Altered infective competence of the human gut microbiome in COVID-19

Abstract

Background: Infections with SARS-CoV-2 have a pronounced impact on the gastrointestinal tract and its resident microbiome. Clear differences between severe cases of infection and healthy individuals have been reported, including the loss of commensal taxa. We aimed to understand if microbiome alterations including functional shifts are unique to severe cases or a common effect of COVID-19. We used high-resolution systematic multi-omic analyses to profile the gut microbiome in asymptomatic-to-moderate COVID-19 individuals compared to a control group.

Results: We found a striking increase in the overall abundance and expression of both virulence factors and antimicrobial resistance genes in COVID-19. Importantly, these genes are encoded and expressed by commensal taxa from families such as Acidaminococcaceae and Erysipelatoclostridiaceae, which we found to be enriched in COVID-19-positive individuals. We also found an enrichment in the expression of a betaherpesvirus and rotavirus C genes in COVID-19-positive individuals compared to healthy controls.

Conclusions: Our analyses identified an altered and increased infective competence of the gut microbiome in COVID-19 patients. Video Abstract.

Keywords: COVID-19; Gut microbiome; Metagenomics; Metatranscriptomics; SARS-CoV-2.

Fig. 1

Sample collection and study design. Schematic of the project study design, including cohort composition, and data analyses

Fig. 2

Composition of the microbial community. a Cladogram representing the microbial community profiles in COVID-19 patients (red) and control group (green). The outer rings represent the relative abundance (%) of the microbial community. b Relative abundance of bacterial species significantly enriched in COVID-19 patients compared to the control group [adj.p < 0.05; Wilcoxon rank-sum test]. c Relative abundance of bacterial species significantly decreased in COVID-19 patients compared to the control group [adj. p < 0.05; Wilcoxon rank-sum test]

Fig. 3

Abundance of virulence factors in the microbial community. a Overall abundance (metagenome) of virulence factors encoded by the microbiome of COVID-19 patients and control group. The significance of the differential abundance is indicated with the adjusted p value [adj.p < 0.05; Wilcoxon rank-sum test]. b Overall expression levels (metatranscriptomics) of virulence factors encoded by the microbiome in COVID-19 patients and the control group [adj.p < 0.05; Wilcoxon rank-sum test]. c Abundance and expression levels of MAG families where a significant increase in encoded and expressed virulence factors was observed in COVID-19 patients [adj.p < 0.05; Wilcoxon rank-sum test, * < 0.05, ** < 0.01, *** < 0.001]. d Abundance and expression levels of virulence factors in MAGs depicting taxonomic families only demonstrating an increased expression of virulence factors, with no significant difference observed at a metagenomic level [adj.p < 0.05; Wilcoxon rank-sum test, * < 0.05, ** < 0.01, *** < 0.001]

Fig. 4

Abundance levels of antimicrobial resistance genes. a Overall ARG abundance and expression levels for COVID-19 and control groups (boxplot), coupled with a breakdown of the respective abundance and expression levels to individual AMR categories [adj.p < 0.05; Wilcoxon rank-sum test, * < 0.05, ** < 0.01, *** < 0.001]. b ARG abundance (top) and expression levels (bottom) of individual AMR categories significantly increased in COVID-19 patients compared to the control group [adj.p < 0.05; Wilcoxon rank-sum test, * < 0.05, ** < 0.01, *** < 0.001]

Fig. 5

Association of AMR with the microbial community. Abundance (a) and expression (b) levels of ARGs and corresponding to AMR categories linked to MAGs. On top (boxplot) depicting the overall ARG abundance, below the average abundance of selected AMR categories per taxonomic family. The plot depicts taxonomic families in which overall a significant increase in abundance or expression of ARGs was observed [adj.p < 0.05; Wilcoxon rank-sum test, * < 0.05, ** < 0.01, *** < 0.001]

Fig. 6

Assessing the infective competence of the gut microbiome. a Correlation of gene abundances of AMR and virulence factors [R = 0.52 and p < 0.01; Spearman’s correlation] in COVID-19 patients (red) and the control group (green). b Correlation of AMR and virulence factors gene expression levels [R = 0.46 and p < 0.01; Spearman’s correlation] in COVID-19 patients (red) and negative controls (green). c Bubble plot depicting the infective competence via the log2 fold change of AMR and virulence factors between COVID-19 patients (red) and control group (green)