Research on the human microbiome has burgeoned in recent years. Microbiome imbalances have been linked to chronic conditions, such as diabetes, cardiovascular disease, and depression. But scientists have also uncovered evidence of the microbiome’s crucial role in infectious diseases, including COVID-19, pointing to it as a promising target for treating them.
The trillions of microorganisms that make up the microbiome populate the gut, skin, urogenital tract, and other regions of the body. While it’s not entirely clear what a healthy microbiota profile looks like at each of these sites, studies have linked shifts in microbiota composition, or dysbiosis, to numerous diseases. Meanwhile, microbiota-based therapies have drawn interest following the positive outcomes of fecal microbiota transplants in treating recurrent Clostridium difficile infection.
From the moment we’re born, the microbiome serves as a crucial defense against infectious diseases, and in fact, our earliest bacterial exposures can take place in utero. Intestinal colonization occurs at delivery, influenced by genetics, mode of delivery, breastfeeding, and other factors, and is essential for normal immune development. Indeed, the resulting microbiome influences T-cell subsets, and the constant interaction between the gut microbiota and intestinal epithelium contribute to innate and adaptive immune signaling through adulthood.
Dysbiosis can cause infectious disease, and infectious disease and its treatment can affect the microbiota and shape disease outcomes. Studies have observed dysbiosis in various infectious diseases, including COVID-19.
“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, with differences in it being linked to the severity of several diseases. “Preliminary studies are beginning to link such differences to COVID-19, as well. This is a promising area to explore.”
Indeed, the microbiota in the gut and lungs may engage in bidirectional crosstalk, known as the gut-lung axis. Microbial metabolites and endotoxins can affect the lungs via the blood, while inflammation in the lung can alter the gut microbiota. This begs the question of whether SARS-CoV-2 can also shape the gut microbiota, as has been shown with respiratory viral infection in mice.
Various lines of evidence suggest that the gut-lung axis may play a role in COVID-19. SARS-CoV-2 causes the disease mainly by latching onto ACE2 receptors on the surface of alveolar epithelial cells — yet intestinal epithelial cells express these receptors, too. Some patients have reported diarrhea, and SARS-CoV-2 RNA has been detected in patient fecal samples. What’s more, acute respiratory distress syndrome (ARDS) is seen in serous COVID-19 disease, and the gut microbiota may contribute to ARDS pathogenesis, based on experimental and clinical evidence. Meanwhile, the decrease in gut microbiota diversity with age can lead to dysbiosis.
Given hat immunocompromised and elderly patients have an elevated risk of serious COVID-19 disease, these observations point to the possibility that the gut-lung axis affects COVID-19 clinical outcomes. They also suggest that restoring gut microbiota composition and diversity through personalized nutrition may represent preventative measures against serious COVID-19 disease. Indeed, studies have shown probiotics to be effective in decreasing the duration and incidence of viral respiratory infections.
But the reasoning for using probiotics in COVID-19 is so far based on indirect evidence, and we have little data on the disease’s effect on the gut microbiota, according to correspondence published in The Lancet Gastroenterology & Hepatology. “Blind use of conventional probiotics for COVID-19 is not recommended until we have further understanding of the pathogenesis of SARS-CoV-2 and its effect on gut microbiota,” the authors wrote.
Vaginal dysbiosis has been observed in bacterial vaginosis (BV), associated with pre-term birth and sexually transmitted infections, among other adverse outcomes. In one study, Zhejiang University researchers showed a major alteration in the absolute and relative abundances of bacterial species in the vagina of women with BV, specifically a higher number of phylotypes in BV-infected women. They also identified three phyla and eight genera significantly associated with the disease, suggesting they could serve as markers for diagnosis, as well as targets for therapy.
Individuals with HIV also exhibit dysbiosis. Another Zhejiang University study of fecal samples from a Chinese population as a proxy of gut microbiota found that HIV-1-infected patients had a significantly higher Firmicutes/Bacteroides ratio than their healthy counterparts. Additionally, highly active anti-retroviral therapy (HAART) lowered HIV-1 viral loads, but 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 by researchers at the University of Washington, University of Cape Town and National Health Laboratory Service, and other institutions saw that the topical microbicide tenofovir reduced HIV incidence by 61% in women with vaginal microbiomes dominated by Lactobacillus — and by a mere 18% in those with vaginal microbiomes dominated by Gardnerella vaginalis and other anaerobic bacteria associated with BV. As it turns out, the latter species metabolize tenofovir, rendering it ineffective, which could explain the staggering rates of HIV infection among young women and girls in South Africa.
The findings might mean that women with vaginal microbiomes inhabited primarily by G. vaginalis and other anaerobic, BV-associated bacteria might be more sensitive to adherence to tenofovir treatment and timing of application. Healthcare workers could use vaginal microbiota or pH screenings to determine which category the women fall under.
There’s also a growing body of evidence that gut dysbiosis plays a role in hepatitis B virus-induced chronic liver disease (HBV-CLD). Researchers at Zhejiang University and other institutions reported that HBV-CLD patients had reduced microbiota diversity — with a significantly higher Firmicutes/Bacteroidetes ratio — compared to healthy patients, suggesting that oral microbiota dysbiosis contributes to HBV-CLD development. Furthermore, HBV infection led to a rise in hydrogen sulfide and methyl mercaptan-producing phylotypes, which could partly explain the bad breath observed in HBV patients. They might also help break down oral defenses and invade the gut, changing its microbiota composition. Further teasing apart the association between oral microbiota dysbiosis and HBV-CLD development could pave the way to diagnostics and personalized treatments based on the presence of certain oral phylotypes.
Efforts to prevent and treat infectious diseases have historically included approaches such as improved sanitation, small-molecule drugs, and vaccines. Although these have proven effective, infectious diseases still kill an estimated nine million people each year, amid rising resistance to antibiotics and other anti-infectives, not to mention COVID-19, for which a vaccine and treatment remain elusive. These converging challenges underscore the need to explore a broader array of strategies, including those based on targeting the microbiome.
ABOUT THE AUTHOR:
Brian Neman serves as the Co-Founder and CEO of Sanguine Biosciences. Brian focuses on all items relating to commercialization and relationships with researchers; he is an adjunct professor of Digital Health at USC, and co-founded Sanguine in 2010 out of his graduate program in healthcare administration at USC. He is also on the boards and committees of various organizations including HD Care, BIOCOM Big Data Committee, and more.