ORIGINAL RESEARCH article
Front. Microbiol.
Sec. Microorganisms in Vertebrate Digestive Systems
Volume 16 - 2025 | doi: 10.3389/fmicb.2025.1630062
This article is part of the Research TopicNew and advanced mechanistic insights into the influences of the infant gut microbiota on human health and disease, Volume IIView all 3 articles
Multi-omics integration reveals gut microbiota dysbiosis and metabolic alterations of cerebrospinal fluid in children with epilepsy
Provisionally accepted
- 1The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
- 2Wenzhou Medical University, Wenzhou, China
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Epilepsy is a complex neurological disorder with an unclear pathogenesis. Emerging evidence suggests that gut microbiota dysbiosis and cerebrospinal fluid (CSF) metabolic alterations play a critical role in epilepsy progression through the gut-brain axis. This study aimed to characterize microbial and metabolic disturbances in pediatric epilepsy and identify potential diagnostic biomarkers through integrative multi-omics analysis of matched fecal and CSF samples.Methods: In this study, we conducted 16S rRNA gene sequencing on fecal samples from a total of 50 participants including 17 common epilepsy (CEP) patients, 23 refractory epilepsy (REP) patients, and 10 non-epilepsy (NEP) patients, along with untargeted metabolomic analysis on 24 paired CSF samples from REP and NEP groups. Multi-omics integration and a random forest model were applied to assess diagnostic performance, identifying microbial and metabolite signatures associated with epilepsy.Results: Children with epilepsy (REP and CEP) exhibited distinct gut microbiota dysbiosis. Specifically, multivariable association modeling using MaAsLin 3 identified 13 discriminatory microbial taxa, with Clostridiales and Clostridiaceae ranking as the most enriched in REP. Functional predictions revealed significant differences in metabolic pathway, alongside disrupted ecological characteristics among epilepsy groups. In addition, CSF metabolomics analysis further revealed key metabolic shifts between REP and NEP, with notable alterations in alpha-Ketoisocaproic acid, alpha-Ketoisovaleric acid, and acetyl-L-carnitine, reflecting distinct metabolic reprogramming in epilepsy. Moreover, correlation analysis revealed strong microbiota-metabolite associations, reinforcing the involvement of the gut-brain axis in epileptogenesis. Independent random forest-based diagnostic models using microbial genera (AUC = 0.913, accuracy = 0.818) or metabolites (AUC = 0.875, accuracy = 0.833) demonstrated high classification accuracy in distinguishing REP from NEP. Notably, the integrated microbiota-metabolite classification model exhibited superior diagnostic performance in REP and CEP groups (AUC = 0.953, accuracy = 0.875), significantly surpassing individual models and highlighting the potential of multi-omics integration for epilepsy diagnostics.These findings reveal concurrent gut microbiota dysbiosis and CSF metabolic disturbances in epilepsy, underscoring their interrelated roles in epileptogenesis and reinforcing our understanding of microbiome-metabolome crosstalk. The integrated multi-omics model demonstrated superior diagnostic performance, emphasizing its potential for precision biomarker discovery and clinical application in epilepsy stratification and intervention.
Keywords: Epilepsy, gut-brain axis, Gut Microbiota, Cerebrospinal Fluid, Metabolomics
Received: 16 May 2025; Accepted: 14 Aug 2025.
Copyright: © 2025 Li, You, Wang, Lin, Shi, Li, Wu and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Zhenwei Liu, Wenzhou Medical University, Wenzhou, China
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