Multi-omics reveals Dengzhan Shengmai formulation ameliorates cognitive impairments in D-galactose-induced aging mouse model by regulating CXCL12/CXCR4 and gut microbiota

Jing-Yi Hou; He Xu; Guang-Zhao Cao; Liang-Liang Tian; Li-Han Wang; Nai-Qiang Zhu; Jing-Jing Zhang; Hong-Jun Yang

doi:10.3389/fphar.2023.1175970

Multi-omics reveals Dengzhan Shengmai formulation ameliorates cognitive impairments in D-galactose-induced aging mouse model by regulating CXCL12/CXCR4 and gut microbiota

Front Pharmacol. 2023 Apr 10:14:1175970. doi: 10.3389/fphar.2023.1175970. eCollection 2023.

Authors

Jing-Yi Hou^{1

2

3}, He Xu⁴, Guang-Zhao Cao⁴, Liang-Liang Tian⁴, Li-Han Wang^{1

2

3}, Nai-Qiang Zhu³, Jing-Jing Zhang⁴, Hong-Jun Yang^{1

2}

Affiliations

¹ Beijing Key Laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment for Major Diseases, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, China.
² Robot Intelligent Laboratory of Traditional Chinese Medicine, Experimental Research Center, China Academy of Chinese Medical Sciences and MEGAROBO, Beijing, China.
³ Postdoctoral Mobile Research Station of China Academy of Chinese Medicine Sciences, Beijing, China.
⁴ Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.

Abstract

Dengzhan Shengmai (DZSM), a traditional Chinese medicine formulation, has been administered extensively to elderly individuals with cognitive impairment (CI). However, the underlying mechanisms by which Dengzhan Shengmai improves cognitive impairment remains unknown. This study aimed to elucidate the underlying mechanism of the effect of Dengzhan Shengmai on aging-associated cognitive impairment via a comprehensive combination of transcriptomics and microbiota assessment. Dengzhan Shengmai was orally administered to a D-galactose-induced aging mouse model, and evaluation with an open field task (OFT), Morris water maze (MWM), and histopathological staining was performed. Transcriptomics and 16S rDNA sequencing were applied to elucidate the mechanism of Dengzhan Shengmai in alleviating cognitive deficits, and enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (PCR), and immunofluorescence were employed to verify the results. The results first confirmed the therapeutic effects of Dengzhan Shengmai against cognitive defects; specifically, Dengzhan Shengmai improved learning and impairment, suppressed neuro loss, and increased Nissl body morphology repair. Comprehensive integrated transcriptomics and microbiota analysis indicated that chemokine CXC motif receptor 4 (CXCR4) and its ligand CXC chemokine ligand 12 (CXCL12) were targets for improving cognitive impairments with Dengzhan Shengmai and also indirectly suppressed the intestinal flora composition. Furthermore, in vivo results confirmed that Dengzhan Shengmai suppressed the expression of CXC motif receptor 4, CXC chemokine ligand 12, and inflammatory cytokines. This suggested that Dengzhan Shengmai inhibited CXC chemokine ligand 12/CXC motif receptor 4 expression and modulated intestinal microbiome composition by influencing inflammatory factors. Thus, Dengzhan Shengmai improves aging-related cognitive impairment effects via decreased CXC chemokine ligand 12/CXC motif receptor 4 and inflammatory factor modulation to improve gut microbiota composition.

Keywords: CXCL12; CXCR4; Dengzhan Shengmai (DZSM); aging; cognitive impairment (CI).

Grants and funding

The authors would like to acknowledge the financial support from National Key R&D Plan (2019YFC1708900), the Fundamental Research Funds for the Central Public Welfare Research Institutes (No. JJPY2022018), Project funded by China Postdoctoral Science Foundation (No. 2022M723528), National Natural Science Foundation of China (No. 81974550), and the Scientific and Technological Innovation Project of the China Academy of Chinese Medical Science (CI 2021B017).