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Gut-Brain Axis Modulation by Short-Chain Fatty Acids Exerts Disease-Modifying Effects in a Murine Model of
Akash A Bera1, Rossella Di Sapia1, Greta Volpedo2
1Department of Acute Brain and Cardiovascular Injury, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
Annals of Neurology
|June 20, 2026
Summary
Supplementing with short-chain fatty acids (SCFAs) modified disease progression in a drug-resistant epilepsy model. This gut-brain axis intervention improved cognition and reduced inflammation, offering a potential new therapy for epilepsy.
Area of Science:
- Neuroscience
- Microbiology
- Pharmacology
Background:
- Drug-resistant epilepsy (DRE) lacks disease-modifying therapies.
- Gut microbiota dysbiosis and altered short-chain fatty acids (SCFAs) are implicated in epilepsy.
- Reduced fecal SCFA production is observed in individuals with DRE.
Purpose of the Study:
- To investigate the disease-modifying effects of SCFA supplementation in a preclinical model of DRE.
- To assess the impact of SCFAs on seizure progression, cognitive function, and neuropathology.
Main Methods:
- Adult male mice underwent status epilepticus (SE) and received SCFA (acetate, propionate, butyrate) or vehicle treatment.
- Seizure activity, cognitive performance, and histopathology were evaluated.
- Metabolomic profiling and analysis of brain SCFA levels and receptor expression were performed.
Main Results:
- SCFA supplementation reduced the proportion of mice with progressive epilepsy and decreased the progression index.
- Treatment improved cognitive deficits, restored hippocampal and intestinal pathology, and reduced seizure clustering.
- Metabolomic data from mice and human epilepsy tissue supported gut-brain axis dysfunction in disease progression.
Conclusions:
- SCFA supplementation demonstrates therapeutic potential for modifying disease trajectory in experimental DRE.
- These findings highlight the gut-brain axis as a target for novel epilepsy therapies.
- SCFA supplementation holds translational relevance for managing DRE.
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