• Many people who recover from COVID-19 report lingering symptoms such as fatigue, muscle weakness, and insomnia, known collectively as post-acute COVID syndrome (PACS) or long COVID.
• Previous research has found that individuals who experience severe COVID-19 tend to have gut dysbiosis, a disruption in the community of microorganisms living in the gut.
• A new study has found the first evidence that there may also be a connection between gut dysbiosis and long COVID.
• Future clinical trials could therefore investigate probiotics, dietary changes, or fecal transplants as potential treatments for long COVID.

As many as three-quarters of people who recover from COVID-19 report experiencing at least one lingering symptom 6 months later.

Common symptoms of this condition, known as PACS or long COVID, include fatigue, muscle weakness, and insomnia.

The exact cause of long COVID remains a mystery, but possible contributory factors are excessive immune responses and cell damage sustained during the illness itself.

It also remains unclear why some people who have had COVID-19 experience lingering symptoms for weeks or months while others recover completely.

In 2020, researchers at the Center for Gut Microbiota Research, part of the Chinese University of Hong Kong, found a clue.

They discovered that people with COVID-19 had distinct changes in their gut microbiota, the community of microorganisms living in their gut, compared with healthy controls.

The collection of genomes of the gut microbiota is known as the gut microbiome.

Fecal samples from people with COVID-19 contained more opportunistic pathogens or disease-causing organisms and fewer “friendly” bacteria.

This disruption in the balance of organisms living in the gut, known as gut dysbiosis, appeared to be more extreme in people with more severe illness.

Because the gut plays a major role in the regulation of the immune system, disturbances in the gut microbiota may not only exacerbate COVID-19 but also cause lingering symptoms as a result of continuing immune disturbances.

The Center for Gut Microbiota Research has now found the first evidence of gut dysbiosis in people with long COVID up to 6 months after their initial SARS-CoV-2 infection.

The scientists found links between specific groups of bacteria and particular symptoms.

At the time of hospital admission, people who went on to develop long COVID tended to have a less diverse and abundant microbiome compared with people who fully recovered.

In fact, the gut microbiome of people who did not develop long COVID was similar to that of a group of healthy controls who provided fecal samples before the pandemic.

The results of the study appear in the journal Gut.

Potential treatments

“Our study demonstrated the association between [a persistently] altered gut microbiome and long COVID, which also suggests that there is an opportunity to ameliorate these symptoms by regulating the gut microbiome,” said Prof. Siew C. Ng, Ph.D., associate director of the Center for Gut Microbiota Research and senior author of the new study.

“There are important implications for future research regarding the mechanisms of disease underlying long COVID where most have tended to ignore the gastrointestinal system, and also for trials of potential therapies and diagnostic approaches,” she told Medical News Today.

She added that possible treatment approaches might include diets that support a healthy and balanced gut microbiota, avoiding antibiotics where possible, probiotic supplements to replace depleted bacterial species, and fecal microbiota transplants.

The researchers believe gut microbiome profiling of people with COVID-19 may also help identify those most likely to develop the condition.

How the study worked

The scientists recruited 106 people with COVID-19 admitted to hospitals in Hong Kong. Most had mild to moderately severe COVID-19.

Their average age was 48 years, and just over half were women. The participants gave stool samples on admission, 1 month later, and 6 months later.

The researchers used a technique called shotgun metagenomic sequencing to analyze a total of 258 samples. They also analyzed control samples provided before the pandemic by 68 people matched for age, sex, preexisting illness, and diet.

Following their discharge from the hospital, 81% of people still had at least one lingering symptom 3 months later. After 6 months, 76% still had a symptom.

The most common symptoms were fatigue, memory difficulties, hair loss, anxiety, and sleep disturbances.

Interestingly, the researchers found no association between the amount of virus in the samples provided at admission to the hospital and whether participants went on to develop long COVID.

However, there were significant links between the participants’ gut microbiome and the condition.

In people with long COVID, there were differences in the abundance of 42 species of bacteria at admission and 3 and 6 months following discharge compared with control samples.

Of these, 28 species were less abundant, and 14 were more abundant.

For example, at 6 months, people with long COVID had significantly less of the friendly species Faecalibacterium prausnitzii (F. prausnitzii) and Blautia obeum in their gut.

They also had a greater abundance of the “unfriendly” species Ruminococcus gnavus and Bacteroides vulgatus.

Friendly bacteria that produce the chemical butyrate, such as Bifidobacterium pseudocatenulatum and F. prausnitzii, were the most likely species to be depleted in people with long COVID 6 months after discharge.

By contrast, people who did not develop long COVID had only 25 changes in the abundance of species at hospital admission compared with controls. And by 6 months after discharge, their gut microbiome was similar to that of the controls.

The researchers also found links between certain species and particular symptoms of long COVID, for example, respiratory symptoms correlated with disease-causing opportunistic bacteria. Neuropsychiatric symptoms and fatigue were associated with nosocomial or hospital-acquired species such as Clostridium innocuum and Actinomyces naeslundii.

Immune-regulating bacteria

Prof. Graham Rook, M.D., an emeritus professor of medical microbiology at University College London, who was not involved in the research, told MNT: “It is entirely reasonable to suggest that the composition of the organisms in the gut might be relevant to the development of PACS. One particularly probable link is via regulation of the immune system.”

He explained that people with long COVID often have raised levels of autoantibodies.

“In other words, the virus has triggered an antibody response to the patients’ own tissues,” he said. “This represents a failure of the regulatory mechanisms that should stop immune responses against the patients’ own tissues.”

In the study, people with long COVID had reduced levels of several gut bacteria that help regulate the immune system, such as F. prausnitzii, Eubacterium rectale, and bifidobacteria species.

Prof. Rook formulated the “old friends hypothesis,” which proposes that humans evolved friendly relationships with bacteria that help keep the immune system in check.

Limitations of the study

The authors note several limitations of their study. In particular, as an observational study, it was unable to establish whether particular features of participants’ gut microbiome actually caused long COVID.

In addition, the scientists had to rely on participants’ subjective responses to a questionnaire about their symptoms.

The authors suggest that the small sample size is a limitation of this study and that further research should attempt to confirm their findings in larger cohorts across different populations.

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