When SARS-CoV-2 first began rampaging around the world, it was thought to primarily affect the respiratory system. It soon became clear that the virus had more far-reaching effects, including on the gastrointestinal system and its bacterial symbionts.

This came as no surprise to Siew Ng, a gastroenterologist in the Center for Gut Microbiota Research at the Chinese University of Hong Kong. “We previously had found quite a lot of impaired gut microbiome in different conditions, including people with infectious disease,” says Ng. COVID-19 patients were no different. “In quite a substantial proportion of people, they also have gut manifestations, such as diarrhea, such as abdominal pain.”

One early study suggested that nearly 20 percent of patients with confirmed SARS-CoV-2 infection had gastrointestinal symptoms. That same study found that COVID-19–infected people shed viral RNA in their feces—another clue that the virus was getting into the gut.

Since then, researchers have identified patterns in the makeup of gut bacteria—a state called ‘dysbiosis’ in which there is loss of diversity and beneficial bacteria but an increase in bad bacteria—that are associated with poorer outcomes and slower recovery from COVID-19. It’s early days for this line of research, but its proponents say that changes in the gut microbiome could potentially flag patients at risk of worse outcomes from COVID-19, or that its makeup could even be altered to help patients avoid severe disease.

The microbiome–COVID-19 connection

SARS-CoV-2 enters host cells via a type of receptor called angiotensin converting enzyme 2, or ACE2. ACE2 is found on multiple cell types in the human body, including those that line the gut, and studies have tied its production there to the gut microbiome. “The ACE2 receptors somehow regulate the microbiota, and the infection causes the dysregulation of the intestinal system and that will cause the dysbiosis of microbiota,” says Tao Lin, a microbiologist at the Baylor College of Medicine in Houston.

The repercussions of that dysbiosis extend far beyond the digestive system—for example, the gut is often described as the largest immune organ in the human body. The microbiome contains both healthy or ‘good’ bacteria, and pathogenic or ‘bad’ bacteria, says Fatima El-Assaad, a medical scientist at the UNSW Microbiome Research Centre in Sydney, Australia. “We know that sometimes some of these good bugs, when they’re absent there is a manifestation of certain diseases, or when there’s an abundance of a certain bad bug, there’s a manifestation of that disease,” El-Assaad says.

See “The Microbiome and Human Health

But microbiome health isn’t as simple as the increase or decrease in one particular species. “These microbes do not live in isolation; they work with their communities,” she says. “It’s like this homeostasis that they’re trying to maintain.”

While it’s not yet fully understood how the gut microbiome influences the health of its host, one mechanism is thought to be through substances called metabolites that bacteria release, says Ken Cadwell, a microbiologist at the NYU School of Medicine in New York.

“Those metabolites themselves can reach other organs and tissue,” Cadwell says. In particular, they appear to have significant influence on the immune system. “The microbiome provides products that are immune-stimulatory: it makes metabolic by-products, as well as bacterial cell wall components, that trigger immune responses.”

A 2019 study illustrated this by giving healthy human volunteers with low pre-existing influenza antibodies a course of antibiotics to perturb their gut microbiomes, then a dose of influenza vaccine. Compared to a control group, those treated with antibiotics showed a significantly reduced immune response to the influenza vaccine. “It’s not even the real lung infection with the virus, but you see an effect of depleting the microbiome,” Cadwell says. “That’s a pretty striking result.”

Conversely, researchers have been examining what happens to the homeostasis of the gut microbiome when a pathogen invades. During the first wave of SARS-CoV-2 infections in Hong Kong in March 2020, Siew Ng and colleagues analyzed the gut microbiota of 15 patients who tested positive for SARS-CoV-2, taking two to three fecal samples each week until the patients left hospital (hospitalization was compulsory for anyone who tested positive to SARS-CoV-2 in Hong Kong at the time, regardless of symptoms).

The team found that all COVID-19 patients had increased levels of pathogenic bacteria species such as Clostridium hathewayi, Actinomyces viscosus, and Bacteroides nordii, and reduced levels of beneficial bacteria such as Faecalibacterium prausnitzii, Lachnospiraceae bacterium, Eubacterium rectale, and Ruminococcus obeum in their guts compared to healthy controls. COVID-19 patients who had been treated with antibiotics during their hospital stays showed even more depleted communities of beneficial bacteria and greater numbers of pathogenic bacteria.

The dysbiosis in the gut microbiota persisted even after patients cleared their SARS-CoV-2 infections, and—most importantly—the degree of difference in the microbiome compared to healthy controls correlated with severity of COVID-19.

Ng and colleagues have since confirmed those findings in a larger study of 100 COVID-19 patients. That study also looked further into the physiological traits associated with the dysbiosis, and found that people with low levels of good bacterial species had higher levels of signaling molecules called cytokines that are associated with inflammation.

The research team has followed some of the patients for 6-12 months, and found that the COVID-19–associated dysbiosis is long-lasting. “What’s intriguing is those who continue to have persistent abnormal gut microbiota are the people who have more persistent symptoms, so-called long COVID,” Ng says. In contrast, people who completely recover from COVID-19 show a similar gut microbiome profile to people who never experienced the disease. “I think that gives us a signal that perhaps the dysbiosis may contribute to some of the outcome or symptoms that we have witnessed,” she says.

