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
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.