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Sub-Inhibitory Concentrations of Metronidazole Enhance Production, Virulence Factor Loading, and Endothelial

Zixiang Wu1, Xia Li1, Song Ge1

  • 1School of Stomatology, Zunyi Medical University, Zunyi 563000, China.

Microorganisms
|January 28, 2026
PubMed

Insights

Sub-inhibitory metronidazole boosts virulence factor-laden extracellular vesicles from Porphyromonas gingivalis, worsening endothelial cell injury. This explains why antibiotics may not fully prevent cardiovascular issues in periodontitis.

Area of Science:

  • Microbiology
  • Cardiovascular Research
  • Cell Biology

Background:

  • Porphyromonas gingivalis is a key periodontal pathogen linked to atherosclerosis.
  • Antibiotic treatment failures in cardiovascular outcomes necessitate exploring alternative mechanisms.

Purpose of the Study:

  • To investigate the impact of sub-inhibitory metronidazole on P. gingivalis extracellular vesicle (EV) production and pathogenicity.
  • To assess the effects of metronidazole-altered EVs on human umbilical vein endothelial cells (HUVECs).

Main Methods:

  • EVs were isolated from P. gingivalis cultures with and without sub-inhibitory metronidazole.
  • EVs were characterized using TEM, NTA, and Western blotting.
  • HUVEC responses were evaluated through viability, migration, cell death, ROS, NF-κB, and cytokine assays.

Main Results:

  • Sub-inhibitory metronidazole increased EV production by 2.3-fold and enriched EVs with virulence factors.
  • Metronidazole-treated EVs (M-EVs) exhibited enhanced cytotoxicity, impairing HUVEC viability and migration.
  • M-EVs induced higher ROS levels, promoted NF-κB activation, and increased pro-inflammatory cytokine secretion.

Conclusions:

  • Sub-inhibitory metronidazole amplifies P. gingivalis EV production and virulence factor loading.
  • This exacerbates endothelial injury, providing a mechanism for limited cardiovascular benefits of antibiotics in periodontitis.
  • Findings highlight the complex interplay between P. gingivalis, EVs, and cardiovascular disease progression.
Keywords:
Porphyromonas gingivalisatherosclerosisextracellular vesicleshuman umbilical vein endothelial cellsmetronidazoleperiodontitis

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