January 11, 2021

expert reaction to observational study on gut bacteria and body’s response to COVID-19

An observational study, published in Gut, looks at gut microbiota composition, COVID-19 severity and immune response.

Prof Daniel M Davis, Professor of Immunology at the University of Manchester, said:

‘Our knowledge of gut microbes has exploded in recent years. Variations have been associated with diseases as diverse as asthma, multiple sclerosis and cancer. So it’s perhaps not so surprising that the severity of COVID-19 also correlates with the composition of a person’s microbiome. But the details here are important. A particularly striking finding was that distinct characteristics in a person’s gut microbes persisted after clearance of the virus. It is possible that these changes could contribute to the symptoms of so-called ‘Long-COVID’. At the moment this idea is still speculative but it demands further investigation, especially given the huge importance of understanding ‘Long-COVID’. Overall, this new research doesn’t yet led to a clear public health message in terms of treatments or therapies, but does set the scene for a hugely important realm of new science.’

Dr Kaitlin Wade, Lecturer in Epidemiology at the University of Bristol, said:

“This is interesting work, but there needs to be an appropriate examination of the quality of evidence before generating strong inference about the role of gut microbiome in COVID-19 causally. It’s important to emphasise this is an observational study, so it cannot indicate whether variation in the gut microbiome is determining COVID-19 severity or whether the virus itself has caused this variation. It’s therefore perfectly possible that changing the gut microbiome may not influence COVID-19 infection prognosis at all. The sample size is also very limited and there could be issues with bias in their selection of hospital patients, including age range.

“The paper doesn’t appear to have sufficiently managed confounding factors, which would give the findings greater credence. Greater precision in the paper’s abstract regarding the actual difference in bacteria between COVID-19 cases and those without the virus would also be helpful in assessing any differences in a more quantifiable way.

“The key message here should be one of considerable caution. Although some evidence potentially linking COVID-19 and the gut microbiome has been found, much further and deeper research is required to understand this complex relationship and draw meaningful conclusions. Until it can be clearly evidenced that changing the gut microbiome alters COVID-19 risk, it would not be appropriate to suggest measures to improve gut health would increase resilience to COVID-19.”

Prof Willem van Schaik, Director of the Institute of Microbiology and Infection at the University of Birmingham, said:

“The ecosystem of bacteria that lives in the human gut (‘the gut microbiome’ in short) has been the topic of intensive study for more than a decade.

“We know that the gut microbiome consists of hundreds of different microbial species that often live in a commensal or symbiotic relationship with the host.  While the gut microbiome is broadly stable in healthy individuals, its composition can change, sometimes dramatically, through dietary interventions, exposure to antibiotics and illness.

“This study compares the microbiome of patients with COVID-19 with healthy controls. More than half of the patients exhibit moderate, severe or critical COVID-19 symptoms, while the control cohort is entirely healthy. As illness has a wide range of effects on human physiology it is to be expected that there is a difference in the gut microbiome of COVID-19 patients and healthy controls and indeed the authors observe this.  In addition, they find that antibiotic therapy affects the gut microbiome which is unsurprising. Finally the authors find that recovered COVID-19 patients, particularly those that had received antibiotic therapy, had a microbiome that was different from the healthy controls. Again, this is in line with previous work which shows that major disruptions of the microbiome, for example through exposure to antibiotics, can have a prolonged impact on the bacterial composition of the microbiome.

“While the manuscript may be of some interest as an addition to the scientific literature on the impact of hospitalisation and antibiotic use on the composition of the microbiome, the press release is highly problematic as it suggests a causative link between the microbiome composition and severity of COVID-19 and the long-term consequences of COVID-19 infections (informally known as ‘long COVID’). As outlined above, antibiotic therapy, hospital admission and infections will change the microbiome, but it is entirely inappropriate to suggest that the microbiome composition determines COVID-19 severity or the risk of ‘long COVID’. This study does not provide data to support that far-reaching claim.”

