{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T21:01:05Z","timestamp":1791666065044,"version":"4.3.4"},"reference-count":53,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T00:00:00Z","timestamp":1729209600000},"content-version":"vor","delay-in-days":291,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001665","name":"French National Research Agency","doi-asserted-by":"publisher","award":["ANR-19-CE17-0033"],"award-info":[{"award-number":["ANR-19-CE17-0033"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,1,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The influence of chronically administered host-targeted drugs on the gut microbiome remains less understood compared to antibiotics. We investigated repetitive exposure effects of three common antiseizure medications [carbamazepine (CBZ), valproic acid, and levetiracetam] on the gut microbial composition, resistome, and metabolome using microcosms constructed from feces of young children. Microcosms were established by cultivating feces for 24\u00a0h (C0). These microcosms were daily transferred into fresh media for seven cycles (C1\u2013C7) with antiseizure medications or carrier molecules, followed by four cycles without any drugs (C8\u2013C11). The microbial dynamics and resistome of microcosms at C0, C1, C7, and C11 were assessed with 16S ribosomal ribonucleic acid gene sequencing or shotgun metagenome sequencing and real-time quantitative polymerase chain reaction analysis of the antimicrobial resistance genes, respectively. Metabolites of CBZ-treated and control microcosms at C0, C1, and C7 were evaluated using non-targeted metabolomics. Our findings revealed that the serial transfer approach longitudinally altered the microcosm composition. Among the medications, CBZ had the most substantial impact on the structure and metabolism of the feces-derived microcosms. The microbiome composition partially recovered during the drug-free period. Specifically, Bacteroides and Flavonifractor were depleted and Escherichia and Clostridium were enriched. Additionally, repetitive CBZ exposure increased the abundance and expression of genes related to various antibiotic resistance mechanisms, more specifically, efflux pumps and antibiotic target\u00a0alteration. CBZ-induced changes in the microbiome were mirrored in the metabolome, with reductions in the citric acid cycle metabolites, glutamine, and spermidine, alongside increased levels of vitamin B6. Our study suggests that repetitive CBZ exposure may negatively impact gut microbial homeostasis and metabolism.<\/jats:p>","DOI":"10.1093\/ismeco\/ycae123","type":"journal-article","created":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T17:55:38Z","timestamp":1729274138000},"source":"Crossref","is-referenced-by-count":7,"title":["Longitudinal exposure to antiseizure medications shape gut-derived microbiome, resistome, and metabolome landscape"],"prefix":"10.1093","volume":"4","author":[{"given":"Camille","family":"Dop","sequence":"first","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Institut National de Recherche pour l\u2019Agriculture, l\u2019Alimentation et l\u2019Environnement (INRAE), AgroParisTech, Micalis Institute , Domaine de Vilvert, Jouy-en-Josas ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phane","family":"Auvin","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM), NeuroDiderot , Paris ,","place":["France"]},{"name":"Pediatric Neurology Department , Assistance Publique-H\u00f4pitaux de Paris ( , Paris ,","place":["France"]},{"name":"APHP), Robert Debr\u00e9 University Hospital , Assistance Publique-H\u00f4pitaux de Paris ( , Paris ,","place":["France"]},{"name":"Institut Universitaire de France , Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanislas","family":"Mondot","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Institut National de Recherche pour l\u2019Agriculture, l\u2019Alimentation et l\u2019Environnement (INRAE), AgroParisTech, Micalis Institute , Domaine de Vilvert, Jouy-en-Josas ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Lepage","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Institut National de Recherche pour l\u2019Agriculture, l\u2019Alimentation et l\u2019Environnement (INRAE), AgroParisTech, Micalis Institute , Domaine de Vilvert, Jouy-en-Josas ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zehra Esra","family":"Ilhan","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Institut National de Recherche pour l\u2019Agriculture, l\u2019Alimentation et l\u2019Environnement (INRAE), AgroParisTech, Micalis Institute , Domaine de Vilvert, Jouy-en-Josas ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,10,18]]},"reference":[{"key":"2024110809261320700_ref1a","author":"World Health Organization (WHO)","journal-title":"Epilepsy"},{"key":"2024110809261320700_ref1","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1007\/s40263-015-0281-8","article-title":"Antiepileptic drug treatment in children with epilepsy","volume":"29","author":"Rosati","year":"2015","journal-title":"CNS Drugs"},{"key":"2024110809261320700_ref2","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.eplepsyres.2015.03.002","article-title":"Antiepileptic drug use for treatment of epilepsy and dyslipidemia: systematic review","volume":"113","author":"Vyas","year":"2015","journal-title":"Epilepsy Res"},{"key":"2024110809261320700_ref3","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1080\/14740338.2019.1625887","article-title":"An update on the problem of osteoporosis in people with epilepsy taking antiepileptic drugs","volume":"18","author":"Miziak","year":"2019","journal-title":"Expert Opin Drug Saf"},{"key":"2024110809261320700_ref4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/19490976.2020.1870402","article-title":"Association between antibiotics and gut microbiome dysbiosis in children: systematic review and meta-analysis","volume":"13","author":"McDonnell","year":"2021","journal-title":"Gut Microbes"},{"key":"2024110809261320700_ref5","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.1017\/S0007114520000380","article-title":"Microbial dysbiosis-induced obesity: role of gut microbiota in homoeostasis of energy metabolism","volume":"123","author":"Amabebe","year":"2020","journal-title":"Br J Nutr"},{"key":"2024110809261320700_ref6","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1016\/j.chom.2015.04.006","article-title":"Antibiotics, pediatric dysbiosis, and disease","volume":"17","author":"Vangay","year":"2015","journal-title":"Cell Host Microbe"},{"key":"2024110809261320700_ref7","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.toxlet.2018.08.002","article-title":"Impact of lincosamides antibiotics on the composition of the rat gut microbiota and the metabolite profile of plasma and feces","volume":"296","author":"Behr","year":"2018","journal-title":"Toxicol Lett"},{"key":"2024110809261320700_ref8","doi-asserted-by":"publisher","first-page":"105664","DOI":"10.1016\/j.nbd.2022.105664","article-title":"Exposure to anti-seizure medications impact growth of gut bacterial species and subsequent host response","volume":"167","author":"Ilhan","year":"2022","journal-title":"Neurobiol Dis"},{"key":"2024110809261320700_ref9","doi-asserted-by":"publisher","first-page":"1671","DOI":"10.1007\/s00213-018-5006-5","article-title":"Differential effects of psychotropic drugs on microbiome composition and gastrointestinal function","volume":"236","author":"Cussotto","year":"2019","journal-title":"Psychopharmacology"},{"key":"2024110809261320700_ref10","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1038\/nature25979","article-title":"Extensive impact of non-antibiotic drugs on human gut bacteria","volume":"555","author":"Maier","year":"2018","journal-title":"Nature"},{"key":"2024110809261320700_ref11","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.cell.2012.10.052","article-title":"Xenobiotics shape the physiology and gene expression of the active human gut microbiome","volume":"152","author":"Maurice","year":"2013","journal-title":"Cell"},{"key":"2024110809261320700_ref12","doi-asserted-by":"publisher","first-page":"2493","DOI":"10.1038\/s41396-021-00945-7","article-title":"Non-antibiotic pharmaceuticals promote the transmission of multidrug resistance plasmids through intra- and intergenera conjugation","volume":"15","author":"Wang","year":"2021","journal-title":"ISME J"},{"key":"2024110809261320700_ref13","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1038\/s41396-018-0275-x","article-title":"Antiepileptic drug carbamazepine promotes horizontal transfer of plasmid-borne multi-antibiotic resistance genes