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. 2022 Jul 1:16:949298.
doi: 10.3389/fnins.2022.949298. eCollection 2022.

Liuwei Dihuang Decoction Alleviates Cognitive Dysfunction in Mice With D-Galactose-Induced Aging by Regulating Lipid Metabolism and Oxidative Stress via the Microbiota-Gut-Brain Axis

Baiyan Liu  1   2 , Bowei Chen  1 , Jian Yi  1   2 , Hongping Long  1 , Huiqiao Wen  1 , Fengming Tian  1 , Yingfei Liu  1 , Lan Xiao  3 , Lisong Li  4
Affiliations

Liuwei Dihuang Decoction Alleviates Cognitive Dysfunction in Mice With D-Galactose-Induced Aging by Regulating Lipid Metabolism and Oxidative Stress via the Microbiota-Gut-Brain Axis

Baiyan Liu et al. Front Neurosci. .

Abstract

Background: Aging is an important cause of cognitive dysfunction. Liuwei Dihuang decoction (LW), a commonly applied Chinese medicine formula, is widely used for the treatment of aging-related diseases in China. Previously, LW was confirmed to be effective in prolonging life span and reducing oxidative stress in aged mice. Unfortunately, the underlying mechanism of LW remains unclear. The aim of this study was to interpret the mechanism by which LW alleviates cognitive dysfunction related to aging from the perspective of the microbiota-gut-brain axis.

Method: All C57BL/6 mice (n = 60) were randomly divided into five groups: the control, model, vitamin E (positive control group), low-dose LW and high-dose LW groups (n = 12 in each group). Except for those in the control group, D-galactose was subcutaneously injected into mice in the other groups to induce the aging model. The antiaging effect of LW was evaluated by the water maze test, electron microscopy, 16S rRNA sequencing, combined LC-MS and GC-MS metabolomics, and ELISA.

Results: Liuwei Dihuang decoction ameliorated cognitive dysfunction and hippocampal synaptic ultrastructure damage in aging mice. Moreover, LW decreased Proteobacteria abundance and increased gut microbiota diversity in aging mice. Metabolomic analysis showed that LW treatment was associated with the significantly differential abundance of 14 metabolites, which were mainly enriched in apelin signaling, sphingolipid metabolism, glycerophospholipid and other metabolic pathways. Additionally, LW affected lipid metabolism and oxidative stress in aging mice. Finally, we also found that LW-regulated microbial species such as Proteobacteria and Fibrobacterota had potential relationships with lipid metabolism, oxidative stress and hippocampal metabolites.

Conclusion: In brief, LW improved cognitive function in aging mice by regulating lipid metabolism and oxidative stress through restoration of the homeostasis of the microbiota-gut-brain axis.

Keywords: Liuwei Dihuang decoction; aging; cognitive function; lipid metabolism; metabolomics; microbiota-gut-brain axis; oxidative stress.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Experimental design of intervention study of Liuwei Dihuang decoction (LW).
FIGURE 2
FIGURE 2
Chemical composition analysis of Liuwei Dihuang decoction. (A) The total composition chromatogram (TCC) in positive ion mode; (B) The TCC in negative ion mode.
FIGURE 3
FIGURE 3
Effects of Liuwei Dihuang decoction on cognitive function and hippocampal synaptic ultrastructure in aging mice. (A) Navigation test. (B) Spatial exploration. (C) Platform crossing. (D) MWM representative figures. (E) Ultrastructure of hippocampal synapses. **p < 0.01 vs. Control group. #p < 0.05, ##p < 0.01 vs. Model group.
FIGURE 4
FIGURE 4
Effects of Liuwei Dihuang decoction on the gut microbiota of aging Mice. (A) Chao 1 index. (B) Observed species index. (C) PCoA analysis. (D) Relative abundance of gut microbiota (phylum level). (E) Relative abundance of gut microbiota (genus level). (F) Cladogram of LEfSe analysis. (G) LDA of LEfSe analysis. (H) PICRUSt2 analysis.
FIGURE 5
FIGURE 5
Effects of LW on the metabolic profile of hippocampal tissue in aging mice. (A) OPLS-DA of LC-MS (Model vs. Control). (B) OPLS-DA of LC-MS (LW vs. Model). (C) Permutation of OPLS-DA model (Model vs. Control). (D) Permutation of OPLS-DA model (LW vs. Model). (E) OPLS-DA of GC-MS (Model vs. Control). (F) OPLS-DA of GC-MS (LW vs. Model). (G) Permutation of OPLS-DA model (Model vs. Control). (H) Permutation of OPLS-DA model (LW vs. Model). (I) Differentially abundant metabolites. (J) Analysis of metabolic pathway enrichment.
FIGURE 6
FIGURE 6
Effects of Liuwei Dihuang decoction on lipid metabolism and oxidative stress in aging mice. (A) ApoE. (B) Adiponectin. (C) FFA. (D) SOD in serum. (E) GSH-Px in serum. (F) MDA in serum. (G) SOD in brain tissue. (H) GSH-Px in brain tissue. (I) MDA in brain tissue. **p < 0.01 vs. Control group. #p < 0.05, ##p < 0.01 vs. Model group.
FIGURE 7
FIGURE 7
Relationship between gut microbes and hippocampal metabolites, lipid metabolism and oxidative stress. (A,B) Correlation of microbiota related to differentially abundant metabolites (phylum level). (C,D) Correlation of microbiota related to differentially abundant metabolites (genus level). (E,F) Correlation of microbiota with factors related to lipid metabolism and oxidative stress (phylum level). (G,H) Correlation of microbiota with factors related to lipid metabolism and oxidative stress (genus level).
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