Abstract
Drugs targeting intestinal bacteria have shown great efficacy for alleviating symptoms of Alzheimer’s disease (AD), and microbial metabolites are important messengers. Our previous work indicated that Rheum tanguticum effectively improved cognitive function and reshaped the gut microbial homeostasis in AD rats. However, its therapeutic mechanisms remain unclear. Herein, this study aimed to elaborate the mechanisms of rhubarb for the treatment of AD by identifying effective metabolites associated with rhubarb-responsive bacteria. The results found that rhubarb reduced hippocampal inflammation and neuronal damage in APP/PS1 transgenic (Tg) mice. 16S rRNA sequencing and metabolomic analysis revealed that gut microbiota and their metabolism in Tg mice were disturbed in an age-dependent manner. Rhubarb-responsive bacteria were further identified by real-time polymerase chain reaction (RT-PCR) sequencing. Four different metabolites reversed by rhubarb were found in the position of the important nodes on rhubarb-responsive bacteria and their corresponding metabolites combined with pathological indicators co-network. Furthermore, in vitro experiments demonstrated o-tyrosine not only inhibited the viabilities of primary neurons as well as BV-2 cells, but also increased the levels of intracellular reactive oxygen species and nitric oxide. In the end, the results suggest that rhubarb ameliorates cognitive impairment in Tg mice through decreasing the abundance of o-tyrosine in the gut owing to the regulation of rhubarb-responsive bacteria. Our study provides a promising strategy for elaborating therapeutic mechanisms of bacteria-targeted drugs for AD.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disease with high incidence, disability and death rates (Sierksma et al, 2020)
Through a more accurate co-network analysis based on indicator and multiomics correlation analyses, we found a significant correlation between the metabolites and microbiota with the development of AD disease
In vitro experiments were conducted to confirm the toxicity of the microbial metabolite o-tyr, which was closely related to the microbiota and pathological indicators in response to rhubarb intervention
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disease with high incidence, disability and death rates (Sierksma et al, 2020). Rhubarb Regulates AD Microbial Metabolites of pro-inflammatory mediators, neuronal apoptosis (Stepanichev et al, 2004; Pistollato et al, 2016; Wu Y. et al, 2019). Remodeling gut microbial homeostasis may represent a more effective therapeutic strategy for the treatment of AD. Rhubarb exhibits excellent therapeutic effect for AD by “tonify the body by removing stasis” and “relaxing bowels and puzzle” according to “brain collateral damage due to toxin” raised by theoretical system of TCM (Li et al, 2019). Our previous studies have suggested that Rheum tanguticum effectively improves cognitive function and reshapes the gut microbial homeostasis in AD animal models (Zhao et al, 2019). It is of great significance to the elaborating therapeutic mechanism of rhubarb for AD from the view of gut microbiota (Mancuso and Santangelo, 2018)
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