within and across bacterial genera","volume":"13","author":"Wang","year":"2019","journal-title":"ISME J"},{"key":"2024110809261320700_ref14","doi-asserted-by":"publisher","first-page":"115073","DOI":"10.1016\/j.watres.2019.115073","article-title":"Aromatic compounds lead to increased abundance of antibiotic resistance genes in wastewater treatment bioreactors","volume":"166","author":"Xia","year":"2019","journal-title":"Water Res"},{"key":"2024110809261320700_ref15","doi-asserted-by":"publisher","first-page":"114473","DOI":"10.1016\/j.ecoenv.2022.114473","article-title":"Effects of carbamazepine on gut microbiota, ARGs and intestinal health in zebrafish","volume":"249","author":"Yang","year":"2023","journal-title":"Ecotoxicol Environ Saf"},{"key":"2024110809261320700_ref16","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.1093\/nar\/gks808","article-title":"Evaluation of general 16S ribosomal RNA gene PCR primers for classical and next-generation sequencing-based diversity studies","volume":"41","author":"Klindworth","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"2024110809261320700_ref17","doi-asserted-by":"publisher","first-page":"10","DOI":"10.14806\/ej.17.1.200","article-title":"Cutadapt removes adapter sequences from high-throughput sequencing reads","volume":"17","author":"Martin","year":"2011","journal-title":"EMBnet j"},{"key":"2024110809261320700_ref18","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1089\/cmb.2012.0021","article-title":"SPAdes: a new genome assembly algorithm and its applications to single-cell sequencing","volume":"19","author":"Bankevich","year":"2012","journal-title":"J Comput Biol"},{"key":"2024110809261320700_ref19","doi-asserted-by":"publisher","first-page":"614","DOI":"10.1093\/bioinformatics\/btt593","article-title":"PEAR: a fast and accurate Illumina paired-end reAd mergeR","volume":"30","author":"Zhang","year":"2014","journal-title":"Bioinformatics"},{"key":"2024110809261320700_ref20","doi-asserted-by":"publisher","first-page":"e2584","DOI":"10.7717\/peerj.2584","article-title":"VSEARCH: a versatile open source tool for metagenomics","volume":"4","author":"Rognes","year":"2016","journal-title":"PeerJ"},{"key":"2024110809261320700_ref21","doi-asserted-by":"publisher","first-page":"R25","DOI":"10.1186\/gb-2009-10-3-r25","article-title":"Ultrafast and memory-efficient alignment of short DNA sequences to the human genome","volume":"10","author":"Langmead","year":"2009","journal-title":"Genome Biol"},{"key":"2024110809261320700_ref22","doi-asserted-by":"publisher","first-page":"1674","DOI":"10.1093\/bioinformatics\/btv033","article-title":"MEGAHIT: an ultra-fast single-node solution for large and complex metagenomics assembly via succinct de Bruijn graph","volume":"31","author":"Li","year":"2015","journal-title":"Bioinformatics"},{"key":"2024110809261320700_ref23","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq275","article-title":"Ab initio gene identification in metagenomic sequences","volume":"38","author":"Zhu","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"2024110809261320700_ref24","doi-asserted-by":"publisher","first-page":"3150","DOI":"10.1093\/bioinformatics\/bts565","article-title":"CD-HIT: accelerated for clustering the next-generation sequencing data","volume":"28","author":"Fu","year":"2012","journal-title":"Bioinformatics"},{"key":"2024110809261320700_ref25","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1038\/nmeth.3176","article-title":"Fast and sensitive protein alignment using DIAMOND","volume":"12","author":"Buchfink","year":"2015","journal-title":"Nat Methods"},{"key":"2024110809261320700_ref26","doi-asserted-by":"publisher","first-page":"D353","DOI":"10.1093\/nar\/gkw1092","article-title":"KEGG: new perspectives on genomes, pathways, diseases and drugs","volume":"45","author":"Kanehisa","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"2024110809261320700_ref27","doi-asserted-by":"publisher","first-page":"D566","DOI":"10.1093\/nar\/gkw1004","article-title":"CARD 2017: expansion and model-centric curation of the comprehensive antibiotic resistance database","volume":"45","author":"Jia","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"2024110809261320700_ref28","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1128\/AAC.00996-10","article-title":"Expression