{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T04:09:25Z","timestamp":1782014965182,"version":"3.54.5"},"reference-count":33,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2023,12,4]],"date-time":"2023-12-04T00:00:00Z","timestamp":1701648000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Pineal Research"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Cholestatic liver disease is characterized by disturbances in the intestinal microbiota and excessive accumulation of toxic bile acids (BA) in the liver. Melatonin (MT) can improve liver diseases. However, the underlying mechanism remains unclear. This study aimed to explore the mechanism of MT on hepatic BA synthesis, liver injury, and fibrosis in 3,5\u2010diethoxycarbonyl\u20101,4\u2010dihydrocollidine (DDC)\u2010fed and <jats:italic>Mdr2<\/jats:italic><jats:sup><jats:italic>\u2013\/\u2013<\/jats:italic><\/jats:sup> mice. MT significantly improved hepatic injury and fibrosis with a significant decrease in hepatic BA accumulation in DDC\u2010fed and <jats:italic>Mdr2<\/jats:italic><jats:sup><jats:italic>\u2013\/\u2013<\/jats:italic><\/jats:sup> mice. MT reprogramed gut microbiota and augmented fecal bile salt hydrolase activity, which was related to increasing intestinal BA deconjugation and fecal BA excretion in both DDC\u2010fed and <jats:italic>Mdr2<\/jats:italic><jats:sup><jats:italic>\u2013\/\u2013<\/jats:italic><\/jats:sup> mice. MT significantly activated the intestinal farnesoid X receptor (FXR)\/fibroblast growth factor 15 (FGF\u201015) axis and subsequently inhibited hepatic BA synthesis in DDC\u2010fed and <jats:italic>Mdr2<\/jats:italic><jats:sup><jats:italic>\u2013\/\u2013<\/jats:italic><\/jats:sup> mice. MT failed to improve DDC\u2010induced liver fibrosis and BA synthesis in antibiotic\u2010treated mice. Furthermore, MT provided protection against DDC\u2010induced liver injury and fibrosis in fecal microbiota transplantation mice. MT did not decrease liver injury and fibrosis in DDC\u2010fed intestinal epithelial cell\u2010specific FXR knockout mice, suggesting that the intestinal FXR mediated the anti\u2010fibrosis effect of MT. In conclusion, MT ameliorates cholestatic liver diseases by remodeling gut microbiota and activating intestinal FXR\/FGF\u201015 axis\u2010mediated inhibition of hepatic BA synthesis and promotion of BA excretion in mice.<\/jats:p>","DOI":"10.1111\/jpi.12929","type":"journal-article","created":{"date-parts":[[2023,12,4]],"date-time":"2023-12-04T10:15:39Z","timestamp":1701684939000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Melatonin improves cholestatic liver disease via the gut\u2010liver axis"],"prefix":"10.1111","volume":"76","author":[{"given":"Xianjiao","family":"Liu","sequence":"first","affiliation":[{"name":"College of Veterinary Medicine Nanjing Agricultural University Nanjing Jiangsu China"},{"name":"Institute of Animal Nutritional Health Nanjing Agricultural University Nanjing Jiangsu China"},{"name":"MOE Joint International Research Nanjing Agricultural University Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyan","family":"Li","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine Nanjing Agricultural University Nanjing Jiangsu China"},{"name":"Institute of Animal Nutritional Health Nanjing Agricultural University Nanjing Jiangsu China"},{"name":"MOE Joint International Research Nanjing Agricultural University Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengdie","family":"Shi","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine Nanjing Agricultural University Nanjing Jiangsu China"},{"name":"Institute of Animal Nutritional Health Nanjing Agricultural University Nanjing Jiangsu China"},{"name":"MOE Joint International Research Nanjing Agricultural University Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Fu","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Integrated Traditional Chinese and Western Medicine Nanjing University of Chinese Medicine Nanjing Jiangsu China"},{"name":"Key Laboratory of New Drug Delivery Systems of Chinese Materia Medica Jiangsu Province Academy of Traditional Chinese Medicine Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubo","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine Nanjing Agricultural University Nanjing Jiangsu China"},{"name":"Institute of Animal Nutritional Health Nanjing Agricultural University Nanjing Jiangsu China"},{"name":"MOE Joint International Research Nanjing Agricultural University Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weili","family":"Kang","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine Nanjing Agricultural University Nanjing Jiangsu China"},{"name":"Institute of Animal Nutritional Health Nanjing Agricultural University Nanjing Jiangsu China"},{"name":"MOE Joint International Research Nanjing Agricultural University Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyan","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine Nanjing Agricultural University Nanjing Jiangsu China"},{"name":"Institute of Animal Nutritional Health Nanjing Agricultural University Nanjing Jiangsu China"},{"name":"MOE Joint