Yigong San improves cognitive decline in a rat model of Alzheimer's disease by regulating intestinal microorganisms

doi:10.12122/j.issn.1673-4254.2024.07.09

Abstract

Abstract:

Objective To investigate the effect of Yigong San (YGS) on learning and memory abilities of rats with lipopolysaccharide (LPS)‑induced cognitive decline and explore its possible mechanism in light of intestinal microbiota. Methods Forty SD rats were randomly divided into control group, model group, donepezil (1.3 mg/kg) group, and high-dose (5.25 g/kg) and low-dose (2.63 g/kg) YGS treatment groups. After 24 days of treatment with the corresponding drugs or water by gavage, the rats in the latter 4 groups received an intraperitoneal injection of LPS (0.5 mg/kg) to establish models of Alzheimer's disease (AD). Water maze test and HE staining were used to evaluate the changes in learning and memory abilities and pathomorphology of the hippocampus. The changes in gut microbial species of the rats were analyzed with 16S rRNA sequencing, and the levels of IL-6, TNF-α, and IL-1β in the brain tissue and serum were detected using ELISA. Results Compared with the AD model group, the YGS-treated rats showed significantly shortened escape latency on day 5 after modeling, reduced neuronal degeneration and necrosis in the hippocampus, lowered pathological score of cell damage, and decreased levels IL-6, TNF-α and IL-1β in the brain tissue and serum. The YGS-treated rats showed also obvious reduction of Alpha diversity indicators (ACE and Chao1) of intestinal microbiota with significantly increased abundance of Prevotellaceae species at the family level and decreased abundance of Desulfovibrionaceae, which were involved in such metabolic signaling pathways as cell community prokaryotes, membrane transport, and energy metabolism. Conclusion YGS improves learning and memory abilities and hippocampal pathomorphology in AD rat models possibly by regulating the abundance of intestinal microbial species such as Prevotellaceae to affect the metabolic pathways for signal transduction, cofactors, and vitamin metabolism.

Key words: Yigong San, lipopolysaccharide, cognitive decline, intestinal microbiota

Jing ZENG, Rong CHEN, Xiangyi REN, Lei HUA, Yong YANG, Jiangping WEI, Xiaomei ZHANG. Yigong San improves cognitive decline in a rat model of Alzheimer's disease by regulating intestinal microorganisms[J]. Journal of Southern Medical University, 2024, 44(7): 1297-1305.

Figures/Tables 6

Fig.1 Effect of Yigong San on learning and memory ability of rats with LPS-induced Alzheimer's disease (AD). A: Escape latency in hidden platform test (n=8). B: Representative trajectory map of hidden platform test on day 5 after modeling. C: Representative trajectory map of spatial probe test. ^P<0.05, ^^P<0.01, ^^^P<0.001 vs the escape latency on the first day in each group; *P<0.05, **P<0.01, ***P<0.001 vs Control; #P<0.05, ##P<0.01, ###P<0.001 vs Model.

Tab.1 Number of platform crossings, platform quadrant accumulation time and average swimming speed (Mean±SD)

Group	Dosage	Times of platform crossing time (s)	Platform quadrant cumulative time (s)	Average swimming speed(cm/s)
Control	-	3.85±1.77^##	34.53±10.21^#	14.43±1.77
Model	-	1.43±0.98**	21.49±2.92*	12.71±2.75
Donepezil	1.3 mg/kg	2.00±0.89	24.45±8.71	9.72±2.60
YGS-H	5.25 g/kg	4.14±2.97^#	26.19±6.33	14.32±1.62
YGS-L	2.63 g/kg	3.29±0.95^##	28.81±5.83	14.60±3.27

Fig.2 Effect of Yigong San on pathomorphology of the hippocampus in rats with LPS-induced AD. A: Control. B: Model. C: YGS-H. D: YGS-L. n=8, *P<0.05 vs Control; ##P<0.01 vs Model.

Fig.3 Effect of Yigong San on brain tissue and serum levels of TNF-α, IL-1β and IL-6 in rats with LPS-induced AD. n=6, **P<0.01, ***P<0.01 vs Control; #P<0.05, ##P<0.01, ###P<0.001 vs Model.

Fig.4 Diversity analysis of intestinal microbiota of the rats. A: Statistical analysis of alpha diversity index (n=6). B: β-diversity analysis-principal coordinates analysis (PCoA). C: β-diversity analysis-non-metricmulti-dimensional scaling (NMDS). *P<0.05, **P<0.01 vs Control; #P<0.05, ##P<0.01, ###P<0.001 vs Model.

Fig.6 Functional gene prediction analysis. A: KEGG metabolic pathway. B: Analysis of the differences in KEGG metabolic pathways among the groups.

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