Danggui Shaoyao San: comprehensive modulation of the microbiota-gut-brain axis for attenuating Alzheimer's disease-related pathology

Jiawei He; Yijie Jin; Chunxiang He; Ze Li; Wenjing Yu; Jinyong Zhou; Rongsiqing Luo; Qi Chen; Yixiao Wu; Shiwei Wang; Zhenyan Song; Shaowu Cheng

doi:10.3389/fphar.2023.1338804

Danggui Shaoyao San: comprehensive modulation of the microbiota-gut-brain axis for attenuating Alzheimer's disease-related pathology

Front Pharmacol. 2024 Jan 12:14:1338804. doi: 10.3389/fphar.2023.1338804. eCollection 2023.

Authors

Jiawei He^{1

2}, Yijie Jin^{1

2}, Chunxiang He^{1

2}, Ze Li^{1

2}, Wenjing Yu^{1

2}, Jinyong Zhou^{1

2}, Rongsiqing Luo^{1

2}, Qi Chen^{1

2}, Yixiao Wu^{1

2}, Shiwei Wang^{1

2}, Zhenyan Song^{1

2}, Shaowu Cheng^{1

2

3}

Affiliations

¹ School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China.
² Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, China.
³ Office of Science and Technology, Hunan University of Chinese Medicine, Changsha, Hunan, China.

Abstract

Background: Alzheimer's disease (AD), an age-associated neurodegenerative disorder, currently lacks effective clinical therapeutics. Traditional Chinese Medicine (TCM) holds promising potential in AD treatment, exemplified by Danggui Shaoyao San (DSS), a TCM formulation. The precise therapeutic mechanisms of DSS in AD remain to be fully elucidated. This study aims to uncover the therapeutic efficacy and underlying mechanisms of DSS in AD, employing an integrative approach encompassing gut microbiota and metabolomic analyses. Methods: Thirty Sprague-Dawley (SD) rats were allocated into three groups: Blank Control (Con), AD Model (M), and Danggui Shaoyao San (DSS). AD models were established via bilateral intracerebroventricular injections of streptozotocin (STZ). DSS was orally administered at 24 g·kg^-1·d^-1 (weight of raw herbal materials) for 14 days. Cognitive functions were evaluated using the Morris Water Maze (MWM) test. Pathological alterations were assessed through hematoxylin and eosin (HE) staining. Bloodstream metabolites were characterized, gut microbiota profiled through 16S rDNA sequencing, and cortical metabolomics analyzed. Hippocampal proinflammatory cytokines (IL-1β, IL-6, TNF-α) were quantified using RT-qPCR, and oxidative stress markers (SOD, CAT, GSH-PX, MDA) in brain tissues were measured with biochemical assays. Results: DSS identified a total of 1,625 bloodstream metabolites, predominantly Benzene derivatives, Carboxylic acids, and Fatty Acyls. DSS significantly improved learning and spatial memory in AD rats and ameliorated cerebral tissue pathology. The formulation enriched the probiotic Ligilactobacillus, modulating metabolites like Ophthalmic acid (OA), Phosphocreatine (PCr), Azacridone A, Inosine, and NAD. DSS regulated Purine and Nicotinate-nicotinamide metabolism, restoring balance in the Candidatus Saccharibacteria-OA interplay and stabilizing gut microbiota-metabolite homeostasis. Additionally, DSS reduced hippocampal IL-1β, IL-6, TNF-α expression, attenuating the inflammatory state. It elevated antioxidative enzymes (SOD, CAT, GSH-PX) while reducing MDA levels, indicating diminished oxidative stress in AD rat brains. Conclusion: DSS addresses AD pathology through multifaceted mechanisms, encompassing gut microbiome regulation, specific metabolite modulation, and the mitigation of inflammation and oxidative stress within the brain. This holistic intervention through the Microbial-Gut-Brain Axis (MGBA) underscores DSS's potential as an integrative therapeutic agent in combatting AD.

Keywords: 16S rDNA; Alzheimer’s disease; Danggui Shaoyao San; metabonomics; microbial-gut-brain axis; nicotinate and nicotinamide metabolism.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Natural Science Foundation of China (82074046 and 82004184); the Science and Technology Innovation Program of Hunan Province (2023RC3166); the Natural Science Foundation of Hunan Province for Excellent Youth Project (2023JJ20033); the Scientific Research Fund of Hunan Provincial Education Department (23A0297); the Hunan provincial “Shennong talent” project; Provincial Discipline Construction Project of Hunan University of Traditional Chinese Medicine (Integrated Traditional Chinese and Western Medicine).