International Research Nanjing Agricultural University Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fenxia","family":"Zhu","sequence":"additional","affiliation":[{"name":"Affiliated Hospital of Integrated Traditional Chinese and Western Medicine Nanjing University of Chinese Medicine Nanjing Jiangsu China"},{"name":"Key Laboratory of New Drug Delivery Systems of Chinese Materia Medica Jiangsu Province Academy of Traditional Chinese Medicine Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kehe","family":"Huang","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine Nanjing Agricultural University Nanjing Jiangsu China"},{"name":"Institute of Animal Nutritional Health Nanjing Agricultural University Nanjing Jiangsu China"},{"name":"MOE Joint International Research Nanjing Agricultural University Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingxiang","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine Nanjing Agricultural University Nanjing Jiangsu China"},{"name":"Institute of Animal Nutritional Health Nanjing Agricultural University Nanjing Jiangsu China"},{"name":"MOE Joint International Research Nanjing Agricultural University Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunhuan","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine Nanjing Agricultural University Nanjing Jiangsu China"},{"name":"Institute of Animal Nutritional Health Nanjing Agricultural University Nanjing Jiangsu China"},{"name":"MOE Joint International Research Nanjing Agricultural University Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,12,4]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.32437"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2021.100255"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2021.112664"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2020.100138"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-019-0074-3"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2022.02.004"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-022-00805-x"},{"key":"e_1_2_11_9_1","doi-asserted-by":"crossref","unstructured":"FoleyMH O'FlahertyS AllenG et al.Lactobacillus bile salt hydrolase substrate specificity governs bacterial fitness and host colonization.Proc Natl Acad Sci.2021;118(6):e2017709118.","DOI":"10.1073\/pnas.2017709118"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-022-00921-7"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.RA119000395"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/jpi.12812"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1080\/10408398.2018.1487927"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10787-022-01011-0"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12576-021-00812-2"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/4610522"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2022.07.007"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.30735"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-021-00912-0"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/jpi.12524"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12896-x"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2021.100250"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12072-020-10070-w"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.21037\/atm-20-5110"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2018.09.007"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.2147\/JEP.S267375"},{"key":"e_1_2_11_27_1","doi-asserted-by":"crossref","unstructured":"HoPP SteinmanLObeticholic acid a synthetic bile acid agonist of the farnesoid X receptor attenuates experimental autoimmune encephalomyelitis.Proc Natl Acad Sci.2016;113(6):1600\u20101605.","DOI":"10.1073\/pnas.1524890113"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-021-00452-1"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2020.01.014"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-023-01368-3"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30975"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.scitotenv.2022.157861"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOG.0000000000000057"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1039\/D2FO01252A"}],"container-title":["Journal of Pineal Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jpi.12929","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,8]],"date-time":"2024-04-08T14:19:51Z","timestamp":1712585991000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jpi.12929"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,4]]},"references-count":33,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2024,1]]}},"alternative-id":["10.1111\/jpi.12929"],"URL":"https:\/\/doi.org\/10.1111\/jpi.12929","archive":["Portico"],"relation":{},"ISSN":["0742-3098","1600-079X"],"issn-type":[{"value":"0742-3098","type":"print"},{"value":"1600-079X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,4]]},"assertion":[{"value":"2023-07-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-11-08","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-12-04","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e12929"}}