Gut Microbiome – COVID-19 Outcome and the Impact of Omicron


The ongoing COVID-19 pandemic has prompted extensive research into its various aspects, with scientists investigating not only the virus itself but also the potential influence of the human microbiome on COVID-19 outcomes.

Two noteworthy previous studies, conducted by Zhang et al. in 2023 and Yeoh et al. in 2021, laid the foundation for this investigation by suggesting that COVID-19 infection alters the gut microbial diversity and composition. Zhang et al. reported that the gut microbial diversity was significantly affected in COVID-19-infected subjects, while Yeoh et al. highlighted specific changes in the microbiome of COVID-19 patients, including the enrichment of certain species like Ruminococcus gnavus, Ruminococcus torques, and Bacteroides dorei, and the depletion of beneficial bacterial species like Bifidobacterium adolescentis, Faecalibacterium prausnitzii, and Eubacterium rectale (E. rectale).

However, the critical question remained unanswered: Does the pre-existing gut microbiome status in the population influence the outcome of COVID-19 infections?

To address this question comprehensively, researchers conducted a groundbreaking study using gut metagenomic data from a diverse adult population comprising 2,871 individuals across 16 countries.

In addition to this, dynamic COVID-19 incidence and mortality data spanning from January 22, 2020, to December 8, 2020, were sourced from the Johns Hopkins Coronavirus Resource Center. To gauge the mortality rate in these countries, an adjusted stable mortality rate (SMR) was calculated.

This allowed researchers to investigate the relationship between the composition of the gut microbiota and COVID-19 SMR.

Microbial Diversity and COVID-19 Mortality

The study commenced by examining the alpha and beta diversity of the gut microbiota. While alpha diversity (a measure of species richness within a single sample) did not show any significant differences, the inverse Simpson index, which assesses diversity while accounting for the abundance of species, exhibited a marginal p-value of 0.054. This suggests that there may be subtle variations in gut microbial diversity associated with COVID-19 outcomes.

Notably, beta diversity (a measure of differences in microbial composition between samples) showed significant variation. Countries with high SMR displayed markedly distinct beta diversity profiles when compared to those with median or low SMR, with a p-value of less than 0.001. Intriguingly, upon excluding bacterial species with low prevalence rates (below 0.2), researchers identified that half of the top 20 bacterial species that negatively correlated with SMR were butyrate producers, a group of bacteria highlighted in green.

The Omicron Variant and Replicability of Findings

The emergence of the Omicron variant introduced a new dynamic to the ongoing pandemic. The study expanded its scope to investigate whether the previously identified relationships between gut microbiota and COVID-19 outcomes held true for this variant. Remarkably, four species overlapped among the top 20 in both COVID-19 and Omicron-related analyses. These species were E. rectale, Roseburia intestinalis (R. intestinalis), Bifidobacterium angulatum, and Parabacteroides unclassified.

E. rectale, a well-known beneficial butyrate producer, emerged as a significant species correlated with the mortality outcome for all SARS-CoV-2 variants, including Alpha, Beta, Gamma variants, and the Omicron variant. This consistency underscores the potential role of E. rectale in influencing COVID-19 mortality across different viral strains.

Validation and Functional Pathways

To validate their findings, the researchers examined the relative abundance of the four identified species in published Hong Kong COVID-19 cohorts conducted prior to the introduction of the vaccination program. The data revealed significantly lower relative abundance of E. rectale and R. intestinalis in patients with severe COVID-19, as opposed to control subjects or patients with mild or moderate symptoms.

Furthermore, the study explored 181 functional pathways and eleven bacterial species significantly correlated with SMR. In an effort to identify associations between these species and pathways, researchers conducted all-against-all association testing. Intriguingly, species negatively correlated with SMR exhibited significant positive correlations with depleted pathways related to carbohydrate degradation, cofactor, carrier, and vitamin biosynthesis. This finding suggests that deficiencies in these functional aspects of the gut microbiota at baseline could potentially be linked to higher COVID-19 mortality rates.

