Nature Communications · Feb 3, 2026

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

By Li Y, Wang H, Zhang D et al.

Dietary capsaicin intake appears to affect the pathogenesis of Alzheimer's disease (AD), while the underlying mechanisms remain unclear. Here, we found in human cohorts that moderate-to-high level of dietary capsaicin intake was associated with improved cognitive performance. Similarly, long-term oral capsaicin administration in male 5×FAD mice ameliorated AD-like pathologies and reshaped gut microbial composition. Gut microbiota transfer from capsaicin-treated mice produced similar effects of capsaicin intake. Moreover, capsaicin elevated the level of host 24(S)-hydroxycholesterol (24-HC), relating to the increase of gut Oscillibacter genus abundance. The 24-HC elevation enhanced microglial phagocytic activity in the brain, and inhibited proinflammatory factors production via liver x receptor β (LXRβ)-mediated transcriptional regulation. Finally, we observed elevation of 24-HC in plasma in AD patients with higher level of dietary capsaicin intake, which correlated with cognitive scores and plasma Aβ and p-tau biomarkers. These findings suggest the potential of capsaicin or capsaicin-rich diets in the prevention or treatment of AD and related diseases.

doi.org/10.1038/s41467-026-68937-9 Open access PubMed 41634017 Interventions