Lingguizhugan decoction ameliorates cognitive impairment in AD-like mice by influencing the microbiome-gut-brain axis mediated by SCFAs.

Background: Lingguizhugan (LGZG) decoction, an ancient Chinese herbal remedy originating from the Eastern Han Dynasty, consists of Poria cocos, Cinnamomi ramulus, Atractylodes macrocephala, and Glycyrrhiza, as described in the Golden Chamber Synopsis. It has a history spanning over 1600 years, in which it has been primarily used for the treatment of inflammation, injuries, and fluid retention; however, the potential of LGZG decoction to ameliorate Alzheimer's disease (AD) progression by modulating the gut-brain axis through attenuation of gut microbiota and their metabolites remains unknown.

Purpose: To examine the in vivo anti-AD effects and mechanism of LGZG decoction in alleviating AD cognitive impairment.

Study Design: Two-part experiments in vivo were designed, one for behavior tests, intestinal and brain histopathology, intestinal microbiome and quantitative determination, and another one for metabolite supplementation study.

Methods: AlCl/D-gal was used to establish an AD-like mouse model. Behavioral tests, such as the Morris water maze test, were used to assess the effect of LGZG decoction on cognitive dysfunction. The concentration of proinflammatory mediators was measured by ELISA. The protein content was detected by western blot analysis and immunohistochemistry. The content of short-chain fatty acids was measured by LC-MS/MS. Evaluation of 16S rRNA gene sequencing for species and strain-level gut microbiome analysis was performed.

Results: LGZG decoction mitigated cognitive impairment in an AD-like mouse model, and decreased the deposition of amyloid-β and the production of proinflammatory cytokines in the brain. LGZG decoction remodeled the intestinal microecology, enhanced the integrity of the intestinal and brain tissue barriers, and modulated Aβ transportation through gut microbiota metabolite SCFAs. The neuroprotective effect of SCFAs on the AD-like model mice may be manifested through the inhibition of pP38 of the MAPK signaling pathway.

Conclusion: Our results suggest that LGZG decoction reshapes the gut microbiota. SCFAs derived from the gut microbiota ameliorate the cognitive decline induced by AlCl/D-gal through the gut-brain axis and reduce brain Aβ aggregation. We propose LGZG decoction as a potential therapeutic option for AD.