{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T03:02:41Z","timestamp":1784516561171,"version":"3.55.0"},"reference-count":49,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Drug-resistant epilepsy in children remains a major therapeutic challenge, and the limited efficacy of pharmacological treatment highlights the need for alternative therapeutic approaches, including the ketogenic diet (KD). Although the clinical efficacy of KD is well established, its metabolic effects are not fully understood. This study aimed to characterize the plasma metabolomic profile of children with drug-resistant epilepsy and to explore metabolic differences associated with ketogenic dietary therapy. Methods: Eighteen children with drug-resistant epilepsy were enrolled, including nine receiving KD and nine receiving a standard diet. Plasma metabolomic profiling was performed using gas chromatography-mass spectrometry (GC-MS). Data were analyzed using multivariate (PCA and OPLS-DA) and univariate statistical approaches. Both variable importance in projection (VIP) scores and metabolic pathway analysis were used to support biological interpretation. Results: A total of 462 annotated GC-MS features were retained after data filtering. OPLS-DA demonstrated clear separation between study groups (R2Y = 0.937; Q2 = 0.594). Eighty-three metabolites had VIP scores &gt; 1, indicating a substantial contribution to the OPLS-DA model, while 22 metabolites differed between groups based on unadjusted p-values. However, only three metabolites remained statistically significant after false discovery rate correction. After false discovery rate correction, \u03b2-hydroxybutyrate and citric acid remained significantly higher in the KD group, whereas 1,4-butanediol was significantly lower. Lower glucose and tryptophan levels were observed only in the unadjusted analyses and should therefore be regarded as exploratory. Similarly, the pathway analysis findings, including those related to amino acid metabolism, were exploratory and require confirmation in larger cohorts. Conclusions: Ketogenic dietary therapy was associated with distinct changes in the plasma metabolomic profile of children with drug-resistant epilepsy. While the most robust findings involved \u03b2-hydroxybutyrate, citric acid, and 1,4-butanediol, the observed changes in glucose and tryptophan, as well as the amino acid-related pathway findings, should be considered exploratory and require validation in larger independent cohorts before being interpreted as biomarkers or evidence of specific metabolic mechanisms.<\/jats:p>","DOI":"10.3390\/nu18142347","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T02:32:08Z","timestamp":1784514728000},"page":"2347","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolomic Profiling of Plasma in Children with Drug-Resistant Epilepsy: The Effect of the Ketogenic Diet on Energy and Amino Acid Pathways"],"prefix":"10.3390","volume":"18","author":[{"given":"Marta","family":"Cie\u015blak","sequence":"first","affiliation":[{"name":"Institute of General and Environmental Chemistry, Faculty of Chemistry, Lodz University of Technology, 116 Zeromskiego Street, 90-924 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3825-522X","authenticated-orcid":false,"given":"Paulina","family":"G\u0105tarek","sequence":"additional","affiliation":[{"name":"Institute of General and Environmental Chemistry, Faculty of Chemistry, Lodz University of Technology, 116 Zeromskiego Street, 90-924 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Safi\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Developmental Neurology and Epileptology, Research Institute of Polish Mother\u2019s Memorial Hospital, 93-338 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0209-4103","authenticated-orcid":false,"given":"Lukasz","family":"Przyslo","sequence":"additional","affiliation":[{"name":"Department of Developmental Neurology and Epileptology, Research Institute of Polish Mother\u2019s Memorial Hospital, 93-338 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5106-4667","authenticated-orcid":false,"given":"Joanna","family":"Ka\u0142u\u017cna-Czapli\u0144ska","sequence":"additional","affiliation":[{"name":"Institute of General and Environmental Chemistry, Faculty of Chemistry, Lodz University of Technology, 116 Zeromskiego Street, 90-924 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.seizure.2025.08.001","article-title":"Global, regional, and national epidemiology of childhood epilepsy from 1990 to 2021: A systematic study based on the GBD 2021","volume":"131","author":"Xu","year":"2025","journal-title":"Seizure"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2879","DOI":"10.1093\/brain\/awab162","article-title":"Early childhood epilepsies: Epidemiology, classification, aetiology, and socio-economic determinants","volume":"144","author":"Symonds","year":"2021","journal-title":"Brain J. 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