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<p>Intracerebral hemorrhage (ICH), a lethal stroke subtype, lacks therapies targeting gut-brain axis dysregulation. While gut microbiota influences ischemic stroke outcomes, how ICH perturbs microbial-metabolite interactions via the microbiota-gut-brain axis (MGBA) remains unknown. We combined a collagenase-induced ICH mouse model with multi-omics (16S rRNA sequencing, metabolomics) and functional assays (BV2 microglia) to investigate gut dysbiosis and metabolite alterations. Intestinal barrier integrity, neuroinflammation, and oxidative stress were assessed. At the phylum level, the control (CON) group exhibited a microbiome dominated by <i>Firmicutes</i>, <i>Actinobacteriota</i>, and <i>Campylobacterota</i>. In stark contrast, the ICH group displayed a pathological shift toward <i>Bacteroidota</i>, <i>Cyanobacteria</i>, and <i>Proteobacteria</i>. These dysbiotic alterations corresponded to intestinal barrier compromise marked by reduced expression of zonula occludens-1 (ZO-1), occludin, and mucin 2 (MUC2), systemic elevation of pro-inflammatory cytokines including interleukin-1β (<i>Il-1β</i>) and tumor necrosis factor-α (<i>Tnf-α</i>), and depletion of neuroprotective metabolites–specifically oleoyl ethanolamide, linoleoyl ethanolamide, and L-valine–whose levels positively correlated with <i>Firmicutes</i> abundance. Mechanistically, in vitro experiments demonstrated that these metabolites collectively suppressed neuroinflammation and neuronal apoptosis, with l-valine exhibiting unique antioxidant activity through Reactive oxygen species scavenging. Molecular docking studies have shown that linoleoyl ethanolamide (LEA) and oleoylethanolamide (OEA) can inhibit the levels of inflammatory cytokines interleukin-6 (<i>Il-6</i>) and tumor necrosis <i>Tnf-α</i> by binding to key sites. Our findings underscore the critical role of gut microbiota-metabolite crosstalk in ICH pathogenesis and identify microbial metabolites as potential therapeutic targets for preserving gut-brain axis homeostasis.</p>

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Restoring Firmicutes-Associated Metabolites: A Gut-Brain Axis Approach to Alleviate Neuroinflammation and Oxidative Stress in Intracerebral Hemorrhage

  • 期刊论文

  • 发表日期：

    2026年3月3日

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  • Yiteng Liu,
  • Biying Zhang,
  • Huaxian Li,
  • Yue Si,
  • Mangmang Qiu,
  • Hao Xu,
  • Cunfang Qi

摘要

Intracerebral hemorrhage (ICH), a lethal stroke subtype, lacks therapies targeting gut-brain axis dysregulation. While gut microbiota influences ischemic stroke outcomes, how ICH perturbs microbial-metabolite interactions via the microbiota-gut-brain axis (MGBA) remains unknown. We combined a collagenase-induced ICH mouse model with multi-omics (16S rRNA sequencing, metabolomics) and functional assays (BV2 microglia) to investigate gut dysbiosis and metabolite alterations. Intestinal barrier integrity, neuroinflammation, and oxidative stress were assessed. At the phylum level, the control (CON) group exhibited a microbiome dominated by Firmicutes, Actinobacteriota, and Campylobacterota. In stark contrast, the ICH group displayed a pathological shift toward Bacteroidota, Cyanobacteria, and Proteobacteria. These dysbiotic alterations corresponded to intestinal barrier compromise marked by reduced expression of zonula occludens-1 (ZO-1), occludin, and mucin 2 (MUC2), systemic elevation of pro-inflammatory cytokines including interleukin-1β (Il-1β) and tumor necrosis factor-α (Tnf-α), and depletion of neuroprotective metabolites–specifically oleoyl ethanolamide, linoleoyl ethanolamide, and L-valine–whose levels positively correlated with Firmicutes abundance. Mechanistically, in vitro experiments demonstrated that these metabolites collectively suppressed neuroinflammation and neuronal apoptosis, with l-valine exhibiting unique antioxidant activity through Reactive oxygen species scavenging. Molecular docking studies have shown that linoleoyl ethanolamide (LEA) and oleoylethanolamide (OEA) can inhibit the levels of inflammatory cytokines interleukin-6 (Il-6) and tumor necrosis Tnf-α by binding to key sites. Our findings underscore the critical role of gut microbiota-metabolite crosstalk in ICH pathogenesis and identify microbial metabolites as potential therapeutic targets for preserving gut-brain axis homeostasis.