of multidrug efflux pump genes acrAB-tolC, mdfA, and norE in Escherichia coli clinical isolates as a function of fluoroquinolone and multidrug resistance","volume":"55","author":"Swick","year":"2011","journal-title":"Antimicrob Agents Chemother"},{"key":"2024110809261320700_ref29","doi-asserted-by":"publisher","first-page":"e365","DOI":"10.1371\/journal.pone.0000365","article-title":"Antibiotic stress, genetic response and altered permeability of E. coli","volume":"2","author":"Viveiros","year":"2007","journal-title":"PLoS ONE"},{"key":"2024110809261320700_ref30","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1186\/s13104-019-4177-4","article-title":"Transcriptional response of OmpC and OmpF in Escherichia coli against differential gradient of carbapenem stress","volume":"12","author":"Chetri","year":"2019","journal-title":"BMC Res Notes"},{"key":"2024110809261320700_ref31","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1007\/s10156-007-0575-Y","article-title":"The AraC-family regulator GadX enhances multidrug resistance in Escherichia coli by activating expression of mdtEF multidrug efflux genes","volume":"14","author":"Nishino","year":"2008","journal-title":"J Infect Chemother"},{"key":"2024110809261320700_ref32","doi-asserted-by":"publisher","first-page":"e61217","DOI":"10.1371\/journal.pone.0061217","article-title":"Phyloseq: an R package for reproducible interactive analysis and graphics of microbiome census data","volume":"8","author":"McMurdie","year":"2013","journal-title":"PLoS One"},{"key":"2024110809261320700_ref33","doi-asserted-by":"publisher","DOI":"10.1007\/978-0-387-98141-3","volume-title":"ggplot2: Elegant Graphics for Data Analysis","author":"Wickham","year":"2009"},{"key":"2024110809261320700_ref34","doi-asserted-by":"publisher","first-page":"1540","DOI":"10.1093\/bioinformatics\/btl117","article-title":"Pvclust: an R package for assessing the uncertainty in hierarchical clustering","volume":"22","author":"Suzuki","year":"2006","journal-title":"Bioinformatics"},{"key":"2024110809261320700_ref35","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1016\/j.chom.2008.09.007","article-title":"Mucosal glycan foraging enhances fitness and transmission of a saccharolytic human gut bacterial symbiont","volume":"4","author":"Martens","year":"2008","journal-title":"Cell Host Microbe"},{"key":"2024110809261320700_ref36","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1186\/1741-7007-11-61","article-title":"Bacteroides thetaiotaomicron and Faecalibacterium prausnitzii influence the production of mucus glycans and the development of goblet cells in the colonic epithelium of a gnotobiotic model rodent","volume":"11","author":"Wrzosek","year":"2013","journal-title":"BMC Biol"},{"key":"2024110809261320700_ref37","doi-asserted-by":"publisher","first-page":"1103836","DOI":"10.3389\/fmicb.2022.1103836","article-title":"Butyrate producers, \u201cthe sentinel of gut\u201d: their intestinal significance with and beyond butyrate, and prospective use as microbial therapeutics","volume":"13","author":"Singh","year":"2023","journal-title":"Front Microbiol"},{"key":"2024110809261320700_ref38","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1128\/CMR.00117-14","article-title":"The challenge of efflux-mediated antibiotic resistance in gram-negative bacteria","volume":"28","author":"Li","year":"2015","journal-title":"Clin Microbiol Rev"},{"key":"2024110809261320700_ref39","doi-asserted-by":"publisher","first-page":"e00321","DOI":"10.1128\/msystems.00321-18","article-title":"Alterations in gut glutamate metabolism associated with changes in gut microbiota composition in children with autism spectrum disorder","volume":"4","author":"Wang","year":"2019","journal-title":"mSystems"},{"key":"2024110809261320700_ref40","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1111\/j.1365-2672.2012.05434.x","article-title":"Role of glutamate metabolism in bacterial responses towards acid and other stresses","volume":"114","author":"Feehily","year":"2013","journal-title":"J Appl Microbiol"},{"key":"2024110809261320700_ref41","doi-asserted-by":"publisher","first-page":"329","DOI":"10.3390\/molecules14010329","article-title":"Vitamin B6: a long known compound of surprising