Gut microbiota-dependent 24-hydroxycholesterol metabolism contributes to capsaicin-induced amelioration of Alzheimer's disease-like pathology in mice.

Moderate-to-high dietary capsaicin intake was associated with improved cognitive performance in human cohorts.

• The association was observed in human cohort studies examining dietary capsaicin intake levels.
• Elevated plasma 24-HC levels were observed in AD patients with higher dietary capsaicin intake.
• Plasma 24-HC levels correlated with cognitive scores and plasma Aβ and p-tau biomarkers in these patients.

Long-term oral capsaicin administration in male 5×FAD mice ameliorated AD-like pathologies and reshaped gut microbial composition.

• The mouse model used was male 5×FAD mice, a transgenic model of Alzheimer's disease-like pathology.
• Capsaicin was administered orally over a long-term period.
• Both AD-like pathological features and gut microbial community composition were altered by capsaicin treatment.

Gut microbiota transfer from capsaicin-treated mice produced similar effects to direct capsaicin intake on AD-like pathology.

• Fecal/gut microbiota transfer experiments were conducted to establish causality between gut microbiota changes and the observed effects.
• Recipient mice showed similar amelioration of AD-like pathologies as mice directly treated with capsaicin.
• This finding indicates that the gut microbiota mediates the beneficial effects of capsaicin.

Capsaicin elevated host 24(S)-hydroxycholesterol (24-HC) levels in relation to increased gut Oscillibacter genus abundance.

• Capsaicin treatment increased the abundance of the gut bacterial genus Oscillibacter.
• This increase in Oscillibacter abundance was associated with elevated levels of 24(S)-hydroxycholesterol (24-HC) in the host.
• The relationship between Oscillibacter and 24-HC suggests a gut microbiota-dependent mechanism of cholesterol metabolism.

Elevated 24-HC enhanced microglial phagocytic activity in the brain and inhibited proinflammatory factor production via LXRβ-mediated transcriptional regulation.

• 24-HC acted on liver x receptor β (LXRβ) to mediate transcriptional regulation of inflammatory pathways.
• Enhanced microglial phagocytic activity would be expected to improve clearance of amyloid-beta and other AD-associated aggregates.
• Inhibition of proinflammatory factors production represents a key anti-neuroinflammatory mechanism downstream of 24-HC elevation.

Plasma 24-HC levels in AD patients with higher capsaicin intake correlated with cognitive scores and plasma Aβ and p-tau biomarkers.

• Plasma Aβ (amyloid-beta) and p-tau (phosphorylated tau) are established biomarkers of Alzheimer's disease pathology.
• The correlation between 24-HC and these biomarkers supports the translational relevance of the mouse findings to human AD.
• This correlation was observed specifically in the subgroup of AD patients with higher dietary capsaicin intake.