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January 2024 will mark four years since the Centers for Disease Control and Prevention (CDC) formally announced the outbreak of COVID-19 about a month after the novel virus was discovered in Wuhan, China at the end of 2019. On March 11, 2020, the World Health Organization (WHO) declared the worldwide COVID-19 pandemic. It was not until 3 years and 2 months later on May 11, 2023 that US President Biden announced an end to the public health emergency and national state of emergency which essentially served as an administrative ‘end’ to the pandemic.

In reality, it is difficult to say when a pandemic is truly ‘over’.

Similar to the flu, new variants of COVID-19 continue to develop with waxing and waning virulence as cases and deaths continue to be tracked and updated twice weekly by the CDC.

COVID-19 is not going away any time soon, but our understanding of the illness and its repercussions has significantly grown, largely due to the amount of scientific research over the past few years. This has allowed us to discover more about the virus itself, its effects on different systems in the body, and how certain predisposing conditions impact how well the immune system responds. Lung injury from COVID-19 causes inflammation that evidence suggests can disrupt gut epithelial barrier integrity, increasing its permeability to gut microbes and their products, thereby allowing them to enter the circulatory system which further worsens inflammation. This occurs via the gut-lung axis (GLA).

A new study published online November 8, 2023, proposes that the gut microbiome plays a role in the inflammatory responses to COVID-19 and may impact severity disease outcomes.

“…revealing significant differences in microbiome composition (but not diversity) between the three disease severity groups.” <.span>

Researchers enrolled 79 subjects (58% male, 88% white) who had a PCR-confirmed COVID-19 infection between April 2020 and July 2021. Out of those enrolled, 31% met obesity criteria (BMI > 30) and about 25% had heart disease. Subjects were broken into three groups of COVID-19 severity (mild, moderate, severe/critical). DNA testing was performed on stool samples from all subjects to assess microbiome diversity and taxonomic composition, revealing significant differences in microbiome composition (but not diversity) between the three disease severity groups. Specifically, 12 microbial species were increased and 15 species were consistently decreased in severe/critical versus mild disease. Among the enriched species were Bacteroides nordii, a member of the pathogenic B. fragilis group, 2 Clostridium species (known producers of trimethylamine or TMA), Shigella flexneri and Finegoldia magna. Among the decreased species were Lactobacillus sakei, Lactobacillus crispatus and 2 butyrate producing bacteria Eubacterium species. Whereas TMA is implicated in the development of heart and kidney disease, butyrate helps to maintain the integrity of intestinal lining. The study adjusted for demographics, use of antibiotics, antivirals, and immunosuppressant medications when exploring differences in microbiota species between the disease severity groups.

“…suggests a ‘causative link for microbiome in driving distinct host inflammatory responses to SARS-CoV-2 infection that are associated with worse clinical outcomes.’”

Microbiome species were correlated to the subjects’ individual biomarkers of inflammation grouped into 3 distinct clusters (or inflammatory profiles). Correlations between microbial species, inflammatory profiles and disease outcomes were identified and grouped into 4 modules. Mild/moderate COVID-19 outcomes and younger age of subjects were associated with an abundance of anti-inflammatory bacteria and a less inflamed biomarker cluster (Module 1). Severe/critical disease outcomes and older age were associated with more pathogenic bacteria and a pro-inflammatory biomarker cluster (Modules 3 and 4).

Researchers concluded that their study suggests a “causative link for microbiome in driving distinct host inflammatory responses to SARS-CoV-2 infection that are associated with worse clinical outcomes.”

Of note, most subjects enrolled in this study were white males. Future studies might evaluate whether race or sex influence the observed associations, as well as the potential impact of vaccines on these findings.

Better understanding the gut microbiome’s role in inflammatory responses to viral infections may help identify populations most at risk for severe COVID-19 and facilitate the development of personalized therapies based on individual microbiotas and patterns of inflammation.