{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T22:10:32Z","timestamp":1781561432511,"version":"3.54.5"},"reference-count":113,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T00:00:00Z","timestamp":1743120000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001602","name":"Science Foundation Ireland","doi-asserted-by":"publisher","award":["SFI\/12\/RC\/2273_P2"],"award-info":[{"award-number":["SFI\/12\/RC\/2273_P2"]}],"id":[{"id":"10.13039\/501100001602","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Experimental Physiology"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The mood stabilizers lithium and valproate are psychotropic medications widely used in clinical practice. Despite their proven benefits, many individuals stop their treatment due to the adverse effects. Chronic diarrhoea is a common reason for discontinuation of these drugs; however, the underlying mechanisms are unknown. Excessive loss of bile acids (BA) into the colon is a major cause of diarrhoea. Therefore, we aimed to investigate the effects of these drugs on BA metabolism. We measured BA levels in the liver, plasma and faeces of Sprague\u2013Dawley rats treated with lithium or valproate for 4\u00a0weeks. Next, we analysed changes in the expression of genes and proteins involved in BA production and enterohepatic circulation. Lithium and valproate markedly increased BA levels across all body sites. This was accompanied by the up\u2010regulation of hepatic cytochrome P450 7A1 (Cyp7a1), the rate\u2010limiting enzyme in <jats:italic>de novo<\/jats:italic> BA synthesis. Under normal conditions, elevated levels of BAs suppress Cyp7a1 via activation of the hepatic farnesoid X receptor (Fxr)\/small heterodimer partner (Shp) and intestinal Fxr\/fibroblast growth factor 19 (Fgf19) pathways. This signalling was disrupted in both treatment groups. The Fxr\u2010mediated responses in the expression of Ntcp, Asbt, Ilbp and Ost\u03b1\/\u03b2 bile transporters were also affected by treatment. In conclusion, lithium and valproate disrupted farnesoid X receptor signalling at the hepatic and intestinal levels, inducing sustained overproduction of bile in rats. These findings provide novel insights into the peripheral effects of these drugs. Given that similar changes in bile circuits underlie the pathophysiology of primary BA diarrhoea in humans, this study suggests a potential mechanism behind chronic diarrhoea in patients undergoing lithium or valproate therapy.<\/jats:p>","DOI":"10.1113\/ep092451","type":"journal-article","created":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T21:21:52Z","timestamp":1743369712000},"page":"1233-1253","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The mood stabilizers lithium and valproate disrupt hepatic and intestinal farnesoid X receptor signalling and increase bile synthesis in the rat"],"prefix":"10.1113","volume":"110","author":[{"given":"Sofia","family":"Cussotto","sequence":"first","affiliation":[{"name":"APC Microbiome Ireland University College Cork  Cork Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna V.","family":"Golubeva","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neuroscience University College Cork  Cork Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alvaro Lopez","family":"Gallardo","sequence":"additional","affiliation":[{"name":"APC Microbiome Ireland University College Cork  Cork Ireland"},{"name":"School of Biochemistry and Cell Biology University College Cork  Cork Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomaz F. S.","family":"Bastiaanssen","sequence":"additional","affiliation":[{"name":"APC Microbiome Ireland University College Cork  Cork Ireland"},{"name":"Department of Anatomy and Neuroscience University College Cork  Cork Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander V.","family":"Zhdanov","sequence":"additional","affiliation":[{"name":"School of Pharmacy University College Cork  Cork Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerard M.","family":"Moloney","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neuroscience University College Cork  Cork Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitriona","family":"Scaife","sequence":"additional","affiliation":[{"name":"Mass Spectrometry Core UCD Conway Institute  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane A.","family":"English","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neuroscience University College Cork  Cork Ireland"},{"name":"INFANT research centre CUH  Cork Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4771-3123","authenticated-orcid":false,"given":"Susan A.","family":"Joyce","sequence":"additional","affiliation":[{"name":"APC Microbiome Ireland University College Cork  Cork Ireland"},{"name":"School of Biochemistry and Cell Biology University College Cork  Cork Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy G.","family":"Dinan","sequence":"additional","affiliation":[{"name":"APC Microbiome Ireland University College Cork  Cork Ireland"},{"name":"Department of Psychiatry and Neurobehavioural Science University College Cork  Cork Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5887-2723","authenticated-orcid":false,"given":"John F.","family":"Cryan","sequence":"additional","affiliation":[{"name":"APC Microbiome Ireland University College Cork  Cork Ireland"},{"name":"Department of Anatomy and Neuroscience University College Cork  Cork Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,3,28]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.2165\/00023210-199809020-00005"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-018-1619-z"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2010.11.026"},{"issue":"1","key":"e_1_2_9_5_1","first-page":"20","article-title":"The involvement of taurine in the action mechanism of sodium valproate (VPA) in the treatment of epilepsy","volume":"43","author":"Anyanwu E.","year":"1993","journal-title":"Acta Physiologica Pharmacologica et Therapeutica Latinoamericana"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s44220-023-00149-2"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s44220-023-00148-3"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.2517-6161.1995.tb02031.x"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3869"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.5009\/gnl14397"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-021-07044-9"},{"issue":"1","key":"e_1_2_9_12_1","article-title":"Molecular and therapeutic potential and toxicity of valproic acid","volume":"2010","author":"Chateauvieux S.","year":"2010","journal-title":"Journal of Biomedicine and Biotechnology"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.25385"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27964"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23984"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-018-5006-5"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1746.2011.06719.x"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-008-0569-3"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M306370200"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R054114"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2001.25503"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2020.00518"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0548-6"},{"issue":"2","key":"e_1_2_9_24_1","first-page":"85","article-title":"Valproate\u2010associated hepatotoxicity and its biochemical mechanisms","volume":"3","author":"Eadie M. J.","year":"1988","journal-title":"Medical Toxicology and Adverse Drug