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. 2024 Aug 16:15:1453436.
doi: 10.3389/fmicb.2024.1453436. eCollection 2024.

Metabolomics combined with intestinal microbiota reveals the mechanism of compound Qilian tablets against diabetic retinopathy

Jiangwei Jia #  1 , Bo Liu #  1 , Xin Wang  1 , Fenglan Ji  1 , Fuchun Wen  1 , Huibo Xu  1 , Tao Ding  1
Affiliations

Metabolomics combined with intestinal microbiota reveals the mechanism of compound Qilian tablets against diabetic retinopathy

Jiangwei Jia et al. Front Microbiol. .

Abstract

Background: Diabetic retinopathy (DR) is one of the common chronic complications of diabetes mellitus, which has developed into the leading cause of irreversible visual impairment in adults worldwide. Compound Qilian tablets (CQLT) is a traditional Chinese medicine (TCM) developed for treating DR, but its mechanism is still unclear. This study explored the mechanism of action of CQLT in treating DR through metabolomics and intestinal microbiota.

Methods: Histopathologic examination of the pancreas and retina of Zucker diabetic fatty (ZDF) rats and immunohistochemistry were used to determine the expression levels of retinal nerve damage indicators ionized calcium binding adaptor molecule-1 (Iba-1) and glial fibrillary acidic protein (GFAP). Rat fecal samples were tested by LC-MS metabolomics to search for potential biomarkers and metabolic pathways for CQLT treatment of DR. Characteristic nucleic acid sequences of rat intestinal microbiota from each group were revealed using 16S rDNA technology to explore key microbes and related pathways for CQLT treatment of DR. At the same time, we investigated the effect of CQLT on the gluconeogenic pathway.

Results: After CQLT intervention, islet cell status was improved, Iba-1 and GFAP expression were significantly decreased, and abnormal retinal microvascular proliferation and exudation were ameliorated. Metabolomics results showed that CQLT reversed 20 differential metabolites that were abnormally altered in DR rats. Intestinal microbiota analysis showed that treatment with CQLT improved the abundance and diversity of intestinal flora. Functional annotation of metabolites and intestinal flora revealed that glycolysis/gluconeogenesis, alanine, aspartate and glutamate metabolism, starch and sucrose metabolism were the main pathways for CQLT in treating DR. According to the results of correlation analysis, there were significant correlations between Iba-1, GFAP, and intestinal microbiota and metabolites affected by CQLT. In addition, we found that CQLT effectively inhibited the gluconeogenesis process in diabetic mice.

Conclusion: In conclusion, CQLT could potentially reshape intestinal microbiota composition and regulate metabolite profiles to protect retinal morphology and function, thereby ameliorating the progression of DR.

Keywords: compound Qilian tablets; diabetic retinopathy; intestinal microbiota; metabolic pathway; metabolomics.

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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
CQLT ameliorated retinal and pancreatic damage in DR rats.
Figure 2
Figure 2
CQLT ameliorated retinal neurodegeneration in DR rats. The effects of CQLT on retinal GFAP and Iba-1 levels were observed under an optical microscope (A). The immunohistochemical results were statistically analyzed using the NIS-ELEMNT BR image analysis system (B,C). *p < 0.05 and ***p < 0.001.
Figure 3
Figure 3
CQLT changed the fecal metabolite profile in DR rats. Correlation plots of QC samples in positive (A) and negative (B) ion modes. PCA in positive (C,E) and negative (D,F) ion modes. OPLS-DA in positive (G,H) and negative (I,J) ion modes. Heatmap of differential metabolites (K) and bubble map of metabolic pathways (L) for CQLT treatment of DR. Each number in the bubble map represents: 1: alanine, aspartate and glutamate metabolism; 2: nicotinate and nicotinamide metabolism; 3: starch and sucrose metabolism; 4: fructose and mannose metabolism; 5: pentose phosphate pathway; 6: glycolysis/gluconeogenesis; 7: amino sugar and nucleotide sugar metabolism.
Figure 4
Figure 4
CQLT alleviated intestinal flora disorders in DR rats. Venn diagrams (A) analyze the ASVs data in each group. Species cumulative box plots of alpha diversity (B). Chao1 (C), Dominance (D), Shannon (E), and Simpson (F) indexes of each group. PCoA analysis based on Bray–Curtis (G), weighted UniFrac (H), and unweighted UniFrac (I) distances. Bar plots of relative abundance of intestinal flora at the phylum (J) and genus (K) levels. *p < 0.05 and **p < 0.01.
Figure 5
Figure 5
Analysis of differential intestinal flora at the genus level. *p < 0.05, **p < 0.01, and ***p < 0.001.
Figure 6
Figure 6
Functional annotation of intestinal flora and correlation analysis between retinal nerve damage indicators, intestinal flora, and metabolites. KEGG functional enrichment analysis of intestinal flora was performed in level 1 (A) and level 2 (B) databases, respectively. Spearman correlation analysis of retinal nerve damage indicators, significantly different metabolites, and intestinal microbiota genera (C). *p < 0.05, **p < 0.01, and ***p < 0.001.
Figure 7
Figure 7
CQLT inhibited the gluconeogenesis process. *p < 0.05, **p < 0.01, and ***p < 0.001.
Figure 8
Figure 8
Potential mechanism of CQLT in treating DR.
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