{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T11:54:49Z","timestamp":1773316489333,"version":"3.50.1"},"reference-count":48,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2024,10,16]],"date-time":"2024-10-16T00:00:00Z","timestamp":1729036800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100012856","name":"Alberta Children's Hospital Research Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012856","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["FRN\u2010162177"],"award-info":[{"award-number":["FRN\u2010162177"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Despite growing interest in the potential use of exogenous ketones for the treatment of epilepsy, their impact on seizures and the gut microbiome and mycobiome remain unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here, we examined the effects of both oral gavage and subcutaneous (SC) injection of a ketone ester (KE) in spontaneously epileptic <jats:italic>Kcna1<\/jats:italic>\u2010null (KO) mice that model seminal aspects of human temporal lobe epilepsy. Electroencephalographic recordings and biochemical analyses were performed in KE\u2010treated KO mice. Fecal microbial and fungal communities were profiled to determine whether the antiseizure activity of KE involves changes in the gut microbiome.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that exogenous KE administration by SC injection was more effective than oral gavage in terms of rendering antiseizure effects while generating similar degrees of ketonemia. However, reductions in mean daily seizure counts were accompanied by overall alterations in the fecal bacterial microbiome. Either oral or SC injection imposed a greater impact on the microbiome in male than female mice. In males, oral KE decreased Bacteroidota phylum and genera of <jats:italic>Ligilactobacillus<\/jats:italic> and <jats:italic>Muribaculaceae<\/jats:italic>, whereas SC injection decreased <jats:italic>Bacteroides<\/jats:italic>, <jats:italic>Lactobacillus<\/jats:italic>, and Lachnospiraceae. The fecal mycobiome was affected by KE injection to a greater degree than by oral gavage, and more in females than in males, as reflected by an increase in <jats:italic>Ascomycota<\/jats:italic> and <jats:italic>Saccharomyces<\/jats:italic>. Correlation analysis between microbiome and seizure counts revealed that in mice receiving KE injection, the seizure count was positively correlated with an amplicon sequencing variant of <jats:italic>Lactobacillus<\/jats:italic> (Spearman rho\u2009=\u2009.64, <jats:italic>p<\/jats:italic>\u2009=\u2009.03) and tended toward a negative correlation with <jats:italic>Saccharomyces<\/jats:italic> (Spearman rho\u2009=\u2009\u2212.57, <jats:italic>p<\/jats:italic>\u2009=\u2009.057).<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Our findings demonstrate that exogenous ketone administration alone can induce antiseizure effects equally via different routes of administration, and that they induce differential shifts in both the bacterial microbiome and mycobiome.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.18150","type":"journal-article","created":{"date-parts":[[2024,10,16]],"date-time":"2024-10-16T12:53:40Z","timestamp":1729083220000},"page":"3676-3688","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Exogenous ketones exert antiseizure effects and modulate the gut microbiome and mycobiome in a clinically relevant murine model of epilepsy"],"prefix":"10.1111","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9405-5907","authenticated-orcid":false,"given":"Chunlong","family":"Mu","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Cumming School of Medicine University of Calgary  Calgary Alberta Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mitchell","family":"Kesler","sequence":"additional","affiliation":[{"name":"Hotchkiss Brain Institute, Cumming School of Medicine University of Calgary  Calgary Alberta Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xingyu","family":"Chen","sequence":"additional","affiliation":[{"name":"Hotchkiss Brain Institute, Cumming School of Medicine University of Calgary  Calgary Alberta Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jane","family":"Shearer","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Cumming School of Medicine University of Calgary  Calgary Alberta Canada"},{"name":"Alberta Children's Hospital Research Institute University of Calgary  Calgary Alberta Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8462-355X","authenticated-orcid":false,"given":"G. Campbell","family":"Teskey","sequence":"additional","affiliation":[{"name":"Hotchkiss Brain Institute, Cumming School of Medicine University of Calgary  Calgary Alberta Canada"},{"name":"Alberta Children's Hospital Research Institute University of Calgary  Calgary Alberta Canada"},{"name":"Department of Cell Biology and Anatomy University of Calgary  Calgary Alberta Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9886-9924","authenticated-orcid":false,"given":"Jong M.","family":"Rho","sequence":"additional","affiliation":[{"name":"Departments of Neurosciences, Pediatrics, and Pharmacology University of California, San Diego, Rady Children's Hospital  San Diego California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,10,16]]},"reference":[{"key":"e_1_2_10_2_1","volume-title":"Improving the lives of people with epilepsy: a technical brief","author":"World Health Organization (WHO)","year":"2022"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2018.24"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2022.06.010"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(16)30158-2"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1010481"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/epi4.12225"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-022-00651-8"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2018.01.011"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2019.01041"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00506.2012"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2019.00045"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.04.027"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2021.106826"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.16813"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2022.103833"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.158521"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.17688"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clnesp.2016.11.003"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.04.027"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1080\/19490976.2022.2121576"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcpp.13779"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2021.103557"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2022.01.005"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2020.102950"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.01.017"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fbr.2023.100327"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2017.11.005"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1159\/000017381"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2023.109513"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.16983"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0097629"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3869"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks1219"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1022"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad407"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.2517-6161.1995.tb02031.x"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2015.05.023"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2016.08.002"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.13444"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a022780"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24424"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2021.105335"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1099\/ijs.0.022954-0"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1099\/ijsem.0.004819"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja0469479"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tetasy.2007.08.010"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1111\/nmo.13985"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12868-021-00679-4"}],"container-title":["Epilepsia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/epi.18150","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T09:06:08Z","timestamp":1734339968000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/epi.18150"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,16]]},"references-count":48,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2024,12]]}},"alternative-id":["10.1111\/epi.18150"],"URL":"https:\/\/doi.org\/10.1111\/epi.18150","archive":["Portico"],"relation":{},"ISSN":["0013-9580","1528-1167"],"issn-type":[{"value":"0013-9580","type":"print"},{"value":"1528-1167","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,16]]},"assertion":[{"value":"2024-03-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-10-01","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-10-16","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}