Scutellarin Modulates the Microbiota-Gut-Brain Axis and Improves Cognitive Impairment in APP/PS1 Mice

Background: Scutellarin, a flavonoid purified from the Chinese herb Erigeron breviscapus, has been reported to prevent Alzheimer's disease (AD) by affecting A beta assembly. Given the low brain uptake rate of scutellarin, we hypothesize that the microbiota-gut-brain axis may be a potential route by which scutellarin prevents AD. Objective: This study aimed to explore the microbiota-gut-brain mechanism by which scutellarin prevented AD. Methods: Scutellarin was administrated to APP/PS1 mouse model of AD for two months, and the behaviors, pathological changes as well as gut microbial changes in APP/PS1 mice were evaluated after scutellarin treatment. Results: This study found that scutellarin improved A beta pathology, neuroinflammation, and cognitive deficits in APP/PS1 mice. It elucidated the effects of scutellarin on the diversity and activity of gut microbiota in APP/PS1 mice and these findings promoted us to focus on inflammation-related bacteria and short-chain fatty acids (SCFAs). Cognitive behaviors were significantly associated with inflammatory cytokines and inflammation-related bacteria, suggesting that microbiota-gut-brain axis was involved in this model and that inflammatory pathway played a crucial role in this axis. Moreover, we observed that cAMP-PKA-CREB-HDAC3 pathway downstream of SCFAs was activated in microglia of AD and inactivated by scutellarin. Furthermore, by chromatin immunoprecipitation (ChIP) assays, we found that the increased association between acetylated histone 3 and interleukin-1 beta (IL-1 beta) promoter in AD mice was reversed by scutellarin, leading to a decreased level of IL-1 beta in scutellarin-treated AD mice. Conclusion: Scutellarin reverses neuroinflammation and cognitive impairment in APP/PS1 mice via beneficial regulation of gut microbiota and cAMP-PKA-CREB-HDAC3 signaling in microglia.