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Cold exposure promotes coronavirus infection by altering the gut microbiota and lipid metabolism to reduce host immunity
doi: 10.2478/fzm-2023-0029
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Abstract:
Objective Cold exposure has been suggested to be advantageous for the spread and infection of the coronavirus, and the gut microbiota influences the severity of the infection by modulating host inflammatory and immune responses. However, it remains unclear whether the promotion of viral infection through cold exposure is linked to the gut microbiota. Methods In this study, we performed an unbiased analysis of gut microbiota, serum, and lung tissue metabolome changes in cold-exposed and virus-infected mice, alongside the assessment of immune-inflammatory indicators in serum and lung tissue. Results The results revealed that both cold exposure and viral infection significantly decreased the percentage of peripheral blood lymphocytes (CD4+ T cells, CD8+ T cells, and B cell) and increased the expression of inflammatory factors (IL-6, IL-1β, TNF-α, and IFN-γ). Meanwhile, cold exposure disrupted the homeostasis of gut microbiota, elevating the abundance of pathogenic bacteria (Staphylococcus) and diminishing the abundance of beneficial bacteria (Alistipes). Notably, in virus-infected mice exposed to a cold environment, the reduction in the abundance of beneficial bacteria Alistipes was more pronounced than in cases of single virus infection and cold exposure. Analysis of altered serum and lung tissue metabolites highlighted glycerophospholipids, fatty acids, and eicosanoids as the most affected metabolites by cold exposure. These metabolites, closely associated with virus infection, exhibited a significant correlation with immune-inflammatory indicators. Conclusion These findings establish a mechanistic connection between cold exposure and virus infection, suggesting that cold exposure-induced dysregulation of gut microbiota and lipid metabolism diminishes host immunity, promoting virus infection. -
Key words:
- cold exposure /
- coronavirus infection /
- gut microbiota /
- lipid metabolism /
- immune
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Figure 1. Phenotypic changes in cold-exposed and virus-infected mice. Con, control group; CH, cold humid exposure group; VI, virus infection group; CH_VI, cold humid environment combined with virus infection group. (A) Experimental process; (B) Viral load detection; (C) Lung index; (D-G) The levels of inflammatory cytokines in lung tissue (IL-1β, IL-6, TNF-α, and IFN-γ); (H) Lung histopathological photographs (H&E staining). Significance was evaluated by one-way ANOVA, follow by Dunnett's multiple comparisons test. *, P < 0.05; **, P < 0.01; ***, P < 0.001; N = 8 each group.
Figure 2. The levels of peripheral blood lymphocyte (CD4+- and CD8+-T cells and B cells) in cold exposure and viral infection mice. Significance was evaluated by one-way ANOVA, follow by Dunnett's multiple comparisons test. *, P < 0.05; **, P < 0.01; N = 8 each group.
Figure 3. Analysis of gut microbiota structure in mice subject to cold exposure and virus infection. Con, control group; CH, cold humid exposure group; VI, virus infection group; CH_VI, cold humid environment combined with virus infection group. (A-B) α diversity analysis (Chao and Shannon) at the genus level; (C) Bar chart showing the phylum-levels composition of the gut microbiome; (D-E) Changes in the abundance of Firmicutes and Bacteroidota in mice subjected to cold exposure and virus infection; (F) Principal coordinates analysis (PCoA) based on genus level; (G) Genus level multi-group comparison chart; (H) Cladogram visualizing the output of the LEfSe analysis; (I) The most significant difference of gut microbial taxa among groups after LDA (LDA > 4). The abbreviations are as follows: p, phylum; c, class; o, order; f, family; and g, genus. *, P < 0.05; **, P < 0.01; N = 3 each group.
Figure 4. Species difference analysis based on genus level. Con, control group; CH, cold humid exposure group; VI, virus infection group; CH_VI, cold humid environment combined with virus infection group. (A) CH vs. Con; (B) VI vs. Con; (C) CH_VI vs. Con. N = 3 each group.
Figure 5. Metabolome analysis of lung tissue specimens. Con, control group; CH, cold humid exposure group; VI, virus infection group; CH_VI, cold humid environment combined with virus infection group. (A-C) Volcano plot showing changes in differential ions between CH, VI, CH_VI and Con group; (D) Venn diagram of DMs in the Con, CH, VI and CH_VI groups; (E) The PCA plots established based on DMs in the Con, CH, VI and CH_VI groups; (F) The categories and number of DMs obtained from the Con, CH, VI and CH_VI groups; (G) Heatmap diagram of DMs in the Con, CH, VI and CH_VI groups; (H) The DMs correlation between major DMs classes in the CH group; (I) The DMs correlation between major DMs classes in the VI group; (J) The DMs correlation between major DMs classes in the CH_VI group.
Figure 6. Metabolome analysis of serum samples. Con, control group; CH, cold humid exposure group; VI, virus infection group; CH_VI, cold humid environment combined with virus infection group. (A-C) Volcano plot showing changes in differential ions between CH, VI, CH_VI and Con group; (D) Venn diagram of DMs in the Con, CH, VI and CH_VI groups; (E) The PCA plots established based on DMs in the Con, CH, VI and CH_VI groups; (F) The categories and number of DMs obtained from the Con, CH, VI and CH_VI groups; (G) Heatmap diagram of DMs in the Con, CH, VI and CH_VI groups; (H) The DMs correlation between major DMs classes in the CH group; (I) The DMs correlation between major DMs classes in the VI group; (J) The DMs correlation between major DMs classes in the CH_VI group.
Figure 7. Pathway enrichment analysis of differential metabolites (DMs) in lung tissue specimens and serum samples. Con, control group; CH, cold humid exposure group; VI, virus infection group; CH_VI, cold humid environment combined with virus infection group. (A) serum; (B) Lung tissue.
Figure 8. Correlation analysis. Con, control group; CH, cold humid exposure group; VI, virus infection group; CH_VI, cold humid environment combined with virus infection group. (A) Spearman correlation analysis of differential metabolites (DMs) in lung tissue with immune-inflammatory indicators; (B) The categories and number of significantly (P < 0.05 and |cor| > 0.5) correlated DMs in lung tissue; (C) Spearman correlation analysis of DMs in serum with immune-inflammatory indicators; (D) The categories and number of significantly (P < 0.05 and |cor| > 0.5) correlated DMs in serum; (E) Spearman correlation analysis of the gut microbiota with immune-inflammatory indicators. Significance levels are indicated as follows: *, P < 0.05.
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