Abstract
Xanthoceraside (XAN) is a natural-derived compound with anti-Alzheimer activity from the husks of Xanthoceras sorbifolia. Although its therapeutic effect had been confirmed in previous studies, the mechanism was still unclear due to its poor solubility and low permeability. In this study, the pharmacological effect of XAN on Alzheimer’s disease (AD) was confirmed by behavior experiments and H&E staining observation. Fecal microbiota transplantation (FMT) experiment also replicated the therapeutic effects, which indicates the potential targets of XAN on gut microbiota. The sequencing of 16S rRNA genes in fecal samples demonstrated that XAN reversed gut microbiota dysbiosis in AD animals. XAN could change the relative abundances of several phyla and genus of bacterial, particularly the ratio of Firmicutes/Bacteroidetes. Among them, Clostridium IV, Desulfovibrio, Corynebacterium, and Enterorhabdus had been reported to be involved in the pathologic developments of AD and other central nervous system disease. In metabolomics study, a series of host endogenous metabolites were detected, including amino acids, lysophosphatidylcholine, dihydrosphingosine, phytosphingosine, inosine, and hypoxanthine, which were all closely associated with the development of AD. Combined with the Spearman’s correlation analysis, it was confirmed that the increases of five bacterial strains and decreases of six bacterial strains were closely correlated with the increases of nine host metabolites and the decreases of another five host metabolites. Therefore, XAN can modulate the structure of gut microbiota in AD rats; the changes of gut microbiota were significantly correlated with endogenous metabolites, and symptom of AD was ultimately alleviated. Our findings suggest that XAN may be a potential therapeutic drug for AD, and the gut microbiota may be potential targeting territory of XAN via microbiome–gut–brain pathway.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a series of symptoms including progressive cognitive deterioration, memory loss, and progressive functional dependence, which eventually leading to death
Accumulating clinical and experimental evidences suggest that gut microbiota (GM) play an essential role in central nervous system (CNS) diseases, including Parkinson diseases (PD), autism spectrum disorders (ASD), and AD (Hsiao et al, 2013; Kumar et al, 2016; Sampson et al, 2016; Zhang et al, 2017)
XAN might exhibit its bioactivity in gut tract by affecting the GM structures instead of adsorbing into blood
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a series of symptoms including progressive cognitive deterioration, memory loss, and progressive functional dependence, which eventually leading to death. Lots of candidates, such as solanezumab, avagacestat, and verubecestat that are explored based on this hypothesis, have all failed in the III clinical trials because of their low efficiencies, indicating the difficulty and impossibility of mono-brain-target design during anti-AD drug studies. This theory only presents partial interpretation instead of a big picture on the treatment of AD. It could be proposed that there’s a close connection between GM and AD through microbiota–gut– brain axis, and GM could be served as a potential new target for therapeutic intervention in AD
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