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Escherichia Coli K1-colibactin meningitis induces microglial NLRP3/IL-18 exacerbating H3K4me3-synucleinopathy in

Van Thi Ai Tran1,2, Xiaohui Zhu1,2, Ariunzaya Jamsranjav1,2

  • 1Institute of Biophysics, Sungkyunkwan University, Suwon, South Korea.

Communications Biology
|March 6, 2025
PubMed

Insights

Escherichia coli K1 meningitis causes severe neurological damage. This study reveals how gut-brain axis inflammation, driven by E. coli K1, leads to neuropathies and potentially synucleinopathy.

Area of Science:

  • Neuroscience
  • Microbiology
  • Immunology
  • Gastroenterology

Background:

  • Escherichia coli K1 (E. coli K1) meningitis can lead to severe central nervous system damage and long-term neurological issues.
  • The precise cellular mechanisms underlying E. coli K1-induced neuropathies are not fully understood, partly due to limitations in existing human multi-organ models for studying gut-brain axis inflammation.

Purpose of the Study:

  • To reconstruct a human gut-brain axis multicellular model to investigate the neuropathogenic mechanisms of E. coli K1 meningitis.
  • To identify how E. coli K1-derived colibactin contributes to systemic inflammation and subsequent neurological damage.

Main Methods:

  • Development of a multicellular human gut-brain axis model.
  • Analysis of inflammatory pathways, including interleukin 6, p38/p65, Serpin-E1, IFN-γ, NLRP3/IL-18, and their effects on the blood-brain barrier, astrocytes, and microglia.
  • Assessment of neuronal damage, including oxidative stress, DNA double-strand breaks, H3K4 trimethylation, and alpha-synuclein phosphorylation.

Main Results:

  • E. coli K1-derived colibactin triggered intestinal and peripheral interleukin 6 release, leading to blood-brain barrier injury and endothelial inflammation via p38/p65 pathways.
  • Cerebral endothelial damage induced Serpin-E1, prompting reactive astrocytes to release IFN-γ, which impaired microglial phagocytosis and worsened neuroinflammation through the NLRP3/IL-18 axis.
  • Microglial IL-18 exacerbated neuronal oxidative stress and DNA damage, culminating in H3K4 trimethylation and alpha-synuclein phosphorylation, suggesting a link to synucleinopathy.

Conclusions:

  • The study elucidates a detailed cellular mechanism by which E. coli K1 meningitis causes neuropathies via gut-brain axis inflammation.
  • The findings highlight the role of colibactin, interleukin-6, Serpin-E1, IFN-γ, and IL-18 in the cascade of neuroinflammation and neuronal damage.
  • The identified pathways suggest potential therapeutic targets for treating post-bacterial meningitis and preventing synucleinopathy initiation.

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