Gut microbiome imbalances influence the likelihood of 'long-Covid'

When the immune system battles Covid-19 it can sometimes spin wildly out of control and cause an outsized response called a cytokine storm. These storms can overburden the body, cause organ failure and tissue damage, jeopardize brain function, and even lead to death.

In a new study, researchers suggest the gut microbiome may mediate the immune response to Covid-19, ramping up or tamping down inflammation while contributing to cytokine storms.

Imbalances in the gut microbiome may also shape the severity of Covid-19, according to the study —determining who bounces back from the disease relatively quickly or who becomes a long-hauler.

The research, published Monday in the journal Gut, adds to growing evidence that gut health is pivotal for mental and physical health.

"Imbalanced gut microbiota or 'dysbiosis' weakens our immune defense, thereby predisposing to more severe SARS-CoV2 infection and potentially contributing to ‘long COVID,’" study co-author Siew C Ng tells Inverse. Ng is a researcher in the division of gastroenterology at the Chinese University of Hong Kong.

"Restoration of dysbiosis offers hope to boost our immunity against SARS-CoV2 and hastens recovery from the disease," Ng says.

Hasan Zaki was not a part of this new study but is a researcher and pathology, immunity, and microbiome expert at the University of Texas, Southwestern. He reasons that gut microbiota is unlikely to be a key factor in Covid-19 pathogenesis — or disease development. Instead, Zaki explains, the microbiome likely influences how the immune system responds to the virus.

"Although no specific gut bacteria is directly linked to the outcome of Covid-19, it is likely that healthy gut microbiome can help develop optimum or balanced immune responses to mitigate SARS-Cov2 infection," Zaki says.

Gut check — In the human body, a huge proportion of the immune system exists in the gastrointestinal tract. But how this gut microbiome — the trillions of tiny bacteria, fungi, protozoa, and viruses that live in the gut — influence how people respond to Covid-19 has been unclear.

To solve this mystery, researchers collected blood and stool samples, as well as medical records, from 100 people admitted to the hospital with laboratory-confirmed Covid-19 between February and May 2020. They contrasted this data with samples from 78 people without Covid-19 who were taking part in another microbiome study before the pandemic. Twenty-seven Covid-19 patients gave stool samples during and 30 days after their stay in the hospital.

They split the Covid-19 group by severity:

• Mild patients did not have evidence of pneumonia on their x-ray scans
• Moderate patients showed fever and respiratory tract symptoms of pneumonia with fever and respiratory tract symptoms
• Severe patients found it very difficult to breathe normally
• Critical patients needed mechanical ventilation or experienced organ failure requiring intensive care

How is gut health related to Covid-19?

Across the board, the gut microbiome make-up differed significantly between patients with and without Covid-19, regardless of whether they had been treated with drugs including antibiotics. This medication finding matters because antibiotics and other drugs are known to interfere with gut microbiota.

Sick Covid-19 patients exhibited higher numbers of three microbiota species than people without the infection: Ruminococcus gnavus, Ruminococcus torques, and Bacteroides dorei.

The same group had far fewer bacterial species that can influence immune system response, such as Bifidobacterium adolescentis, Faecalibacterium prausnitzii, and Eubacterium rectale. Lower numbers of the first two species were particularly associated with severe Covid-19.

"Restoring this important bacteria may be important in the combat against Covid-19," Ng says.

The distinct microbiome imbalance was also linked to elevated levels of inflammatory cytokines and blood markers of tissue damage, such as C-reactive protein and certain enzymes. In all of the patients tested 30 days after their hospital stay, the microbiome imbalances lingered even after the virus cleared.

According to Zaki, the findings are "interesting but not surprising" given that gut microbiota is a known regulator of our immune system. When the gut microbiome is out of whack, so is immune function.

"At this moment, there is a lack of data establishing a clear link between the severity of Covid-19 and gut microbiota composition," Zaki tells Inverse.

While this study sheds light on a relatively unfocused area of Covid-19 research, scientists still don't know whether the altered gut microbiota is an effect of the disease or an underlying cause of disease development, the researcher explains.

"Although this study suggests that certain gut bacteria are positively or negatively correlated with some key cytokines induced during Covid-19, it is difficult to generalize without multiple studies from different geographical locations," Zaki says.

How to improve your gut health

Taken together, these findings suggest gut microbiome disturbances could explain why some symptoms like fatigue, shortness of breath, and joint pain linger for months post-infection.

Gut health is also involved in other inflammatory diseases like Crohn's disease, obesity, and Alzheimer's. The study authors, in turn, suspect supporting the microbiome is a worthwhile strategy to counter inflammation due to Covid-19.

"It is highly likely that the cytokine storm of Covid-19 patients might be associated with the gut microbiota composition – a higher abundance of proinflammatory [bacteria] and lower abundance of anti-inflammatory bacteria," Zaki says.

It is "certainly possible" that post covid symptoms or related health complications are linked to gut microbiota composition, he adds, although more studies are needed.

Importantly, the observational study only found correlations, not direct causation. More research is needed to illuminate just how pivotal gut health is to fighting Covid-19 and vice versa.

"Bolstering of beneficial gut species depleted in Covid19 could serve as a novel avenue to mitigate severe disease, underscoring the importance of managing patients' gut microbiota during and after Covid-19," the study team explained in a statement.

"Clinical management not only should aim at clearing the virus but also restoring the abnormal gut microbiota," Ng says.

To support gut health, eat lots of fibrous, nutrient-rich vegetables, food with naturally occurring probiotics such as yogurt and sauerkraut, and exercise regularly. It may also be helpful to add a pre or probiotic supplement to your routine after consulting a healthcare provider.

"Maintaining a healthy microbiome through healthy diet would definitely benefit in fighting against Covid-19," Zaki says.

"Avoiding high fat and high sugar diets, and taking fruits, yogurt, and fiber-containing foods would be practical means to develop a healthy gut microbiome."

Abstract:

Objective: Although COVID-19 is primarily a respiratory illness, there is mounting evidence suggesting that the GI tract is involved in this disease. We investigated whether the gut microbiome is linked to disease severity in patients with COVID-19, and whether perturbations in microbiome composition, if any, resolve with clearance of the SARS-CoV-2 virus.

Methods: In this two-hospital cohort study, we obtained blood, stool, and patient records from 100 patients with laboratory-confirmed SARS-CoV-2 infection. Serial stool samples were collected from 27 of the 100 patients up to 30 days after clearance of SARS-CoV-2. Gut microbiome compositions were characterized by shotgun sequencing total DNA extracted from stools. Concentrations of inflammatory cytokines and blood markers were measured from plasma.

Results: Gut microbiome composition was significantly altered in patients with COVID-19 compared with non-COVID-19 individuals irrespective of whether patients had received medication (p<0.01). Several gut commensals with known immunomodulatory potential such as Faecalibacterium prausnitzii, Eubacterium rectale, and bifidobacteria were underrepresented in patients and remained low in samples collected up to 30 days after disease resolution. Moreover, this perturbed composition exhibited stratification with disease severity concordant with elevated concentrations of inflammatory cytokines and blood markers such as C reactive protein, lactate dehydrogenase, aspartate aminotransferase, and gamma-glutamyl transferase.

Conclusion: Associations between gut microbiota composition, levels of cytokines, and inflammatory markers in patients with COVID-19 suggest that the gut microbiome is involved in the magnitude of COVID-19 severity possibly via modulating host immune responses. Furthermore, the gut microbiota dysbiosis after disease resolution could contribute to persistent symptoms, highlighting a need to understand how gut microorganisms are involved in inflammation and COVID-19.