Experience"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.102569"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1136\/flgastro-2020-101436"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R900009-JLR200"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfz154"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40345-016-0068-y"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.8.5015"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1097\/00132981-200306000-00022"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1214\/aoms\/1177729885"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2019.129456"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2012.08.002"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M300128-JLR200"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00054.2017"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1083503"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2021.105992"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2005.09.001"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI23076"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2010.12.011"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00232-017-9998-2"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2019.04.018"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00726-011-0962-7"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1323599111"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv1070"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2010.11.011"},{"issue":"2","key":"e_1_2_9_48_1","first-page":"129","article-title":"Influence of lithium on biliary electrolyte and bile acid excretion in young and adult rats","volume":"65","author":"Kersten L.","year":"1985","journal-title":"Acta Physiologica Hungarica"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1515\/jbcpp-2013-0134"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.25740"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2006.02.007"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI107720"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1248\/bpb.b16-00597"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M078279"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00010.2008"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2017.06.001"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2017.06.002"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chemolab.2021.104248"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-019-0190-7"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0193824"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kft221"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2010.01.014"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1773909"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pathophys.2006.02.001"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0924-977X(03)00070-1"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOG.0000000000000344"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12888-018-1622-1"},{"key":"e_1_2_9_69_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.284.5418.1365"},{"key":"e_1_2_9_70_1","doi-asserted-by":"publisher","DOI":"10.1097\/FBP.0b013e32833da5da"},{"key":"e_1_2_9_71_1","doi-asserted-by":"publisher","DOI":"10.1111\/apt.12466"},{"key":"e_1_2_9_72_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00049.2019"},{"key":"e_1_2_9_73_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1399-5618.2001.30404.x"},{"key":"e_1_2_9_74_1","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2002.31724"},{"key":"e_1_2_9_75_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.10026"},{"key":"e_1_2_9_76_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2015.00199"},{"key":"e_1_2_9_77_1","doi-asserted-by":"publisher","DOI":"10.2174\/1568008054863781"},{"key":"e_1_2_9_78_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-007-7079-x"},{"key":"e_1_2_9_79_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.72.121801.161712"},{"key":"e_1_2_9_80_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00210-003-0776-6"},{"key":"e_1_2_9_81_1","doi-asserted-by":"publisher","DOI":"10.1007\/s007260070004"},{"key":"e_1_2_9_82_1","doi-asserted-by":"publisher","DOI":"10.1186\/1423-0127-17-S1-S2"},{"key":"e_1_2_9_83_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI106931"},{"key":"e_1_2_9_84_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1746.2008.05652.x"},{"key":"e_1_2_9_85_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2021.112021"},{"key":"e_1_2_9_86_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27694"},{"key":"e_1_2_9_87_1","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.2020.34.s1.05988"},{"key":"e_1_2_9_88_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2018-00134"},{"key":"e_1_2_9_89_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0183284"},{"key":"e_1_2_9_90_1","doi-asserted-by":"publisher","DOI":"10.1139\/o69-133"},{"key":"e_1_2_9_91_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1131"},{"key":"e_1_2_9_92_1","doi-asserted-by":"publisher","DOI":"10.1002\/jat.3645"},{"key":"e_1_2_9_93_1","doi-asserted-by":"publisher","DOI":"10.1002\/jat.3644"},{"key":"e_1_2_9_94_1","doi-asserted-by":"publisher","DOI":"10.1080\/19490976.2020.1732268"},{"key":"e_1_2_9_95_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.2040-4603.2020.tb00108.x"},{"key":"e_1_2_9_96_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(15)00314-2"},{"key":"e_1_2_9_97_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4899-0182-8_41"},{"key":"e_1_2_9_98_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1974.tb04309.x"},{"key":"e_1_2_9_99_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.1986.tb03525.x"},{"key":"e_1_2_9_100_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2013.04.007"},{"key":"e_1_2_9_101_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0030-1253225"},{"key":"e_1_2_9_102_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.05.005"},{"key":"e_1_2_9_103_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2014.32"},{"key":"e_1_2_9_104_1","doi-asserted-by":"publisher","DOI":"10.1177\/1756283X10377126"},{"key":"e_1_2_9_105_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.1840010411"},{"key":"e_1_2_9_106_1","doi-asserted-by":"publisher","DOI":"10.1186\/1423-0127-17-S1-S1"},{"key":"e_1_2_9_107_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.479865"},{"issue":"2","key":"e_1_2_9_108_1","first-page":"57","article-title":"The potential health benefits of taurine in cardiovascular disease","volume":"13","author":"Xu Y.\u2010J.","year":"2008","journal-title":"Experimental and Clinical Cardiology"},{"key":"e_1_2_9_109_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijge.2011.09.019"},{"key":"e_1_2_9_110_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.20.15482"},{"key":"e_1_2_9_111_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0066923"},{"key":"e_1_2_9_112_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2014.01.051"},{"key":"e_1_2_9_113_1","doi-asserted-by":"publisher","DOI":"10.1159\/000107687"},{"key":"e_1_2_9_114_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.368175"}],"container-title":["Experimental Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/EP092451","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T06:27:00Z","timestamp":1758090420000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/EP092451"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,28]]},"references-count":113,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2025,9]]}},"alternative-id":["10.1113\/EP092451"],"URL":"https:\/\/doi.org\/10.1113\/ep092451","archive":["Portico"],"relation":{},"ISSN":["0958-0670","1469-445X"],"issn-type":[{"value":"0958-0670","type":"print"},{"value":"1469-445X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,28]]},"assertion":[{"value":"2024-11-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}