Leaky gut and the immune system in ME/CFS

Key points

• Individuals with ME/CFS may have a compromised intestinal barrier – so-called ‘leaky gut syndrome’ – where harmful agents more easily escape from the gut into the bloodstream.
• A recent study explored immune responses potentially linked to a compromised intestinal barrier in ME/CFS.
• The researchers analysed blood samples from two cohorts – one at rest and another undergoing rigorous exercise testing. They looked for substances such as antibodies, inflammation markers, intestinal damage markers and signalling proteins.
• Patients with ME/CFS had higher antibody responses and indicators of gut damage.
• Following exercise, acute immune responses were suppressed in patients with ME/CFS, but compensatory mechanisms were noted.
• The altered immune responses to harmful agents demonstrated in the patients with ME/CFS may explain the increased susceptibility to infection reported by many individuals with ME/CFS.
• Furthermore, the study findings may also shed light on why individuals with ME/CFS  experience worsening of symptoms – such as fatigue, cognitive changes, headaches and nausea – following exertion.
• This study provides a useful foundation for further, larger-scale studies in the field, advancing our understanding of this debilitating condition.

Background

The intestines (i.e. the gut) have a protective lining known as the intestinal barrier. The intestinal barrier acts as a filter allowing essential nutrients from food to enter the bloodstream but preventing pathogens, such as harmful bacteria, from making the crossing. It has been suggested that people with ME/CFS may have alterations to this barrier, making it easier for pathogens to enter the blood circulation – a concept termed ‘leaky gut syndrome’, where pathogens ‘leak’ from the gut into the blood due to a compromised intestinal barrier.

In a ‘healthy’ individual, if a pathogen enters the bloodstream, the immune system reacts to protect the body in a manner that is proportional to the level of threat. Dr Melanie Uhde and colleagues recently explored how the immune system in individuals with ME/CFS responds to pathogens potentially entering the circulation via a compromised intestinal barrier.

What were the aims of the study?

The researchers aimed to:

1. Investigate whether ME/CFS is linked to specific immune responses that may arise due to a compromised intestinal barrier and the movement of microbes – such as bacteria – across the gut lining into the bloodstream.
2. Examine whether patients with ME/CFS exhibit more damage to the gut lining, potentially leading to more microbes entering the bloodstream.
3. Study whether and how immune responses are influenced by intense exercise, which is known to increase gut permeability and movement of microbes.
4. Analyse differences in how the body processes energy (metabolic differences) during exercise to gain insights into immune responses related to gut permeability and microbial movement in ME/CFS.

What were the methods?

The study had two main groups of participants. The first group had 131 individuals with ME/CFS and 86 healthy control participants. Individuals with ME/CFS in this group met both the Canadian Consensus Criteria (CCC)and the Fukuda criteria, and demonstrated a reduced quality of life based on the RAND-36 health-related quality of life survey.

The second group was much smaller and included 9 individuals with ME/CFS and 7 healthy control participants who underwent a maximum exercise challenge. Whilst the paper refers to patients within this group as having ME/CFS, they use the Fukuda criteria which is intended for classifying chronic fatigue syndrome (CFS) and does not require the presence of post-exertional malaise.

The researchers used specific tests to measure various components in the blood of the participants.

1. Antibodies against bacterial components – Blood levels of antibodies (IgG, IgA and IgM) against bacterial flagellin and bacterial lipopolysaccharide (LPS) – components of bacteria – were measured. Antibodies are proteins within the immune system that help to clear away pathogens, hence measuring the aforementioned antibodies allows the researchers to understand how the immune system is interacting with bacteria.
2. Markers of acute inflammation/immune response – Inflammation is the way the immune system initially responds to infection. Levels of inflammatory markers, lipopolysaccharide binding protein (LBP) and soluble CD14 (sCD14), were measured in order to provide information about the immediate (acute) responses of the immune system to bacteria.
3. Markers of intestinal damage – Blood levels of intestinal fatty acid-binding protein (FABP2), a specific marker of intestinal cell damage, were measured to assess if the integrity of the intestinal barrier is compromised.
4. Antibodies against dietary components – According to the researchers, gliadin (a protein in wheat) and casein (a protein in milk) are two of the most frequently found and commonly consumed dietary proteins. The researchers measured IgG, IgA and IgM produced against gliadin and casein to identify if these proteins were crossing the gut lining and eliciting an immune response. 
5. Signalling proteins – Concentrations of cytokines (IL-10, IFN-γ and TNF-α) were measured. These cytokines are signalling proteins pivotal in immune and inflammatory responses in the body.
6. Products of metabolism – A comprehensive analysis of metabolites – substances involved in or produced during metabolism – was performed. This included glucose and citrate, crucial for the generation of energy during intense exercise and for proper functioning of particular immune responses.

