Guipi Tang alleviates vascular dementia by regulating purine metabolism via gut microbiota-derived pantothenic acid

Background

Vascular dementia (VD) is the second-most common type of dementia. Chronic cerebral hypoperfusion (CCH) is a crucial trigger of VD. CCH can disrupt the gut microbiota (GM), thereby exacerbating VD. Guipi Tang (GPT) is a traditional Chinese medicine (TCM) formula for alleviating dementia. However, the mechanism by which GPT alleviates VD remains unclear.

Purpose

We employed multi-omics techniques to investigate the mechanism of action of GPT in mitigating VD through the metabolites of the GM.

Methods

We used a bilateral common carotid artery occlusion model and 16S rDNA sequencing, metabolomics, and RNA-sequencing (RNA-seq) analyses to explore the mitigating effects of GPT on VD. We also used antibiotic treatment, metabolite-backfilling, and other experiments to investigate the role of the GM and its metabolites.

Results

GPT repaired the damage to the hippocampal neurons, blood-brain barrier, and intestinal barrier in VD rats, significantly increased the abundance of Faecalibaculum, and promoted the production of the metabolite pantothenic acid (PA), which was introduced into the bloodstream and translocated in the brain. RNA-Seq and dual-luciferase reporter gene assays also showed that PA regulates purine metabolism and inhibits adenosine triphosphate (ATP) conversion by inhibiting the Vax1-AK8 pathway.

Conclusion

GPT regulates brain purine metabolism to alleviate VD by modulating the Faecalibaculum-PA-Vax1-AK8 pathway. This study provides new insights into the pathogenesis of VD and highlights the potential of GPT as an effective therapeutic and preventive agent.