Integrated analysis of gut microbiome and host immune responses in COVID-19

doi:10.1007/s11684-022-0921-6

Front. Med.

2022, Vol. 16

Issue (2) : 263-275 https://doi.org/10.1007/s11684-022-0921-6

RESEARCH ARTICLE

Integrated analysis of gut microbiome and host immune responses in COVID-19

Xiaoguang Xu¹, Wei Zhang^1,², Mingquan Guo³, Chenlu Xiao⁴, Ziyu Fu¹, Shuting Yu¹, Lu Jiang¹, Shengyue Wang¹, Yun Ling³, Feng Liu¹, Yun Tan¹(

), Saijuan Chen¹(

)

¹. Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
². School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
³. Shanghai Public Health Clinical Center, Shanghai 201508, China
⁴. Department of Laboratory Medicine, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

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Abstract

Emerging evidence indicates that the gut microbiome contributes to the host immune response to infectious diseases. Here, to explore the role of the gut microbiome in the host immune responses in COVID-19, we conducted shotgun metagenomic sequencing and immune profiling of 14 severe/critical and 24 mild/moderate COVID-19 cases as well as 31 healthy control samples. We found that the diversity of the gut microbiome was reduced in severe/critical COVID-19 cases compared to mild/moderate ones. We identified the abundance of some gut microbes altered post-SARS-CoV-2 infection and related to disease severity, such as Enterococcus faecium, Coprococcus comes, Roseburia intestinalis, Akkermansia muciniphila, Bacteroides cellulosilyticus and Blautia obeum. We further analyzed the correlation between the abundance of gut microbes and host responses, and obtained a correlation map between clinical features of COVID-19 and 16 severity-related gut microbe, including Coprococcus comes that was positively correlated with CD3⁺/CD4⁺/CD8⁺ lymphocyte counts. In addition, an integrative analysis of gut microbiome and the transcriptome of peripheral blood mononuclear cells (PBMCs) showed that genes related to viral transcription and apoptosis were up-regulated in Coprococcus comes low samples. Moreover, a number of metabolic pathways in gut microbes were also found to be differentially enriched in severe/critical or mild/moderate COVID-19 cases, including the superpathways of polyamine biosynthesis II and sulfur oxidation that were suppressed in severe/critical COVID-19. Together, our study highlighted a potential regulatory role of severity related gut microbes in the immune response of host.

Keywords COVID-19 SARS-COV-2 gut microbiome immune response

Corresponding Author(s): Yun Tan,Saijuan Chen

About author: Mingsheng Sun and Mingxiao Yang contributed equally to this work.

Just Accepted Date: 12 January 2022 Online First Date: 07 March 2022 Issue Date: 26 April 2022

Cite this article:

Xiaoguang Xu,Wei Zhang,Mingquan Guo, et al. Integrated analysis of gut microbiome and host immune responses in COVID-19[J]. Front. Med., 2022, 16(2): 263-275.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-022-0921-6
https://academic.hep.com.cn/fmd/EN/Y2022/V16/I2/263

Tab.1 Clinical features of the enrolled COVID-19 cases

Fig.1 Severe/critical COVID-19 showed less diversity of gut microbes. (A) PCA analysis shows the differences of composition of the gut microbes in severe/critical, mild/moderate COVID-19 and healthy controls. The abundance of gut microbes in each sample is used for PCA analysis. The red, blue and orange circles represent healthy controls, mild/moderate samples and severe/critical samples, respectively. (B) The severe/critical COVID-19 group shows less gut microbe diversity compared to the mild/moderate COVID-19 one. The gut microbe diversity per sample (alpha diversity) is calculated by the Shannon or Simpson method. Higher scores represent higher diversity of the gut microbes. (C) Illustration of the most abundant gut microbes at the phylum level in each sample. k, kingdom; p, phylum.

Fig.2 Identification of severity-related gut microbes in COVID-19. (A) Feature gut microbe between severe/critical and mild/moderate COVID-19. (B) Feature gut microbe between severe/critical COVID-19 and health control. (C) Feature gut microbes between mild/moderate COVID-19 and health control. Gut microbes at genus levels and LDA (Linear discriminant analysis)>3.0 are plotted. LDA values are shown by colors, and P values are shown by the sizes of the circles. (D) Illustration of top differential species between severe/critical and mild/moderate COVID-19 cases compared to healthy controls.

Fig.3 Correlation between severity-related gut microbes and clinical features of COVID-19. (A and B) Analysis of the correlation between severity-related gut microbes and the blood features. The Pearson correlation coefficient and P value are used for plotting. Similar scores are clustered by the unsupervised clustering. Sixteen severity-related gut microbes and 34 blood features are used for plotting. Representative correlations are shown in panel B. (C and D) Analysis of the correlation between severity-related gut microbes and markers associated with organ damage or dysfunction. Representative correlations are shown in panel D. (E–G) Analysis of the correlation between severity-related gut microbes and cytokines or markers associated with coagulation. Representative correlations are shown in panel G.

Fig.4 Potential impact of severity-related gut microbes on the transcriptomic features of PBMCs in COVID-19. (A) Differentially expressed genes in PBMCs between Coprococcus comes high and low groups. Samples are divided into two groups based on the median abundance of the Coprococcus comes in gut microbes. Genes expressed at higher levels in Coprococcus comes high group (right) or Coprococcus comes low group (left) are shown in red. (B) Gene ontology analysis using genes upregulated in the Coprococcus comes low group. (C) Differentially expressed genes in PBMCs between Enterococcus faecium high and low groups. Samples are divided into two groups based on the median abundance of the Enterococcus faecium in gut microbes. Genes expressed at higher levels in Enterococcus faecium high group (right) or Enterococcus faecium low group (left) are shown in red. (D) Gene ontology analysis for genes upregulated in the Enterococcus faecium high group.

Fig.5 Differentially enriched metabolic pathways between severe/critical and mild/moderate COVID-19. (A) Differentially enriched metabolic pathways between mild/moderate and severe/critical COVID-19. The enrichment of each sample in the 506 metabolic pathways is calculated, and the fold change and P value of the enrichment score between the mild/moderate and severe/critical groups are analyzed. Top differentially enriched pathways are plotted. (B and C) Representative illustration of species contributions to the differential enriched KEGG metabolic pathway between mild/moderate and severe/critical COVID-19. The species contributions to DNA abundance of GOLPDLCAT-PWY, PWY-5304, POLYAMINSYN3-PWY, NAGLIPASYN-PWY, and PYRIDOXSYN-PWY are plotted.

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