{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T21:01:16Z","timestamp":1791666076756,"version":"4.3.4"},"reference-count":59,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia Open"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:label\/>\n                    <jats:p>Drug\u2010resistant epilepsy (DRE) affects approximately one\u2010third of patients with epilepsy and represents a major unmet clinical need. While traditional hypotheses of pharmacoresistance have focused on alterations in drug targets, efflux transporter overexpression, and intrinsic disease severity, the gut microbiome has recently emerged as a potentially modifiable factor that may function as a systems\u2010level modifier of these established mechanisms rather than a standalone pathway. The gut microbiome harbors a vast repertoire of drug\u2010metabolizing enzymes capable of directly biotransforming orally administered antiseizure medications (ASMs)\u2014including valproic acid, lamotrigine, carbamazepine, and oxcarbazepine\u2014thereby altering their pharmacokinetics, bioavailability, and therapeutic efficacy. Additionally, microbial metabolites modulate host cytochrome P450 enzymes, nuclear receptors, and efflux transporters such as P\u2010glycoprotein, while bacterial \u03b2\u2010glucuronidases influence the enterohepatic recirculation of glucuronidated ASMs. Conversely, chronic ASM exposure reshapes the gut microbial ecosystem, creating a self\u2010perpetuating cycle of dysbiosis and pharmacoresistance. This narrative review synthesizes current evidence on microbiome\u2013ASM interactions in DRE, proposes a concrete experimental pipeline for characterizing ASM\u2010specific microbial biotransformation, and outlines a framework for integrating physiologically based pharmacokinetic modeling with microbiome data. We discuss clinical implications for epileptologists\u2014including the role of therapeutic drug monitoring in detecting microbiome\u2010mediated pharmacokinetic variability, the concept of microbiome\u2010neutral ASM selection, and earlier deployment of the ketogenic diet as a microbiome\u2010targeted intervention. We highlight the translational potential of pharmacomicrobiomics\u2014the study of how microbiome variation influences drug disposition and response\u2014and identify critical knowledge gaps that warrant future investigation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Plain Language Summary<\/jats:title>\n                    <jats:p>About one in three people with epilepsy continue to have seizures despite treatment. This review summarizes growing evidence that the gut microbiome\u2014the community of bacteria living in the intestines\u2014can influence how seizure medications work by altering their absorption, metabolism, and clearance. The medications themselves can reshape the microbiome in return, creating a cycle that may sustain treatment failure. Understanding this gut\u2013drug relationship may open new paths to personalized epilepsy care through diet, probiotics, and microbiome\u2010guided prescribing.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/epi4.70325","type":"journal-article","created":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T10:32:45Z","timestamp":1785580365000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The gut microbiome and drug\u2010resistant epilepsy: Microbiome\u2013antiseizure medication interactions and implications for pharmacoresistance"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-5530-1136","authenticated-orcid":false,"given":"Khaled","family":"Zammar","sequence":"first","affiliation":[{"name":"Neurology Department Neuroscience Institute, Hamad Medical Corporation  Doha Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9707-9266","authenticated-orcid":false,"given":"Majd A.","family":"AbuAlrob","sequence":"additional","affiliation":[{"name":"Neurology Department Neuroscience Institute, Hamad Medical Corporation  Doha Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2340-3553","authenticated-orcid":false,"given":"Musab","family":"Ali","sequence":"additional","affiliation":[{"name":"Neurology Department Neuroscience Institute, Hamad Medical Corporation  Doha Qatar"},{"name":"School of Medicine Weill Cornell Medicine\u2010Qatar  Doha Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8748-0083","authenticated-orcid":false,"given":"Simona","family":"Lattanzi","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine Marche Polytechnic University  Ancona Italy"},{"name":"Neurological Clinic AOU of Marche  Ancona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8625-7365","authenticated-orcid":false,"given":"Boulenouar","family":"Mesraoua","sequence":"additional","affiliation":[{"name":"Neurology Department Neuroscience Institute, Hamad Medical Corporation  Doha Qatar"},{"name":"School of Medicine Weill Cornell Medicine\u2010Qatar  