ETHNOPHARMACOLOGICAL RELEVANCE: Coptis chinensis Franch. (CCF), as an extensively used traditional Chinese medicine, has therapeutic effects on Alzheimer's disease (AD), but its mechanism of action has not yet been elucidated. AIM OF THE STUDY: This study aims to reveal the mechanism of action of CCF via the gut-brain axis, and provide a new strategy for the clinical treatment of AD. MATERIALS AND METHODS: APPswe/PS1DeltaE9 mice were used as AD models, and were given CCF extract by intragastric administration. Barnes maze was used to test the therapeutic effect of CCF on the treatment of AD. To reveal the mechanism of action of CCF in the treatment of AD, Vanquish Flex UHPLC-orbitrap fusion lumos mass was chosen to detect endogenous differential metabolite; MetaboAnalyst 5.0 was applied to derive relevant metabolic pathways; similarly, to explore the effects of CCF on the gut-brain axis, Vanquish Flex UPLC-Orbitrap fusion lumos mass was utilized to detect the changes in the content of SCFAs in AD mice after CCF administration; the prototype components and metabolites in CCF were identified by UPLC/ESI/qTOF-MS, then their effects on Bifidobacterium breve were explored. RESULTS: CCF shortened the latency time of AD mice, improved the target quadrant ratio of AD mice, and made the maze roadmap simpler of AD mice; CCF regulated fifteen potential metabolites of AD mice, interestingly, ILA (indole-3-lactic acid) in SCFAs (short-chain fatty acids) was also included; CCF acted on histidine and phenylalanine metabolic pathways of AD mice; CCF increased the contents of acetic acid and ILA in AD mice; magnoflorine, jatrorrhizine, coptisine, groenlandicine, thalifendine, palmatine, berberine, epiberberine, hydroxylated jatrorrhizine, and 3-methoxydemethyleneberberine in CCF were detected in fecal samples of AD mice; magnoflorine, palmatrubine, 13-methylberberine, berberine, coptisine, and palmatine promoted the growth of Bifidobacterium breve. CONCLUSIONS: we have demonstrated that CCF acts on the gut-brain axis by regulating SCFAs to treat AD. CI - Copyright (c) 2023 Elsevier B.V. All rights reserved.