Immunosuppression in ME may underlie energy deficits that drive ME symptomology

Interview of Dr. Armin Alaedini by Bronc

In October of 2023 the UK the Department of Health and Social Care held a public consultation to improve the care/life outcomes for people with ME. It included an acknowledgement that there has been a lack of biomedical research into ME but failed to accept the very negative impact this has had on the lives of people living with the illness. It also failed to point the finger at those responsible for this which includes the National Institute of Clinical Excellence and the Medical Research Council amongst others.

Despite calling for more research into ME there is acknowledgement that this will need substantial sums of money for this to happen. The DHSC consultation also asked for views about its plans which included a section about disability benefits and how the Department of Work and Pensions wants to improve the service it provides to those people who claim disability benefits. This laughable comment ignores the war on people claiming disability benefits which has been waged by the DWP since 2010. To compound matters the British government recently announced that it wants to make it harder for people to claim disability benefits and snoop on their bank accounts.

The DWP has consistently failed to acknowledge the debilitating nature of ME and instead focuses on the fluctuating nature of the illness to deny many people with ME disability benefits such as ESA and PIP.

Thankfully, there is plenty of evidence revealing how people with ME suffer from a suppressed immune response which accounts for many of the debilitating symptoms of the illness.

I recently talked with Dr. Armin Alaedini about his recent research into this issue. Dr Alaedini is an assistant professor at Columbia University and principal investigator at the Alaedini Lab. Its research is aimed at identifying ‘novel biomarkers, understanding disease mechanism, and finding therapeutic targets in gastrointestinal and neuropsychiatric disease.’ He is chair of ME/CFS Biospecimen Resource Access Committee at the National Institute of Neurological Disorders and Stroke and a member of the Neurobiology of Pain Study Section at NIH.

Dr Alaedini took time out of his busy schedule to talk to me about his research into ME.

How did you get involved in the field of ME research?

I have always been interested in the study of complex medical conditions, especially those that are poorly understood and understudied. I became specifically involved in ME research because of my acquaintance with Dr. Suzanne Vernon, who at that time was the chief scientific officer at The Solve ME/CFS Initiative. I was fortunate to have her support for a NIH-funded project, which resulted in our recent publication that demonstrates how microbial translocation links gastrointestinal, immunologic, and metabolic defects in ME/CFS.

In the paper you co-authored, Suppressed immune and metabolic responses to intestinal damage-associated microbial translocation in myalgic encephalomyelitis/chronic fatigue syndrome, it notes that the relationship between immunologic, metabolic and gastrointestinal abnormalities remains unclear. In your study you examined two groups of people with ME: one at rest and one undergoing an exercise challenge. They were compared to a group of healthy people. Can you explain what differences you noted between the healthy control group and the people with ME and between the two groups of people with ME? What may have caused this elevated antibody response to microbial agents in people with ME?

I had been particularly intrigued by the fact that gastrointestinal complaints are common in ME/CFS. Data from the patients in our study clearly confirmed this, showing that gastrointestinal symptoms were indeed much more common and more severe in ME/CFS study participants than in the non-ME/CFS controls. Along with this, we found a specific marker of injury or damage to the intestinal lining, called FABP2, to be higher in the blood of ME/CFS participants than in controls, providing a potential biological link to least some of the associated gastrointestinal symptoms. Increased intestinal permeability due to damage can lead to greater translocation of dietary and microbial antigens, which are typically constrained within the gut lumen, across the intestinal barrier. This, in turn, may result in an immune response to those translocated dietary and microbial products to counter and remove the potentially inflammatory antigens from systemic circulation.

Indeed, our data pointed to a significant increase in antibody responses to microbial and dietary antigens in ME/CFS patients in comparison to controls. What especially surprised us, however, was the fact that we did not observe an expected rise in the more immediate, or what we call “acute-phase”, innate immune responses. Specifically, we found that despite the increased markers of intestinal damage and higher antibody responses, ME/CFS patients did not exhibit a significant acute-phase immune response to counter circulating microbial products. This was suggestive of a suppressed systemic immune response that could possibly explain some of the ME/CFS symptoms.

Your study also noted ‘Enhanced antibody response to dietary antigens in ME/CFS’. What might be causing this?

The antibody response to dietary antigens is likely part of the same process resulting from a dysfunctional intestinal barrier that results in an enhanced immune response to the contents of the gut lumen. These would include both microbial and dietary antigens that the immune system is generally tolerant to and does not mount a significant antibody response against under normal conditions.

People with ME suffer from post exertion malaise which means that exercise will exacerbate their symptoms. What differences did you note between the healthy participants and people with ME who took the exercise challenge? What might be causing the differences in their response to exercise?

Intense exercise is known to cause increased intestinal permeability. Therefore, a maximal exercise challenge can be a particularly useful tool to better understand the effect of gut barrier function on the dysfunctional immune responses we were seeing in the ME/CFS cohort. The data from the exercise challenge confirmed our earlier data, suggesting that ME/CFS patients have a dysfunctional immune response, characterized by a suppressed innate/acute-phase response that is ineffective at countering microbial translocation from the intestinal tract into systemic circulation.

At the same time, another part of the immune response, the adaptive immune system, tries to compensate for this dysfunction by producing antibodies against those microbial antigens. However, the antibody response appears to be inadequate, as the ME/CFS patients continued to have increased circulating microbial antigens. We hypothesize that these microbial antigens can trigger downstream inflammatory responses that impact the central nervous system and may contribute to some of the hallmark symptoms of ME/CFS, such as fatigue.

We also compared metabolic responses in response to exercise between ME/CFS and control study participants. Of particular significance, we found a suppression of glucose and citrate metabolic responses in ME/CFS that to some extent correlated with the suppressed innate immune responses in these patients. This dysfunctional metabolic response is not only conceivably capable of contributing to the observed immunosuppression in ME/CFS, but it may also further underlie energy deficits that drive ME/CFS symptomology.

In your study you observed an increase in antibody responses to both microbial and dietary antigens, reflecting greater epithelial cell damage, which point to enhanced translocation of gut luminal antigens across a compromised intestinal barrier in ME/CFS. Did your findings point to a possible treatment for this damage to the intestinal barrier?

Indeed, the data point to a number of potential targets to consider for therapy in the context of ME/CFS. These include reducing or repairing the intestinal damage in order to decrease the microbial translocation; blocking or sequestering the already translocated microbial antigens; reversing the identified defects in the acute-phase immune responses towards the microbial antigens, and targeting the suppressed metabolic pathways.

What further research is needed to address the issues highlighted in your study?

More research is needed to better understand the relevance and level of contribution of the identified defects in the intestinal barrier, immune response, and metabolic pathways to ME/CFS symptomology, as well as to further characterize the molecular pathways involved, in order to move this research closer to development of effective treatments for ME/CFS.