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<p>The blood–brain barrier (BBB) plays a crucial role in protecting the central nervous system (CNS) from harmful substances but poses challenges to the effective delivery of many therapeutic drugs. While the inflammatory effects of lipopolysaccharides (LPS) are documented, the combined effects of specific LPS types on BBB integrity require further investigation. This study investigates the distinct and combined impacts of LPS derived from <i>Escherichia coli</i>&#xa0;(EC) and <i>Bacteroides fragilis</i>&#xa0;(BF) on BBB integrity. A range of assays was employed, including Limulus amebocyte lysate (LAL) endotoxin detection, CCK-8 cell viability assays, transepithelial electrical resistance (TEER) measurement, FITC-Dextran permeability, immunofluorescence and Western blot analysis of NF-κB p65 and phosphorylated p65 (p-p65) nuclear translocation, tight junctions (TJs) proteins (ZO-1, claudin-5, occludin), inflammation cytokines (TNF-α, IL-6) and COX-2 levels by qPCR and ELISA, Rhodamine 123 (Rh123) efflux assays, and Evans Blue (EB) staining in mice to assess BBB permeability <i>in vivo</i>. The results showed that EC-LPS had higher endotoxin activity compared to BF-LPS (EU ratio of 4.7:1), and despite equal EU concentrations, EC-LPS induced a stronger inflammatory response and more significant BBB disruption. Notably, the co-treatment group (EC-LPS + BF-LPS) showed no synergistic effect on BBB permeability, with BF-LPS antagonizing the effect of EC-LPS. Further confirmation through TLR4 and NF-κB inhibitors revealed that this BBB permeability mechanism is TLR4 receptor and NF-κB pathway-dependent.</p>

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Differential activation of NF-κB pathway by Escherichia coli and Bacteroides fragilis lipopolysaccharides affects blood–brain barrier permeability

  • 期刊论文

  • 发表日期：

    2026年2月19日

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  • Xiao Liu,
  • Guangyu Ju,
  • Xinyi Wang,
  • Rao Liu,
  • Qi Ding,
  • Shuanghu Yuan,
  • Junchao Qian

摘要

The blood–brain barrier (BBB) plays a crucial role in protecting the central nervous system (CNS) from harmful substances but poses challenges to the effective delivery of many therapeutic drugs. While the inflammatory effects of lipopolysaccharides (LPS) are documented, the combined effects of specific LPS types on BBB integrity require further investigation. This study investigates the distinct and combined impacts of LPS derived from Escherichia coli (EC) and Bacteroides fragilis (BF) on BBB integrity. A range of assays was employed, including Limulus amebocyte lysate (LAL) endotoxin detection, CCK-8 cell viability assays, transepithelial electrical resistance (TEER) measurement, FITC-Dextran permeability, immunofluorescence and Western blot analysis of NF-κB p65 and phosphorylated p65 (p-p65) nuclear translocation, tight junctions (TJs) proteins (ZO-1, claudin-5, occludin), inflammation cytokines (TNF-α, IL-6) and COX-2 levels by qPCR and ELISA, Rhodamine 123 (Rh123) efflux assays, and Evans Blue (EB) staining in mice to assess BBB permeability in vivo. The results showed that EC-LPS had higher endotoxin activity compared to BF-LPS (EU ratio of 4.7:1), and despite equal EU concentrations, EC-LPS induced a stronger inflammatory response and more significant BBB disruption. Notably, the co-treatment group (EC-LPS + BF-LPS) showed no synergistic effect on BBB permeability, with BF-LPS antagonizing the effect of EC-LPS. Further confirmation through TLR4 and NF-κB inhibitors revealed that this BBB permeability mechanism is TLR4 receptor and NF-κB pathway-dependent.