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Updated: May 6, 2026
Sub-acute Cerebral Microhemorrhages Induced by Lipopolysaccharide Injection in Rats
Published on: October 17, 2018
Microbial metabolite trimethylamine N-oxide exacerbated microglial-mediated neuroinflammation in hemorrhagic stroke
Tao Ye1, Xuandong Kong2, Xinhuang Lv1
1Department of Neurology, the Second Affiliated Hospital of Wenzhou Medical University, 325027, Wenzhou, Zhejiang, China.
Background:
Trimethylamine-N-oxide (TMAO), a metabolite produced by gut microbiota, has been linked to brain disease; however, its role in intracerebral hemorrhage (ICH) remains unclear.
Methods:
Animal experiments were conducted to demonstrate the effects of TMAO on collagenase-induced rat models of ICH. Neurological function was evaluated using the modified neurological severity score (mNSS), and neuronal damage was assessed by NeuN staining. Microglial activation and pro-inflammatory cytokine expression were examined. To further investigate the mechanism of TMAO, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis on its predicted molecular targets. BV2 microglia were treated with TMAO to assess the levels of reactive oxygen species (ROS), cyclooxygenase-2 (COX-2), NOD-like receptor protein 3 (NLRP3), and caspase-1. Moreover, ICH rats were intragastrically treated with TMAO precursor L-carnitine (LC), and antibiotic cocktail treatment was used to deplete the gut microbiota, then assessed the effect.
Results:
Our results showed that TMAO administration exacerbated neurological deficits and microglial-mediated neuroinflammation in ICH rats. NOD-like receptor signaling pathway was a key mechanism promoting ICH pathogenesis and confirmed that TMAO supplementation exacerbated microglial activation by regulating NLRP3 inflammasome activity in vitro. Moreover, gut microbiota depletion attenuated TMAO-induced activation of NLRP3 and the subsequent neuroinflammatory response in ICH.
Conclusion:
Collectively, these findings showed that Microbial Metabolite TMAO contributes to ICH-induced neuroinflammation by activating the NLRP3 signaling pathway.
Insights
Gut microbe metabolite trimethylamine-N-oxide (TMAO) worsens brain injury after intracerebral hemorrhage (ICH). TMAO activates the NLRP3 inflammasome, increasing neuroinflammation and neurological deficits in ICH models.
Area of Science:
- Neuroscience
- Microbiology
- Immunology
Background:
- Trimethylamine-N-oxide (TMAO), a gut microbiota metabolite, is implicated in brain diseases.
- The specific role of TMAO in intracerebral hemorrhage (ICH) pathogenesis is not well understood.
Purpose of the Study:
- To investigate the effects of TMAO on ICH in a rat model.
- To elucidate the underlying mechanisms of TMAO's action in ICH, focusing on neuroinflammation and the NLRP3 pathway.
Main Methods:
- Collagenase-induced ICH rat models were used to assess TMAO effects on neurological function (mNSS) and neuronal damage (NeuN staining).
- Microglial activation, pro-inflammatory cytokines, ROS, COX-2, NLRP3, and caspase-1 were examined in vivo and in vitro (BV2 microglia).
- Gene Ontology and KEGG analyses were performed; gut microbiota was depleted using antibiotics, and TMAO precursor L-carnitine was administered.
Main Results:
- TMAO administration worsened neurological deficits and microglial-mediated neuroinflammation in ICH rats.
- TMAO upregulated NLRP3 inflammasome activity, exacerbating microglial activation and ICH pathogenesis.
- Depletion of gut microbiota attenuated TMAO-induced NLRP3 activation and neuroinflammation.
Conclusions:
- Microbial metabolite TMAO exacerbates ICH-induced neuroinflammation.
- The NLRP3 signaling pathway is a key mechanism through which TMAO contributes to ICH pathogenesis.
- Targeting gut microbiota or TMAO may offer therapeutic strategies for ICH.