complexity","volume":"14","author":"Mooney","year":"2009","journal-title":"Molecules"},{"key":"2024110809261320700_ref42","doi-asserted-by":"publisher","first-page":"1031502","DOI":"10.3389\/fnut.2022.1031502","article-title":"Intermediate role of gut microbiota in vitamin B nutrition and its influences on human health","volume":"9","author":"Wan","year":"2022","journal-title":"Front Nutr"},{"key":"2024110809261320700_ref43","doi-asserted-by":"publisher","first-page":"1051","DOI":"10.3390\/ijms18051051","article-title":"The roles of glutamine in the intestine and its implication in intestinal diseases","volume":"18","author":"Kim","year":"2017","journal-title":"IJMS"},{"key":"2024110809261320700_ref44","doi-asserted-by":"publisher","first-page":"1934","DOI":"10.3389\/fmicb.2016.01934","article-title":"The neuro-endocrinological role of microbial glutamate and GABA Signaling","volume":"7","author":"Mazzoli","year":"2016","journal-title":"Front Microbiol"},{"key":"2024110809261320700_ref45","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1046\/j.1528-1157.2001.042suppl.3008.x","article-title":"GABAergic mechanisms in epilepsy","volume":"42","author":"Treiman","year":"2001","journal-title":"Epilepsia"},{"key":"2024110809261320700_ref46","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1038\/s41564-018-0307-3","article-title":"GABA-modulating bacteria of the human gut microbiota","volume":"4","author":"Strandwitz","year":"2019","journal-title":"Nat Microbiol"},{"key":"2024110809261320700_ref47","doi-asserted-by":"publisher","first-page":"104158","DOI":"10.1016\/j.isci.2022.104158","article-title":"Bacteroides ovatus colonization influences the abundance of intestinal short chain fatty acids and neurotransmitters","volume":"25","author":"Horvath","year":"2022","journal-title":"iScience"},{"key":"2024110809261320700_ref48","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1515\/JBCPP.1996.7.1.1","article-title":"Polyamines induce blood\u2013brain barrier disruption and edema formation in the rat","volume":"7","author":"Glantz","year":"1996","journal-title":"J Basic Clin Physiol Pharmacol"},{"key":"2024110809261320700_ref49","doi-asserted-by":"publisher","first-page":"e1832857","DOI":"10.1080\/19490976.2020.1832857","article-title":"Spermidine improves gut barrier integrity and gut microbiota function in diet-induced obese mice","volume":"12","author":"Ma","year":"2020","journal-title":"Gut Microbes"},{"key":"2024110809261320700_ref50","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1515\/JBCPP.2010.21.2.169","article-title":"Spermidine influence on the nitric oxide synthase and arginase activity relationship during experimentally induced seizures","volume":"21","author":"Stojanovi\u0107","year":"2010","journal-title":"J Basic Clin Physiol Pharmacol"},{"key":"2024110809261320700_ref51","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1016\/j.braindev.2011.01.010","article-title":"Vitamin B6 treatment of intractable seizures","volume":"33","author":"Ohtahara","year":"2011","journal-title":"Brain Dev"},{"key":"2024110809261320700_ref52","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.1080\/14737175.2019.1648212","article-title":"Update on the treatment of vitamin B6 dependent epilepsies","volume":"19","author":"Mastrangelo","year":"2019","journal-title":"Expert Rev Neurother"}],"container-title":["ISME Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ismecommun\/advance-article-pdf\/doi\/10.1093\/ismeco\/ycae123\/59878195\/ycae123.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ismecommun\/advance-article-pdf\/doi\/10.1093\/ismeco\/ycae123\/60530661\/ycae123.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ismecommun\/advance-article-pdf\/doi\/10.1093\/ismeco\/ycae123\/60530661\/ycae123.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,8]],"date-time":"2024-11-08T09:26:52Z","timestamp":1731058012000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ismecommun\/article\/doi\/10.1093\/ismeco\/ycae123\/7826681"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1]]},"references-count":53,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2024,1,8]]}},"URL":"https:\/\/doi.org\/10.1093\/ismeco\/ycae123","relation":{},"ISSN":["2730-6151"],"issn-type":[{"value":"2730-6151","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,1]]},"published":{"date-parts":[[2024,1]]},"article-number":"ycae123"}}