COVID and the Microbiome

Research on the human microbiome has grown fast in recent years. Scientists have linked microbiome imbalances to chronic conditions like diabetes, cardiovascular disease, and depression. They’ve also found evidence that the microbiome plays a key role in infectious diseases, including COVID-19 — making it a promising target for treatment.

Trillions of microorganisms make up the microbiome. They live in the gut, on the skin, in the urogenital tract, and elsewhere in the body. It’s not entirely clear what a healthy microbiota profile looks like at each of these sites. But studies have linked shifts in microbiota composition, or dysbiosis, to many diseases. Microbiota-based therapies have drawn more interest since fecal microbiota transplants produced positive results treating recurrent Clostridium difficile infection.

From the moment we’re born, the microbiome serves as a crucial defense against infectious diseases. Our earliest bacterial exposures may even happen in utero. Intestinal colonization occurs at delivery, shaped by genetics, mode of delivery, breastfeeding, and other factors. This colonization is essential for normal immune development. The resulting microbiome influences T-cell subsets. The constant back-and-forth between gut microbiota and intestinal epithelium shapes innate and adaptive immune signaling through adulthood.

Dysbiosis can cause infectious disease. Infectious disease and its treatment can, in turn, change the microbiota and shape disease outcomes. Studies have observed dysbiosis in various infectious diseases, including COVID-19.

The Microbiome’s Link to COVID-19 Outcomes

“One of the major unknowns with COVID-19 is the variation in outcome,” says Martin J. Blaser, Professor of Medicine and Microbiology at Rutgers Robert Wood Johnson Medical School and Henry Rutgers Chair of the Human Microbiome. “It now appears most of the risk is due to differences in the people themselves. Age is clearly a factor, as are certain well-known conditions, but still, most risk is unknown.” This brings us to the microbiome, he explains, since differences in it link to how severe several diseases become. “Preliminary studies are beginning to link such differences to COVID-19, as well. This is a promising area to explore.”

The microbiota in the gut and lungs may engage in bidirectional crosstalk, known as the gut-lung axis. Microbial metabolites and endotoxins can travel through the blood to affect the lungs. Inflammation in the lung, in turn, can alter the gut microbiota. This raises the question of whether SARS-CoV-2 can also shape the gut microbiota, as researchers have shown with respiratory viral infection in mice.

Several lines of evidence suggest that the gut-lung axis may play a role in COVID-19:

• SARS-CoV-2 mainly causes disease by latching onto ACE2 receptors on alveolar epithelial cells — but intestinal epithelial cells carry these receptors too
• Some patients have reported diarrhea, and researchers have detected SARS-CoV-2 RNA in patient fecal samples
• Acute respiratory distress syndrome (ARDS) shows up in serious COVID-19 disease, and the gut microbiota may contribute to ARDS pathogenesis, based on experimental and clinical evidence
• The decrease in gut microbiota diversity with age can lead to dysbiosis

Immunocompromised and elderly patients face a higher risk of serious COVID-19 disease. Together, these observations suggest the gut-lung axis may affect COVID-19 outcomes. Restoring gut microbiota composition and diversity through personalized nutrition could work as a preventive measure. Studies have shown probiotics can be effective at reducing the duration and incidence of viral respiratory infections.

But the case for using probiotics in COVID-19 still rests on indirect evidence. We have little data on the disease’s effect on the gut microbiota, according to correspondence published in The Lancet Gastroenterology & Hepatology. As the authors put it, blind use of conventional probiotics for COVID-19 isn’t recommended yet. We first need to better understand how SARS-CoV-2 causes disease and how it affects gut microbiota.

Dysbiosis in Other Infectious Diseases

Bacterial Vaginosis

Researchers have also observed vaginal dysbiosis in bacterial vaginosis (BV). BV is linked to pre-term birth, sexually transmitted infections, and other adverse outcomes. In one study, Zhejiang University researchers found a major shift in bacterial species in the vagina of women with BV. BV-infected women had a higher number of phylotypes. They also identified three phyla and eight genera strongly linked to the disease. These could work as markers for diagnosis and as treatment targets.

HIV

People with HIV also show dysbiosis. A Zhejiang University study looked at fecal samples from a Chinese population, used as a proxy for gut microbiota. It found that HIV-1-infected patients had a significantly higher Firmicutes/Bacteroides ratio than healthy people. Highly active anti-retroviral therapy (HAART) lowered HIV-1 viral loads. But it didn’t return fecal microbiota diversity and composition to healthy levels.

The vaginal microbiome, meanwhile, might influence the risk of HIV infection. A study of 688 South African women looked at the topical microbicide tenofovir. Researchers from the University of Washington, University of Cape Town, National Health Laboratory Service, and other institutions conducted the study. It reduced HIV incidence by 61% in women whose vaginal microbiomes were dominated by Lactobacillus. But it reduced HIV incidence by only 18% in women whose microbiomes were dominated by Gardnerella vaginalis and other anaerobic bacteria associated with BV. It turns out those anaerobic species metabolize tenofovir, making it ineffective. This could explain the high HIV infection rates among young women and girls in South Africa.

These findings suggest that women with vaginal microbiomes dominated by G. vaginalis and other BV-associated bacteria may need closer monitoring. This includes attention to how well they adhere to tenofovir treatment and its timing. Healthcare workers could use vaginal microbiota or pH screenings to identify which category a given woman falls into.

Hepatitis B

There’s also growing evidence that gut dysbiosis plays a role in hepatitis B virus-induced chronic liver disease (HBV-CLD). Researchers at Zhejiang University and other institutions studied HBV-CLD patients. They reported reduced microbiota diversity, with a significantly higher Firmicutes/Bacteroidetes ratio, compared to healthy patients. This suggests oral microbiota dysbiosis contributes to HBV-CLD development. HBV infection also raised levels of hydrogen sulfide and methyl mercaptan-producing phylotypes, which could partly explain the bad breath seen in HBV patients. These phylotypes might also help break down oral defenses and invade the gut, changing its microbiota composition. Untangling the link between oral microbiota dysbiosis and HBV-CLD could open the door to diagnostics and personalized treatments based on specific oral phylotypes.

Why This Matters

Efforts to prevent and treat infectious diseases have historically relied on better sanitation, small-molecule drugs, and vaccines. These have worked well. But infectious diseases still kill an estimated nine million people each year. And antibiotic resistance keeps rising. And then there’s COVID-19, for which a reliable vaccine and treatment have at times remained elusive. These converging challenges show why we need to explore a broader range of strategies, including those based on targeting the microbiome.