What are the associations of metabolome, microbiome, and immune perturbations with severe COVID-19?

In a recent study posted to the bioRxiv* preprint server, researchers observed that coronavirus disease 2019 (COVID-19) progression and inflammatory responses are associated with changes in the metabolome and microbiome.

Background

COVID-19 typically manifests as a mild to moderate disease, but some patients develop pneumonia that might be complicated by coagulopathy, acute respiratory distress syndrome (ARDS), and multi-organ failure. Recent studies suggest that dysregulated immune responses drive COVID-19 severity. Multiple studies observed high levels of pro-inflammatory cytokines, T cell lymphopenia, and fewer non-classical monocytes and neutrophil precursors in peripheral blood samples of patients with severe COVID-19.

Trillions of microbial cells colonize the gut and upper respiratory tract mucosal surfaces. Their composition and diversity are highly variable across individuals. The metabolites produced by the microbiota can influence human biology. Prior research revealed an association of COVID-19 severity with gut microbiota composition and specific inflammatory mediators.

The study and findings

In the present study, researchers characterized the interplay between the immune system, metabolome, and microbiome, by applying an integrated systems approach using longitudinal samples from COVID-19 patients and controls. The study included a subset of subjects enrolled in the prospective COVID-19 patient (Pa-COVID-19) cohort between March and June 2020.

Longitudinal samples of plasma, urine, oropharyngeal (OP) swabs, and stool were collected from 30 patients hospitalized with COVID-19 and 15 age- and sex-matched uninfected controls. Twenty-two patients had mild COVID-19, and eight developed a severe illness. Three patients succumbed to infection in the hospital.

The median length of stay in the hospital was 8.5 days. Peripheral blood mononuclear cells (PBMCs) were collected from 14 patients within ten days of symptom onset and 11 controls, and tracheobronchial secretions (TBS) were obtained from four ventilated patients.

The researchers performed metabolomic analyses of urine and plasma, whole metagenome sequencing of TBS, OP, and stool specimens, single-cell ribonucleic acid sequencing (scRNA-seq) of PBMCs, quantitative reverse-transcription polymerase chain reaction (qRT-PCR) of OP samples, and multiplex enzyme-linked immunosorbent assay (ELISA) of plasma cytokines.

COVID-19 patients had significantly reduced taxonomic diversity in their gut microbiota than controls. These depletions showed strong associations with COVID-19 severity and correlated negatively with the number of days in the hospital. Further, severe COVID-19 was associated with a lower abundance of numerous commensals in the gut, including Bifidobacterium, Roseburia, Intestinibacter, Faecalibacterium, Ruminococaceae, and Lachnospiraceae.

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Severe COVID-19 was associated with the depletion of Kingella and Aggregatibacter in the oropharynx. The abundance, richness, and diversity of oropharyngeal microbiota were lower in COVID-19 patients than in controls, which appeared to have been mainly driven by antibiotics. Achromobacter and Klebsiella were enriched in some TBS samples of ventilated patients who developed hospital-acquired pneumonia (HAP).

Interferons (IFNs), tumor necrosis factor (TNF)-α, interleukin (IL)-10, and several inflammatory cytokines were elevated in the plasma of COVID-19 patients relative to controls. IFNs declined in the later clinical course, whereas inflammatory cytokines remained persistently elevated in patients with severe illness. Classical monocytes were elevated in severe COVID-19 patients compared to mild COVID-19 patients and controls.

Only severe COVID-19 patients had depleted levels of natural killer (NK) cells. A high expression of IFN-stimulated genes (ISGs) was noted in COVID-19 patients’ PBMCs, which correlated with systemic expression levels of type I and II IFNs. Metabolomic analyses uncovered significant differences between COVID-19 patients and controls.

COVID-19 patients had significantly lower plasma levels of tryptophan metabolites, including dietary-derived tryptophan, 5-hydroxytryptophan (serotonin precursor), and microbial metabolites, many of which happen to be ligands for the immunoregulatory aryl hydrocarbon receptor (AhR). Severe COVID-19 was associated with higher levels of taurocholic acid and lower glycodeoxycholic acid levels, a secondary bile acid produced by the microbiota.

Finally, the various -omics data were integrated into the mixed-models analysis framework to identify associations between the immune, microbiome, and metabolomic parameters. This analysis established robust and significant associations between many features of the immune response, microbiome, and metabolome with COVID-19 severity. Further, the researchers created a model based on the strongest and interlinked associations between the -omics datasets. This uncovered a strong link between tryptophan metabolism and the dysregulated immune response in severe COVID-19.

Conclusions

The findings suggest that the plasma metabolome was the most affected -omics domain in COVID-19, as concentrations of microbiota- and host-derived metabolites in the plasma correlated strongly with the clinical severity of COVID-19. The researchers provided novel insights into the interaction between the metabolomic, microbiome, and immune perturbations and severe COVID-19. The disrupted network of the microbiome-tryptophan metabolism-immune response might represent a potential target for interventions in severe COVID-19 patients.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Tarun Sai Lomte

Tarun is a writer based in Hyderabad, India. He has a Master’s degree in Biotechnology from the University of Hyderabad and is enthusiastic about scientific research. He enjoys reading research papers and literature reviews and is passionate about writing.