ORIGINAL RESEARCH article
Front. Microbiol.
Sec. Microorganisms in Vertebrate Digestive Systems
This article is part of the Research TopicRodent Model Organisms: Therapeutic Treatments and Drugs Interaction with the Gut Microbiome, Volume IIView all 35 articles
Gut microbiota-derived EPA alleviates neuroinflammation associated with white matter injury by influencing H3K9ac/BDNF/TrkB pathway
Provisionally accepted
- 1Second Affiliated Hospital of Dalian Medical University, Dalian, China
- 2Dalian Women and Children’s Medical Group, Dalian, China
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Abstract Background: The objective of our investigation was to explore the features of gut microbiota dysbiosis and the concentrations of gut metabolites in relation to white matter injury (WMI). Furthermore, we sought to evaluate the influence of gut dysbiosis on neuroinflammation in WMI via intestinal metabolites, and its contribution to pathogenesis. Methods: A cerebral hypoxia-ischemia-induced WMI model was established in 3-day-old Sprague-Dawley rats. Liquid chromatography-mass spectrometry/gas chromatography-mass spectrometry analyses and 16S rRNA gene sequencing were undertaken to ascertain WMI biomarkers. Mechanistic experiments were used to analyse activation of the H3K9ac/BDNF/TrkB pathway and neuroinflammation. Results: The analysis of 16S rRNA sequencing disclosed gut microbiota dysbiosis in WMI rats, quantified using linear discriminant analysis effect size. Overall, 341 differentially expressed metabolic markers between the WMI and Sham groups were discovered. The Kyoto Encyclopedia of Genes and Genomes network enhancement evaluation revealed significant downregulation of 20 metabolic processes in the WMI group, which is strongly related to changes in fecal microbial metabolites, and the synthesis process of unsaturated fatty acids was the most significant. Gut microbiota dysbiosis may influence WMI by downregulating metabolites such as eicosapentaenoic acid (EPA). Fecal microbiota transplantation increased EPA concentration in the brain tissue of WMI rats. Gut microbiota-derived EPA promoted H3K9ac and BDNF/TrkB expression and inhibited the transcription of pro-inflammatory TNF-α and IL-1β molecules. These EPA-mediated effects were reversed by TrkB inhibition. Conclusions: WMI induces gut dysbiosis involving down-regulation of unsaturated fatty acid synthesis. Fecal microbiota transplantation leads to increased levels of EPA. Gut microbiota-derived EPA increases levels of acetylated histone H3K9ac, causes activation of the BDNF/TrkB pathway, reduces neuroinflammation, and improves WMI-associated myelination disorders. It provides a basis for targeted treatment of white matter injury in the future.
Keywords: EPA, fecalmicrobiota transplantation, Gut Microbiota, histone acetylation, Microbiota-gut-brain axis, Neuroinflammation, white matter injury
Received: 26 Sep 2025; Accepted: 16 Feb 2026.
Copyright: © 2026 Wang, Zhang, Cui, Zhu, Wang, Wang, Xiao and Yang. 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:
Xuwu Xiao
Liu Yang
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