Doha Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,1]]},"reference":[{"key":"e_1_2_18_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(18)32596\u20100"},{"key":"e_1_2_18_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2018.24"},{"key":"e_1_2_18_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528\u20101167.2009.02397.x"},{"key":"e_1_2_18_5_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2017.3949"},{"key":"e_1_2_18_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2017.00301"},{"key":"e_1_2_18_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2023.120766"},{"key":"e_1_2_18_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/epi4.12461"},{"key":"e_1_2_18_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.16744"},{"key":"e_1_2_18_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2025.115720"},{"key":"e_1_2_18_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010019\u20101291\u20103"},{"key":"e_1_2_18_12_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aag2770"},{"key":"e_1_2_18_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2016.08.002"},{"key":"e_1_2_18_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2008.07.009"},{"key":"e_1_2_18_15_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00018.2018"},{"key":"e_1_2_18_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.10.027"},{"key":"e_1_2_18_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.05.001"},{"key":"e_1_2_18_18_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2024.1276551"},{"key":"e_1_2_18_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035\u2010023\u201003757\u20102"},{"key":"e_1_2_18_20_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2024.1386205"},{"key":"e_1_2_18_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2018.09.013"},{"key":"e_1_2_18_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.micpath.2019.103853"},{"key":"e_1_2_18_23_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2021.696632"},{"key":"e_1_2_18_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.18367"},{"key":"e_1_2_18_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2020.517797"},{"key":"e_1_2_18_26_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm10010005"},{"key":"e_1_2_18_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jocn.2024.01.023"},{"key":"e_1_2_18_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s44220\u2010025\u201000498\u20100"},{"key":"e_1_2_18_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.17009"},{"key":"e_1_2_18_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2010.178"},{"key":"e_1_2_18_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010019\u201050542\u20100"},{"key":"e_1_2_18_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.16813"},{"key":"e_1_2_18_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/epi4.12114"},{"key":"e_1_2_18_34_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.742449"},{"key":"e_1_2_18_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/ismeco\/ycae123"},{"key":"e_1_2_18_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2022.106925"},{"key":"e_1_2_18_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2022.105664"},{"key":"e_1_2_18_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.micpath.2021.105340"},{"key":"e_1_2_18_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.04.027"},{"key":"e_1_2_18_40_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v23.i33.6164"},{"key":"e_1_2_18_41_1","doi-asserted-by":"publisher","DOI":"10.1111\/apha.14104"},{"key":"e_1_2_18_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41522\u2010018\u20100073\u20102"},{"key":"e_1_2_18_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2018.06.015"},{"key":"e_1_2_18_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2022.104061"},{"key":"e_1_2_18_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/epi4.70037"},{"key":"e_1_2_18_46_1","doi-asserted-by":"publisher","DOI":"10.3920\/BM2018.0014"},{"key":"e_1_2_18_47_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035\u2010025\u201004993\u20104"},{"key":"e_1_2_18_48_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v23.i19.3565"},{"key":"e_1_2_18_49_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1910437"},{"key":"e_1_2_18_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010017\u201010203\u20106"},{"key":"e_1_2_18_51_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415\u2010018\u20108943\u20103"},{"key":"e_1_2_18_52_1","doi-asserted-by":"publisher","DOI":"10.1080\/00498250902745082"},{"key":"e_1_2_18_53_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.13392"},{"key":"e_1_2_18_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2008.08.032"},{"key":"e_1_2_18_55_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R116.767434"},{"key":"e_1_2_18_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010022\u201001913\u20100"},{"key":"e_1_2_18_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010022\u201001964\u20103"},{"key":"e_1_2_18_58_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2024.25593"},{"key":"e_1_2_18_59_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2008"},{"key":"e_1_2_18_60_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1102999108"}],"container-title":["Epilepsia Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/epi4.70325","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/epi4.70325","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/epi4.70325","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T10:32:47Z","timestamp":1785580367000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/epi4.70325"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,1]]},"references-count":59,"alternative-id":["10.1002\/epi4.70325"],"URL":"https:\/\/doi.org\/10.1002\/epi4.70325","archive":["Portico"],"relation":{},"ISSN":["2470-9239","2470-9239"],"issn-type":[{"value":"2470-9239","type":"print"},{"value":"2470-9239","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,1]]},"assertion":[{"value":"2026-03-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"epi4.70325"}}