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<p>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&#xa0;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 <i>Oscillibacter</i> genus abundance. The 24-HC elevation&#xa0;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&#xa0;level of&#xa0;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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月3日

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  • Yawen Li,
  • Hui Wang,
  • Dongyuan Zhang,
  • Shiqi Wang,
  • Zheng Li,
  • Jingjie Li,
  • Shentao Tai,
  • Dandan Tong,
  • Bifeng Wang,
  • Dingbing Lu,
  • Shulu Yuan,
  • Weiqi Sun,
  • Biyu Yang,
  • Chaobo Bai,
  • Qi Wang,
  • Jiuyang Ding,
  • Zhihao Wang,
  • Yang Gao,
  • Haitao Yu,
  • Kun Cui,
  • Chang Liu,
  • Jian Mao,
  • Yun Yao,
  • Fengyu Liu,
  • You Wan,
  • Junliang Yuan,
  • Xuemei Liu,
  • Jie Zheng

摘要

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.