Discussion: Understanding the Role of E. rectale and R. intestinalis in COVID-19 Mortality

In this pioneering study, we have unveiled a crucial association between the pre-existing mean relative abundance (mRA) of two specific gut bacterial species, Eubacterium rectale (E. rectale) and Roseburia intestinalis (R. intestinalis), and regional COVID-19 mortality rates in a population-based gut microbiota analysis. These findings mark a significant step forward in understanding the intricate relationship between the gut microbiome and COVID-19 outcomes.

Biological Significance of E. rectale and R. intestinalis

The depletion of both E. rectale and R. intestinalis has been previously documented not only in COVID-19 patients but also in individuals with ulcerative colitis (UC), a chronic inflammatory bowel disease (IBD). This commonality suggests that the reduction of these beneficial species may be linked to the attenuation of the host’s inflammatory response (Pittayanon et al., 2020; Shen et al., 2022).

Specifically, the diminished abundance of E. rectale has been correlated with reduced levels of C-X-C motif ligand 10 (CXCL10) and tumor necrosis factor-alpha (TNF-α), both of which are key markers indicating the initiation of an immune response during the early stages of COVID-19 (Yeoh et al., 2021).

R. intestinalis, on the other hand, plays a role in inhibiting the development of Crohn’s disease (CD), another type of IBD. It does so by promoting the differentiation of anti-inflammatory regulatory T cells (Tregs), potentially providing a basis for innovative therapeutic approaches for CD (Shen et al., 2022).

Interestingly, this reduction in butyrate-producing taxa, which includes E. rectale and other species like Blautia, is not unique to COVID-19.

Previous studies on influenza A virus infection have also shown a decline in these beneficial bacteria (Fuentes et al., 2021; Bhar et al., 2022). This suggests that the role of butyrate-producing species may extend beyond COVID-19 to other viral infections, warranting further investigation.

Functional Pathways and Butyrate Biosynthesis

The pathway analysis in our study revealed a compelling association between the depletion of these bacterial species and reduced functional pathways. This observation suggests that the protective role of the gut microbiome in the population may be attributed to their biosynthetic functions. Of particular interest are the carbohydrate degradation pathways, which are likely contributed to by butyrate-producing species. Butyrate is known for its beneficial effects on the intestinal epithelium, including its anti-inflammatory properties (Flint et al., 2012). The fermentation of carbohydrates by these bacteria is essential for butyrate production, which, in turn, supports gut health.

Study Limitations and Future Directions

While this study provides valuable insights, it is essential to acknowledge its limitations. First, we did not delve into the mechanisms by which gut microorganisms interact with the immune system. Future research should aim to unravel the intricacies of how the microbiota-derived metabolites or immune activation contribute to infection response, potentially paving the way for novel therapeutic interventions.

Second, the study did not consider individual or regional antibiotic usage, which can profoundly influence metagenomic profiles and mortality rates. The alteration of bacterial community structures following antibiotic treatment has been well-documented (Hill et al., 2010), and long-term antibiotic exposure can be associated with increased all-cause mortality (Heianza et al., 2020; Verdecchia et al., 2020). Future studies should explore the interplay between antibiotics, the gut microbiome, and infectious disease outcomes.

Third, the study’s sample size was imbalanced across different countries, limiting its ability to represent populational species’ relative abundance accurately. While we conducted a validation cohort in the Hong Kong population to affirm our findings, larger-scale studies are needed to validate the predictive potential of E. rectale and R. intestinalis as indicators of COVID-19 outcomes.

Lastly, this study focused primarily on COVID-19 mortality as the outcome of interest. However, the low abundance of E. rectale may have associations with other disease conditions beyond COVID-19. Future investigations should explore these potential links, taking into account a broader spectrum of health outcomes.

Conclusion and Future Prospects

In summary, our study has shed light on the negative association between the populational gut abundance of two crucial butyrate-producing bacteria, E. rectale and R. intestinalis, and regional COVID-19 mortality rates. This discovery opens up exciting possibilities for microbiota modulation as a potential key in reducing COVID-19-related mortality. Developing butyrate-producing probiotics, particularly in conjunction with high-fiber diets, could assist in enriching these beneficial species (Kasahara et al., 2018). Nevertheless, further evaluation of these potential next-generation probiotics in animal models of COVID-19 and clinical trials in humans is necessary to translate these findings into practical therapeutic interventions. This research represents a promising avenue for future investigations into the profound impact of the gut microbiome on infectious disea

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