A recent study by Cadwell and his colleagues, not yet peer reviewed, found that SARS-CoV-2 infection caused dysbiosis in mice. The researchers also analyzed fecal samples from 101 patients with COVID-19 and found similar dysbiosis in their bacterial make-up, including low diversity of bacterial species. This was especially the case in patients who developed secondary bloodstream infections.

Asima Bhattacharyya, a physiologist at the National Institute of Science Education and Research in Bhubaneswar, India, and colleagues suggest that gut dysbiosis contributes to the COVID-19 phenomenon of ‘silent hypoxia,’ in which patients have extremely low blood oxygen levels but don’t feel breathless. In an opinion article published last month, the researchers hypothesize that because one of the short-chain fatty acids released by ‘good’ gut bacteria—butyrate—interacts with neurotransmitters in the brain, its absence during COVID-19 could make patients less conscious of disease symptoms such as hypoxia. “Maybe there is a very strong correlation between the gut microbes with brain function, brain neurochemistry, and the composition of these neurotransmitters that actually makes our brain responsive to different changes that are happening around us,” Bhattacharyya says.

The causality question

But in all human studies so far linking SARS-CoV-2 to dysbiosis, patients’ gut microbiota were only sampled after they were infected with the virus. This raises the question of whether pre-existing gut dysbiosis contributed to more severe COVID-19 or whether COVID-19 was the cause of the gut dysbiosis. It’s a “chicken and egg” question, says immunologist Eran Elinav of the Weizmann Institute of Science in Israel.

It’s now well established that people with diabetes, obesity, and high blood pressure are at higher risk of severe COVID-19. Those conditions are also associated with less healthy gut microbiomes, which could potentially help explain this connection.

There’s also the possibility that patients with severe COVID-19 are more likely to be treated with antibiotics, which could—as Ng’s study suggested—cause further disturbance to the gut microbiota. “Whether the virus actually is affected in its ability to transmit and its ability to cause disease by the microbiome—in other words, the question of causality—in my view, is still unresolved,” Elinav says.

Ng and colleagues are also hoping to explore this question with their own animal studies, in which they analyze the gut microbiota both before and after COVID-19 to see whether pre-existing gut dysbiosis leads to more severe COVID-19, or whether SARS-CoV-2 changes the gut microbiome to different degrees that predict COVID-19 outcomes.

Treating the microbiome

Whether or not SARS-CoV-2 infection is causing disturbance of the gut microbiome or exacerbating it, the possibility exists that improving the gut microbiome in COVID-19 patients—for example, by boosting the number and diversity of beneficial bacteria—might also improve COVID-19 symptoms.

One treatment for severe gut dysbiosis, such as occurs in people with Clostridium difficile infection, is a transplant of fecal microbes from a healthy donor. While this is unlikely to become a mainstream treatment for COVID-19, there are also less intensive approaches that could be used to boost the populations of good bacteria in people diagnosed with COVID-19, and perhaps help avoid more severe outcomes from the disease.

The possibility exists that improving the gut microbiome in COVID-19 patients—for example, by boosting the number and diversity of beneficial bacteria—might also improve COVID-19 symptoms.

Firstly, Cadwell argues for more careful use of antibiotics, given the evidence that they can throw the gut microbiome out of whack. “I don’t want to be too critical of physicians on the frontline, especially during a crisis, but there’s this temptation to over-prescribe antibiotics, especially if you feel like nothing else works,” he says.

A more interventional approach, says El-Assaad, might be to use probiotics with beneficial gut bacteria. Ng and colleagues have already conducted a pilot study using a probiotic and prebiotic formulation that was developed based on data from thousands of individuals, designed to boost good gut bacteria levels in people with COVID-19. While the results are yet to be published, Ng says the 25 patients who received the specially formulated probiotics—around two-thirds of whom had mild disease and one-third with moderate-to-severe disease—had higher levels of good bacteria in their gut, were more likely to recover fully from COVID-19, and had lower levels of inflammatory molecules in their blood than the 30 controls who received standard care. Larger controlled clinical trials are now underway, and Ng, who is a non-executive scientific cofounder of the biotech that has licensed the patent of the formula, says that if they go well, “then perhaps bolstering the beneficial gut species that’s known to be depleted in COVID-19 could serve as quite a safe and novel way of mitigating the infection.”

There’s another aspect to the interaction between COVID-19 and the gut microbiome: changes in behavior and diet during the pandemic may also be changing the gut microbiome. “Our hygiene habits have been drastically changed,” Elinav says, pointing out that people are washing their hands more, using disinfectants, socially distancing, and changing their dietary habits. “The fact that we’re all trying to keep cleaner is good for COVID, I’m not sure it’s good for the microbiome,” he says.

Studies have also suggested that, during lockdowns, people eat more carb-rich “comfort food” and less fresh fruit and fish, dietary shifts that may impact gut microbe communities. They may also eat more and exercise less, all while experiencing more stress. In contrast, some people report eating healthier during lockdowns—perhaps because of an increase in home cooking—and exercising more. Either way, Elinav says, “whether these [COVID-related diet and behavior changes] would impact our health down the line is an open and fascinating question that many of us are trying to study.”