Hydroxypropyl-β-cyclodextrin-complexed resveratrol protects A53T transgenic Parkinson’s disease mice via modulating signaling pathways of the microbiota-gut-brain axis

Abstract Background Parkinson's disease (PD) is a neurological disorder characterized by motor and gastrointestinal dysfunctions. There is a significant need for more effective treatment options. Resveratrol (RES) is a potent antioxidant and anti-inflammatory phytoalexin known for its health-promoting benefits. However, little is known about its potential in treating PD by modulating the microbial gut-brain axis, and its clinical application has been limited due to poor water solubility, rapid metabolism, and limited systemic bioavailability. Our study aimed to evaluate the therapeutic potential of RHSD, a resveratrol-cyclodextrin inclusion complex, in treating PD through the gut-brain axis in human SNCA-transgenic (A53T) mice PD models. Results We have demonstrated that administering RHSD can prevent neurodegeneration, improve motor skills, and restore the levels of phosphorylated tyrosine hydroxylase in A53T mice, while also leading to a positive impact on gastrointestinal function. Our metagenomic sequencing indicated significant changes in the richness, evenness, and composition of the gut microbiome in A53T mice, with a significant increase in the levels of Lactobacillus murinus , Lactobacillus reuteri, Enterorhabduscaecimuris, Lactobacillus taiwanensis , and Lactobacillus animals following RHSD administration. Furthermore, metabolomics profiling showed that the levels of gut microbiome metabolites were reversed after RHSD treatment, with altered metabolites primarily present in metabolic pathways such as drug metabolism-cytochrome P450, retinol metabolism, purine metabolism, tyrosine metabolism, and methane metabolism. The altered gut microbiota showed significant correlations with microbiota metabolites. With an integrated analysis of microbiota metabolites and host transcriptomics, our research provides insights into the potential interaction between abnormalities in amino acid metabolism, mitochondrial dysfunction, oxidative stress, and neuroinflammation in Parkinson's disease. Conclusions This study illustrates the profound impact of RHSD administration on rectifying gut microbiota dysbiosis and improving the A53T mouse model. We also observed that the proliferation and metabolism of multiple probiotic strains of Lactobacillus were significantly altered. Moreover, our research supports the hypothesis that microbiota-related metabolites could regulate the transcription of host genes, including dopamine receptors and calcium stabilization. Our findings thus highlight the potential of RHSD as a viable therapeutic candidate for treating PD by targeting several signaling pathways of the microbiota-gut-brain axis.