Prof Neil Mabbott, Personal Chair of Immunopathology at The Roslin Institute & Royal (Dick) School of Veterinary Studies, University of Edinburgh, said:

“The virus responsible for COVID-19 is able to infect the cells that line the gut, and humans can shed viral RNA in their faeces.  This study reports that COVID-19 may also cause changes to the abundance of certain bacterial species in the gut microbiome, and that the extent of these changes may depend on the severity of the infection. 

“This is an interesting study but many important questions remain.  Further studies are required to determine whether these changes to the gut microbiome directly affect the severity of COVID-19 in patients, or whether they are simply a consequence of the effects of the infection on the gut and the immune system.  It is also not certain whether these differences were present in the COVID-19 patients before they succumbed to infection, and whether similar changes are observed in patients in other geographical regions.”

Prof Angus Dalgleish FMedSci, Principal of the Institute for Cancer Vaccines and Immunotherapy, and Professor of Oncology, St Georges, University of London, said:

“It is now well established that the status of the microbiome of the gut greatly impacts on whether or not cancer patients will respond to immunotherapy.  This has led to an enthusiasm for faecal transplants where bacteria (good) from responders is given to those non-responders who have excess (bad) bacteria, but this is not yet standard of care for cancer patients outside of trials and special clinics.

“The details of different bacteria involved have tended to cloud the main issue which is that good bacteria are associated with a high fibre diet and a lower inflammatory state. The data from this paper should therefore not be too surprising as a bad outcome from COVID infection is already known to be associated with bad diets (obesity and diabetes) and those with higher background inflammatory states such as cardiac disease and hypertension. (A raised CRP a classic inflammatory marker is reported to be associated with a bad microbiome and inflammatory /cytokine response in this article).

“This is an observational study and the results have been repeated multiple times in most patients.  They have also correlated the bad bugs with raised inflammatory markers which is associated with poor outcomes in cancer patients as well.  This is a good study and the results make sense to further optimise diet and reduce inflammation in those with and at risk of COVID.”

Prof Graham Rook, Emeritus Professor of Medical Microbiology at UCL, said:

“We know that the microorganisms in the gut (microbiota) drive development, expansion and ‘education’ of the immune system in early life, and help to maintain it in adult life. We also know that the  microorganisms in the gut set up mechanisms that ‘police’ the immune system, and attempt to stop it from attacking things it should not attack (such as our own tissues), and to stop it from causing excessive inflammation.  So it is a reasonable hypothesis that an abnormal population of microorganisms in the gut could contribute to the excessive inflammation seen in severe COVID-19, and to autoinflammatory and autoimmune disorders occurring during the infection, or appearing later during “long COVID”.   

“The authors do indeed show that  changes in the composition of the gut microbiota correlate with  the severity of COVID-19 infection and with blood levels of some of the molecules that mediate inflammation.  They also show that the abnormal composition of the gut microbiota persists at least 30 days after the infection has been cleared, and that the changes seen are similar to those recorded in some other chronic inflammatory conditions.  So the circumstantial evidence that disturbance of the composition of the gut microbiota could play a role in COVID-19 and “long COVID” is strong. 

“However, changes to the microbiota could be secondary to the COVID-19 disease rather than a cause of susceptibility to the disease, and even the psychological stress caused by hospitalisation for COVID-19 will cause changes to the microbiota.  So this paper contains findings that are compatible with the hypothesis that the composition of the gut microbiota influences the severity of COVID-19 and the predisposition to ‘long COVID’, and it will encourage further research to prove the hypothesis one way or the other.  My guess is that the hypothesis will be shown to be correct, and that it will prove to be one of the reasons for the disproportionate  susceptibility of individuals of low socioeconomic status (SES), who for numerous reasons, particularly bad diet, have suboptimal microbiotas.  It would be exciting if transfer of microbiota from appropriate donors could be used to treat ‘long COVID’ but more definitive studies will be needed.”

‘Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19’ by Yun Kit Yeoh et al. was published in Gut at 23.30 UK time on Monday 11 Jan.

doi:10.1136/gutjnl-2020-323020

Declared interests

Prof Mabbott: “I have no conflict of interest to declare.”

No others received.