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Circadian disruption promotes epileptic seizures via the Ruminococcus gnavus-arginine-NOX4-ferroptosis axis

In a pentylenetetrazol (PTZ) kindling rat model, circadian rhythm disruption (continuous light exposure) significantly shortened seizure latency and increased seizure frequency. This effect was mediated by increased Ruminococcus gnavus abundance, which suppressed arginine synthesis, activated NOX4, and induced ferroptosis in the hippocampus.

Last updated: Jul 17, 2026•0 RCTs•📖 Read as article →

Evidence Score

Evidence Score24/100
Human RCT☆☆☆☆☆
Meta-analysis☆☆☆☆☆
Mechanism★★★★★
Safety★★★★☆
Confidencelow

Study Evidence

Study 1. Circadian disruption promotes epileptic seizures via the Ruminococcus gnavus-arginine-NOX4-ferroptosis axis.

observational

Yu F, He J, Chen Y, Zhu Y · Brain research bulletin (2026)

Participants: N/A
Duration: N/A
Intervention: Continuous light exposure to induce circadian rhythm disruption, with additional experiments including antibiotic microbiota depletion, fecal microbiota transplantation, R. gnavus monocolonization, NOX4 inhibitor GLX351322, and L-arginine supplementation
Outcome: Seizure latency, seizure frequency, hippocampal oxidative stress markers (MDA, SOD), ferroptosis markers (mitochondrial cristae reduction, ACSL4 upregulation, GPX4 downregulation), and serum/hippocampal L-arginine levels
Effect Size: N/A
Population: Pentylenetetrazol (PTZ) kindling rat model

Result:

PubMed: 42437603DOI: 10.1016/j.brainresbull.2026.112037

Mechanism Graph

Circadian disruption increases Ruminococcus gnavus abundance in gut microbiota
↓
R. gnavus suppresses ASS1 expression in kidney, reducing L-citrulline-to-L-arginine conversion
↓
Arginine deficiency upregulates NOX4 in hippocampus, causing oxidative stress (elevated MDA, reduced SOD)
↓
Oxidative stress induces ferroptosis (mitochondrial damage, ACSL4 up, GPX4 down), promoting seizures

Limitations

  • ⚠Study conducted in a rat model, not directly translatable to humans
  • ⚠Only one seizure induction method (PTZ kindling) was used, limiting generalizability to other epilepsy types

Frequently Asked Questions

What is the main finding of this study?▼

Circadian disruption worsens epileptic seizures through a gut-brain axis involving R. gnavus, arginine deficiency, NOX4 activation, and ferroptosis.

Can L-arginine supplementation help with seizures?▼

Yes, in this rat model, L-arginine supplementation prolonged seizure latency and reduced seizure frequency by reversing ferroptosis via downregulating NOX4-ACSL4 and upregulating GPX4.

What is the role of Ruminococcus gnavus in epilepsy?▼

R. gnavus enrichment from circadian disruption suppresses kidney ASS1, reducing arginine production, which triggers a cascade leading to hippocampal ferroptosis and increased seizure severity.

What therapeutic targets does this study suggest?▼

Potential targets include NOX4 (inhibited by GLX351322), L-arginine supplementation, and modulation of gut microbiota to reduce R. gnavus abundance.

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References

  1. 1.Yu F, He J, Chen Y, Zhu Y. "Circadian disruption promotes epileptic seizures via the Ruminococcus gnavus-arginine-NOX4-ferroptosis axis.." Brain research bulletin, 2026. PMID: 42437603 DOI: 10.1016/j.brainresbull.2026.112037
Disclaimer: This content is for educational purposes only and is not medical advice. Evidence scores reflect the quality and quantity of available research, not clinical recommendations. Always consult a healthcare professional before starting any supplement or intervention.