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Butyrate ameliorates quinolinic acid–induced cognitive decline in obesity models

Summary

This research shows that overweight and obese individuals have higher levels of a toxic compound called quinolinic acid in their bodies, which is linked to memory problems and brain shrinkage. The good news is that butyrate, a substance naturally produced by gut bacteria when we eat fiber, can protect against these harmful effects. Butyrate works by activating genes that produce brain-derived neurotrophic factor (BDNF), a protein essential for brain health and memory formation. The study suggests that increasing butyrate through diet or supplements could help prevent cognitive decline associated with obesity.

Background

Obesity is a risk factor for neurodegenerative diseases and cognitive dysfunction including Alzheimer’s disease. Low-grade inflammation is common in obesity, but the mechanism linking inflammation to cognitive impairment remains unclear. Quinolinic acid (QA), a neuroinflammatory neurotoxin produced by microglia during inflammation, may play a role in obesity-related cognitive decline.

Objective

To investigate the role of quinolinic acid in obesity-induced cognitive impairment and determine whether the gut microbiota metabolite butyrate can counteract QA-induced cognitive and neural impairments.

Results

Elevated serum and cortical QA levels in obese humans and mice were negatively correlated with cognitive function and associated with reduced gray matter volume. Butyrate supplementation prevented QA-induced cognitive decline, dendritic spine loss, and reduced BDNF levels. The mechanism involved butyrate’s inhibition of HDAC2, leading to increased histone H3K18 acetylation at BDNF promoters PII and PIV, thereby restoring BDNF expression.

Conclusion

Increased quinolinic acid is associated with cognitive decline in obesity, while butyrate alleviates this neurodegeneration through epigenetic enhancement of BDNF expression. These findings suggest butyrate as a potential therapeutic intervention for obesity-related cognitive impairment.
  • Published in:Journal of Clinical Investigation,
  • Study Type:Pre-clinical and Clinical Research Study,
  • Source: PMID: 36787221; DOI: 10.1172/JCI154612
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