What did they find?

The researchers found increased antibody responses to both bacterial and dietary components, and higher expression of FABP2 in individuals with ME/CFS compared with healthy controls. These findings suggest increased levels of gut damage and enhanced movement of antigens (substances which trigger the immune system) across the intestinal barrier in ME/CFS.

Due to the increase in antibodies and markers of intestinal damage, the researchers also expected a rise in markers of acute inflammation (LBP and sCD14). However, there were no significant differences in markers of acute inflammation in patients with ME/CFS compared with healthy controls. In a previous study on the same cohorts, the researchers similarly found no significant difference between patients with ME/CFS and controls in relation to levels of C-reactive protein (CRP), another highly sensitive marker of acute inflammatory response. They speculated that these findings may either be due to limited movement of microbes across the gut lining at the time of the blood collection or a defect in certain acute immune responses in ME/CFS.

To explore these possibilities, the researchers examined the cohort undergoing the intense exercise challenge. According to the researchers, endurance exercise in healthy adults is known to increase intestinal permeability which in turn increases the movement of microbes from the gut into the circulation, subsequently resulting in systemic activation of the immune system. As expected, the maximal exercise challenge resulted in a significant increase in markers of acute inflammation in the control group. However, a similar increase was lacking in patients with ME/CFS, reinforcing the notion of a suppressed acute immune response that struggles to deal with circulating microbes.

On the other hand, an increased IgM antibody response to dietary and microbial components was observed in the ME/CFS cohort, in contrast to a more muted response in the control group. The researchers speculate that this increased antibody response could be a compensatory mechanism to address the insufficient acute immune response linked to LBP and sCD14.

It was noted that levels of the signalling protein, IL-10, increased significantly in response to exercise in the patients with ME/CFS but not in the healthy control participants. IL-10 is primarily an anti-inflammatory cytokine which helps in regulating immune system responses. The researchers further speculated whether the observed increase in IL-10 levels in ME/CFS during maximal exercise could be part of a mechanism to limit the inflammatory reaction triggered by circulating microbes (mediated by LBP and sCD14), whilst enhancing antibody-mediated clearance of microbial and dietary antigens. They also thought that an observed lack of exercise-induced elevation in glucose and citrate levels in the group of patients with ME/CFS, as opposed to the control group, could be tied in with this process.

Discussion

In summary, the study investigated how ME/CFS is linked to altered immune responses and compromised intestinal barrier integrity. Individuals with ME/CFS displayed increased antibody responses to microbes and dietary components, alongside higher levels of intestinal damage markers, indicating a compromised, i.e. leaky, intestinal barrier. 

The exercise challenge demonstrated that patients with ME/CFS had a suppressed acute immune response compared with healthy control participants. However, the heightened IgM antibody response and elevated levels of the anti-inflammatory cytokine IL-10, and related metabolic changes, during exercise suggest compensatory mechanisms to the weakened acute immune response.

Interestingly, the researchers imply that the study findings could be highly relevant to the clinical history and presentation of ME/CFS. Individuals with ME/CFS often report susceptibility to infections – a feature that could be indicative of an altered immune system. Additionally, they mention that the findings could be highly relevant to the symptomatic response to exertion in ME/CFS as certain symptoms of endotoxaemia (elevated blood levels of bacterial LPS) such as fatigue, cognitive changes, nausea and headache mirror those reported by individuals with ME/CFS during post-exertional malaise (PEM).

The researchers acknowledge the study limitations, most notably for the exercise challenge cohort which had a small sample size and used the Fukuda criteria to recruit patients. Nevertheless, this study deepens our understanding of the immune system and gut in relation to ME/CFS and provides a useful foundation for future larger-scale studies.