The relationship between the microbiome and the immune system in ME/CFS has been getting more and more attention.
The microbiome comprises trillions of microbes largely residing in the gut, and it plays a pivotal role in health and disease. But, despite its significance, further exploration is needed to understand whether the microbiome is involved in the development of ME/CFS. Furthermore, people with severe and very severe ME/CFS are disproportionately overlooked and under-represented in research. This is why recent research by Dr Seton and colleagues at the Quadram Institute is particularly welcome.
Recruiting individuals with severe and very severe ME/CFS for studies is essential for understanding the full spectrum of ME/CFS and exploring potential variations in disease mechanisms. On the other hand, it is challenging because, regardless of whether individuals are willing to take part, it may not always be possible. This may be because of functional impairments hindering their ability to participate in research activities, the logistical difficulty of reaching those often unable to leave their homes, and the presence of multiple comorbidities making it harder to distinguish the effects of ME/CFS from those of other health conditions.
Making steps towards providing more research into severe ME/CFS, Dr Seton and colleagues chose to investigate the reactivity of antibodies to the gut microbiome in individuals with severe ME/CFS in comparison to matched household controls (people without the condition who live in the same household). Their pilot study essentially explored the relationship between the gut microbiome and immune dysfunction in relation to ME/CFS.
Whilst the study contributes to the limited body of research on severe ME/CFS, the challenges of recruiting patients with severe ME/CFS in addition to other limitations make it difficult to draw firm conclusions from the study findings. Nevertheless, this should not deter future researchers from studying severe and very severe ME/CFS as these subgroups deserve attention, and understanding the severe end of the spectrum could provide valuable insights about ME/CFS as a whole.
What did the study do?
The pilot study aimed to test the hypothesis that ME/CFS develops as a result of increased intestinal permeability – i.e. a leaky gut – leading to the movement of microbes from the gut into the blood circulation, triggering the immune system to produce antibodies against the body’s own gut microbes.
Specifically, the researchers examined the reactivity of certain antibodies in the blood to microbes in stool, comparing individuals with severe ME/CFS with healthy controls. The antibodies of interest were immunoglobulin A (IgA) and immunoglobulin G (IgG), both of which play vital roles in immune responses.
A secondary objective of the study was to “assess the feasibility and identify potential barriers to including severe ME/CFS patients in research”.
Recruitment began in October 2017, aiming to recruit ten severe house- or bed-bound individuals with ME/CFS; however, recruitment concluded in April 2020 due to the COVID-19 pandemic, with only half of the intended number of individuals enrolled.
Overall, the study recruited five pairs of participants – five with severe ME/CFS and five household controls. According to the researchers, participants with ME/CFS had a confirmed diagnosis based on a hybrid of the NICE 2007 guideline and the Fukuda criteria. It must be noted that neither criteria mandates the presence of post-exertional malaise (PEM), the cardinal feature of ME/CFS; however, this is not to say that the participants did not experience PEM, rather that it was not mentioned in the paper.
The rationale for using individuals living in the same environment as controls was that it could make it easier to identify microbiome changes related to ME/CFS by minimising external influences such as living conditions and diet. However, the study acknowledges that there were limitations perpetuated by this approach, including not matching for age and gender, which are potentially confounding factors in immunological and microbiome-related research. Furthermore, irritable bowel syndrome (IBS) was reported in all individuals with ME/CFS but in none of their household controls.
During a home visit, stool samples and blood samples were obtained from each participant. The serum (liquid part of blood) was separated out to isolate antibodies for assessment. Stool samples from the ME/CFS participants were compared to healthy control samples to determine the proportion of IgA antibody-coated microbes. The presence of antibody-coated microbes in stool shows that the immune system is recognising and reacting to microbes in the gut.
Subsequently, the researchers explored how serum IgG antibodies from individuals with ME/CFS reacted to their own stool microbes and those of their household controls, and vice versa. Following exposure, the researchers measured the proportion of IgG antibody-coated microbes.
Additionally, they assessed stool consistency and explored the stool microbiome, in terms of both microbial species diversity and genetic makeup.
What did they find?
The primary finding of the study was that, in comparison to healthy controls, individuals with severe ME/CFS have differences in how their immune system responds to their own gut microbes and the gut microbes of others.
Reacting to own stool microbes
- Participants with ME/CFS had fewer IgG antibodies responding to their own stool microbes compared with household controls. The researchers mention that these reduced responses were not due to lower levels of serum IgG overall in individuals with ME/CFS.
Reacting to other’s stool microbes
- Participants with ME/CFS had fewer IgG antibodies responding to stool microbes from their matched household counterpart compared with healthy controls.
- Overall, healthy controls had more IgG antibodies responding to stool microbes than individuals with ME/CFS. Furthermore, IgG antibodies from controls responded more to ME/CFS stool microbes than ME/CFS antibodies responded to their own stool microbes.
Similarities
Individuals with severe ME/CFS and their household controls also displayed similarities. Despite the presence of IBS in the ME/CFS cohort, there were no significant differences in stool consistency compared with controls. Analysis of IgA antibody in the stool revealed that there were no substantial distinctions between the two groups, which could indicate certain aspects of the immune response are similar in ME/CFS compared to healthy individuals. In ME/CFS, despite a reduced amount of IgG binding to each microbe, the proportion of microbes bound by antibodies (i.e. the overall coverage of the microbiome) was similar to controls.
Overall, these results seem to imply that, whilst the immune system of people with severe ME/CFS recognise a similar proportion of microbes as healthy individuals, the immune response mounted is weaker.
Discussion
Contrary to the initial hypothesis, the pilot study indicates that individuals with severe ME/CFS exhibit immune dysfunction showing a reduced ability of certain antibodies (IgG) to respond to microbes in the gut. Despite forming part of the hypothesis, the researchers state, “the presence of increased intestinal permeability within the severe ME/CFS patient cohort was not investigated in the present study”.
This study is not without its limitations and confounding factors that warrant careful consideration. The small sample size affects the generalisability of the findings, and the inclusion of participants with comorbidities adds complexity to isolating ME/CFS-specific effects. The limited control group, comprised solely of one household control per participant with ME/CFS, may restrict the ability to draw broader comparisons. Additionally, there were challenges in achieving precise matching (e.g. age and gender) between individuals with ME/CFS and their household controls – factors which are known to confound findings.
The researchers themselves acknowledge several limitations of the study and the challenges of studying individuals with severe ME/CFS, and additionally underscore the importance of refining methods for future research to improve understanding of severe ME/CFS.
ME Research UK is currently funding more research at the Quadram Institute exploring the microbiome in ME/CFS.
