Our bodies are home to trillions of microorganisms, predominantly bacteria along with other residents such as fungi and viruses. This collective community, known as the microbiome, plays a pivotal role in both health and disease. Due to advances in technology, we are learning more about the microbiome in relation to ME/CFS and long COVID.
Usually, the immune system works in partnership with the microbiome to protect the body from harmful invaders. However, when an infection occurs, the balance of microorganisms in the body gets disturbed – this is known as microbiome dysbiosis. Numerous studies have provided evidence for microbiome dysbiosis in both ME/CFS and long COVID. However, further research is needed to determine if changes in the body’s microscopic inhabitants are a cause or a consequence of these conditions.
A recent review by Guo and colleagues examined research related to microbiome dysbiosis in post-acute infection syndromes (PAIS) which encompass ‘chronic sequelae caused by the inability to recover from acute infectious diseases’. The review primarily focuses on ME/CFS and long COVID, both falling within the sphere of PAIS. The authors delve into key theories regarding the microbiome within the oral cavity and gut in relation to these conditions. Furthermore, based on research, they suggest potential clinical applications and highlight knowledge gaps.
Microbiome dysbiosis in ME/CFS and long COVID
While acute infections can trigger microbial dysbiosis, changes in the microscopic community tend to reverse, to a certain extent, over time in most individuals. This has been demonstrated in a longitudinal study which followed patients with COVID-19 over a year, and revealed a gradual recovery in oral and gut microbiomes in the majority. Despite this, persistent microbiome dysbiosis has been found in those with long COVID; i.e., those with persistent symptoms have persistent gut changes.
While the COVID-19 pandemic has provided more opportunities to study individuals from the onset of infection to recovery (or lack thereof, in the case of long COVID), previously acquired knowledge about the microbiome in patients with ME/CFS has proven invaluable. Several studies have shown clear distinctions in the gut microbiome in people with ME/CFS compared with healthy controls. Notably, reductions in the gut bacteria Eubacterium rectale and Faecalibacterium prausnitzii in ME/CFS have been demonstrated, with lower levels of the latter potentially linked to increased fatigue severity. Similarly, both species have been found to be reduced in long COVID, alongside reductions in other commensal bacteria (bacteria which are helpful to the body in the right quantities).
The theories
The authors acknowledge that our current understanding of how infection leads to microbiome dysbiosis is inadequate, citing only one study linking alterations in the microbiome with immune-mediated loss of appetite in mice. While it also remains unexplained why some individuals fail to recover from acute infections with a continuing microbiome dysbiosis, the authors propose potential mechanisms based on research.
Persistent pathogens
Alongside other infectious agents, viruses may stick around in the body even after the initial symptoms fade. As viruses often play a role in inflammation and other complex pathways, these lingering pathogens might continue to interfere with the microbiome and trigger prolonged illness. Studies have found enterovirus-related substances in individuals with ME/CFS years after diagnosis, ‘suggesting at least a subgroup of ME/CFS is caused by enterovirus infection’. Additionally, the prolonged presence of SARS-CoV-2 (the cause of COVID-19) has been shown to contribute to degradation of the gut barrier which could potentially be implicated in microbial dysbiosis.
Additional infections
What is worse than one infection? Multiple infections. Co-infection with human herpesvirus (HHV) has been frequently reported in ME/CFS, including Epstein-Barr virus (EBV) – a type of herpesvirus. Likewise, the authors mention that SARS-CoV-2 infection often coincides with the reactivation of dormant viruses such as these and opportunistic bacterial pathogens. Mounting evidence shows that co-infections and secondary infections can worsen or prolong symptoms. Potentially this could be a result of additional infections causing further alterations in the microbiome, although more research is needed to determine if this is causation rather than correlation.
Gut-brain connection
The gut and the brain communicate via the gut-brain axis (GBA) – a two-way communication system involving neural, hormonal and immunological pathways that impact on overall health. The authors state “given that over 70% of both microorganisms and immune cells reside in the intestinal tract, it is tempting to speculate on the critical role microbiome plays in modulating GBA pathway in PAIS”. They propose that changes in the gut microbiome could lead to signals being sent to the brain that lead to inflammation and the neurological symptoms seen in ME/CFS and long COVID. One justification for this theory is that many of the gut bacterial species altered in PAIS have immunomodulatory properties, which can affect levels of inflammation in the body.
Potential management
Based on the research reviewed, the authors propose potential strategies for rebalancing the microbiome to alleviate the symptoms of conditions such as ME/CFS and long COVID. However, it is important to note that these approaches should be considered with caution, as the exact nature of the link between microbiome dysbiosis and the development of these conditions is still to be determined. It is also worth mentioning that none of these treatments have been recommended by NICE.
Some approaches under consideration include the following:
Probiotics
Probiotics are beneficial (live) microorganisms commonly introduced into the body through consumption or supplements. When ingested in sufficient quantities, they potentially help to balance out the community of microorganisms in the gut. While there has been a randomised, controlled trial that demonstrated a positive effect on symptoms of long COVID, similar studies for ME/CFS are inconclusive due to overall poor study quality.
Faecal transplants
A faecal transplant is exactly what is sounds like – transferring donated faeces (i.e., stool) from one individual to another in order to share beneficial microorganisms and encourage rebalancing of the gut microbiome. This has achieved impressive therapeutic effects for recurrent Clostridium difficile infection, and meanwhile randomised, controlled trials are underway which could shed light on whether faecal transplants are useful for ME/CFS and long COVID.
Antibiotics
Due to the possibility of bacterial co-infection, using antibiotics in the management of PAIS seems like a reasonable idea, and indeed antibiotics were frequently prescribed to acutely unwell COVID-19 patients. However, the authors summarise why antibiotic usage is contentious: “Antibiotic usage can eliminate bacterial pathogens while also affecting the normal symbiotic microbiota, and excessive use can lead to increased bacterial resistance and dysbiosis of the microbiota.” In other words, in an attempt to get rid of ‘bad’ bacteria, ‘good’ bacteria and the gut microbiome balance could be adversely affected.
Repurposing medication
Research shows that metformin, a medication usually prescribed for diabetes, alters the gut microbiome. Accordingly, the authors cite a recent study that “revealed that the administration of metformin induced a 42% reduction in COVID-19 sequelae relative to controls”. However, it should be noted that the paper is yet to be peer-reviewed. ME Research UK has previously funded research related to the use of metformin in ME/CFS.
Conclusion
While microbiome dysbiosis is evident in ME/CFS and long COVID, we are still uncovering whether this is a cause or a consequence of these conditions. Furthermore, potential management approaches require further investigation and careful consideration. The microbiome holds promise for those affected by ME/CFS and long COVID, however more research is needed.
Funded by ME Research UK, Dr Amy Proal and her team are using new computer-based technologies to search for viruses – such as polio-type enteroviruses and herpesviruses – which may hide out in the tissues and nerves of people with ME/CFS. ME Research UK will be providing progress updates about this study.
