Da-Bu-Yin-Wan and Qian-Zheng-San regulate neuroinflammation and intestinal permeability through the microbiota-gut-brain axis in Parkinson's disease mice

BACKGROUND: Parkinson's disease (PD) is marked by progressive neurodegeneration and is becoming more widespread across the globe. Da-Bu-Yin-Wan and Qian-Zheng-San (BYQZF) is a compound from Chinese medicine known for its neuroprotective effects, but the specific active ingredients and mechanisms in relation to Parkinson's disease are not clearly comprehended. PURPOSE: This investigation aimed to investigate how BYQZF works in treating PD. METHODS: Behavioral tests, histopathology, and Western blot were used to validate MPTP-induced PD mouse models. Mice were treated with BYQZF or SCFAs. The evaluation included gut microbiota, lipid metabolism and inflammation. To evaluate composition of microbiota, short-chain fatty acids, and canonical inflammatory signaling pathway, methods such as 16S rRNA sequencing, metabolomics, GC-MS, western blotting and RT-qPCR were utilized. The dependency on microbiota was confirmed with a model mimicking germ-free conditions. RESULTS: BYQZF improved motor/non-motor dysfunction, α-syn aggregation, and the decline of dopaminergic neurons in mice with PD, while also alleviating neuroinflammation and oxidative stress. The balance of gut microbiota was restored, SCFAs levels were increased, and the integrity of the intestinal barrier was improved. BYQZF suppressed the activation of the TLR4/MyD88/NF-κB pathway within the microbiota-gut-brain axis, thus decreasing inflammation both systemically and in the nervous system. Supplementation with SCFAs could replicate the aforementioned benefits of BYQZF, whereas depletion of the gut microbiota attenuated its efficacy. CONCLUSION: BYQZF enriched gut bacteria such as Lachnospiraceae and Ruminococcaceae, which led to increased levels of SCFAs (particularly butyrate) in the serum. This increase was significantly positively correlated with improvements in intestinal barrier function, alleviation of neuroinflammation in the brain, and restoration of movement abilities in PD mice.