"Front. Immunol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1242364","DOI":"10.1155\/2020\/1242364","article-title":"Biliary microbiota and bile acid composition in cholelithiasis.","volume":"2020","author":"Petrov","year":"2020","journal-title":"Biomed. Res. Int."},{"key":"B30","doi-asserted-by":"publisher","first-page":"e13558","DOI":"10.1111\/eci.13558","article-title":"A systematic review of the correlation between serum asymmetric dimethylarginine, carotid atherosclerosis and ischemic stroke.","volume":"51","author":"Qin","year":"2021","journal-title":"Eur. J. Clin. Invest."},{"key":"B31","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1016\/j.cmet.2013.01.003","article-title":"Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist.","volume":"17","author":"Sayin","year":"2013","journal-title":"Cell Metab."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1965.e","DOI":"10.1053\/j.gastro.2017.02.013","article-title":"Association between screen-detected gallstone disease and cancer in a cohort study.","volume":"152","author":"Shabanzadeh","year":"2017","journal-title":"Gastroenterology"},{"key":"B33","doi-asserted-by":"publisher","first-page":"416","DOI":"10.3390\/biom11030416","article-title":"Arginine metabolites as biomarkers of myocardial ischaemia, assessed with cardiac magnetic resonance imaging in chronic kidney disease.","volume":"11","author":"Shah","year":"2021","journal-title":"Biomolecules"},{"key":"B34","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1007\/s00011-016-0998-y","article-title":"H nuclear magnetic resonance (NMR)-based serum metabolomics of human gallbladder inflammation.","volume":"66","author":"Sharma","year":"2017","journal-title":"Inflamm. Res."},{"key":"B35","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1016\/s1499-3872(17)60019-5","article-title":"Gut microbiota dysbiosis in patients with non-alcoholic fatty liver disease.","volume":"16","author":"Shen","year":"2017","journal-title":"Hepatobiliary Pancreatic Dis. Int."},{"key":"B36","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.gpb.2019.03.001","article-title":"Inulin can alleviate metabolism disorders in ob\/ob mice by partially restoring leptin-related pathways mediated by gut microbiota.","volume":"17","author":"Song","year":"2019","journal-title":"Genomics Proteomics Bioinformatics"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1451","DOI":"10.1111\/j.1440-1746.2009.05842.x","article-title":"The preliminary experimental and clinical study of the relationship between the pigment gallstone and intestinal mucosal barrier.","volume":"24","author":"Su","year":"2009","journal-title":"J. Gastroenterol. Hepatol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.1042\/CS20201363","article-title":"Arrb2 causes hepatic lipid metabolism disorder via AMPK pathway based on metabolomics in alcoholic fatty liver.","volume":"135","author":"Sun","year":"2021","journal-title":"Clin. Sci. (Lond.)"},{"key":"B39","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1006\/jsre.2000.5827","article-title":"Iron deficiency diminishes gallbladder neuronal nitric oxide synthase.","volume":"90","author":"Swartz-Basile","year":"2000","journal-title":"J. Surg. Res."},{"key":"B40","doi-asserted-by":"publisher","first-page":"81","DOI":"10.3389\/fgene.2015.00081","article-title":"Mucin glycan foraging in the human gut microbiome.","volume":"6","author":"Tailford","year":"2015","journal-title":"Front. Genet."},{"key":"B41","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1136\/gutjnl-2016-313332","article-title":"Gut microbial profile is altered in primary biliary cholangitis and partially restored after UDCA therapy.","volume":"67","author":"Tang","year":"2018","journal-title":"Gut"},{"key":"B42","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1136\/gut.2003.028431","article-title":"Octreotide induced prolongation of colonic transit increases faecal anaerobic bacteria, bile acid metabolising enzymes, and serum deoxycholic acid in patients with acromegaly.","volume":"54","author":"Thomas","year":"2005","journal-title":"Gut"},{"key":"B43","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1016\/j.bbrc.2019.06.053","article-title":"Clostridium butyricum miyairi 588 has preventive effects on chronic social defeat stress-induced depressive-like behaviour and modulates microglial activation in mice.","volume":"516","author":"Tian","year":"2019","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B44","doi-asserted-by":"publisher","first-page":"163","DOI":"10.3389\/fmed.2017.00163","article-title":"Interactions between bacteria and bile salts in the gastrointestinal and hepatobiliary tracts.","volume":"4","author":"Urdaneta","year":"2017","journal-title":"Front. Med. (Lausanne)"},{"key":"B45","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.cmet.2016.05.005","article-title":"Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism.","volume":"24","author":"Wahlstrom","year":"2016","journal-title":"Cell Metab."},{"key":"B46","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1186\/s12876-020-01195-1","article-title":"Intestinal flora imbalance affects bile acid metabolism and is associated with gallstone formation.","volume":"20","author":"Wang","year":"2020","journal-title":"BMC Gastroenterol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1186\/s12876-017-0629-2","article-title":"Alteration of gut microbiota in association with cholesterol gallstone formation in mice.","volume":"17","author":"Wang","year":"2017","journal-title":"BMC Gastroenterol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1111\/bph.14095","article-title":"Tauroursodeoxycholic acid inhibits intestinal inflammation and barrier disruption in mice with non-alcoholic fatty liver disease.","volume":"175","author":"Wang","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1016\/s0168-8278(00)80183-x","article-title":"Isolation and characterization of cholic acid 7alpha-dehydroxylating fecal bacteria from cholesterol gallstone patients.","volume":"32","author":"Wells","year":"2000","journal-title":"J. Hepatol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1186\/1471-2164-14-669","article-title":"Gut microbiota dysbiosis and bacterial community assembly associated with cholesterol gallstones in large-scale study.","volume":"14","author":"Wu","year":"2013","journal-title":"BMC Genomics"},{"key":"B51","doi-asserted-by":"publisher","first-page":"10397","DOI":"10.1039\/d0fo02272a","article-title":"Modulation of gut homeostasis by exopolysaccharides from Aspergillus cristatus (MK346334), a strain of fungus isolated from Fuzhuan brick tea, contributes to immunomodulatory activity in cyclophosphamide-treated mice.","volume":"11","author":"Xie","year":"2020","journal-title":"Food Funct."},{"key":"B52","doi-asserted-by":"publisher","first-page":"1601","DOI":"10.3892\/ijmm.2020.4516","article-title":"Molecular characterization of gut microbiota in high-lipid diet-induced hyperlipidemic rats treated with simvastatin.","volume":"45","author":"Zhang","year":"2020","journal-title":"Int. J. Mol. Med."},{"key":"B53","doi-asserted-by":"publisher","first-page":"109591","DOI":"10.1016\/j.biopha.2019.109591","article-title":"Prebiotic, immuno-stimulating and gut microbiota-modulating effects of Lycium barbarum polysaccharide.","volume":"121","author":"Zhu","year":"2020","journal-title":"Biomed. Pharmacother."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.716654\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,19]],"date-time":"2021-08-19T09:51:48Z","timestamp":1629366708000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.716654\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,19]]},"references-count":53,"alternative-id":["10.3389\/fphys.2021.716654"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2021.716654","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,19]]},"article-number":"716654"}}