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Health Rising covered this fascinating gut/immune/metabolic study in an earlier blog. Now Bronc is back with an interview with Dr. Armin Alaedini – the senior author of this study. Note that we just covered a study suggesting that the gut could play a major role in the low serotonin levels, ACE2 dysregulation, and at least some of the autonomic nervous system and immune issues in ME/CFS. 

The “Serotonin Surprise”: Massive Study Suggests Low Serotonin is Key Factor in Long COVID and Post-Infectious Diseases

First, Bronc, a patient in the UK, gives us a brief update on the situation with the health service there, and then dives into the Alaedini interview.

Update From the UK

Here in the UK, the Department of Health and Social Care has announced a plan to improve the care provided to people with ME. It includes an acknowledgment that there has been a lack of biomedical research into ME but fails to acknowledge the very negative impact this has had on the lives of people living with the illness. It also fails to point the finger at those responsible for this – the National Institute of Clinical Excellence, and the Medical Research Council amongst others. It’s also one thing to call for more research into ME – as has been done – it’s quite another to provide the substantial sums of funding needed to accomplish that – and that has not happened.

At the same time, the DHSC has issued a consultation asking for views about the plan which includes a section about disability benefits and how the Department of Work and Pensions can improve the service it provides to those people who claim disability benefits. This tragically laughable comment ignores the war the DWP has waged on people claiming disability benefits since 2010. 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. To compound matters, the British government recently announced that it wants to make it harder for people to claim disability benefits.

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.

Suppressed Immune Response Could Account for Many of the Debilitating Symptoms of ME – An Interview with Armin Alaedini

Armin Alaedini

Dr. Alaedini has published 4 studies on gut issues in ME/CFS.

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 mechanisms, and finding therapeutic targets in gastrointestinal and neuropsychiatric diseases.

He is also the chair of the 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. He’s the senior author of 4 ME/CFS gut studies.

Dr Alaedini took time out of his busy schedule to talk to Bronc from Phoenix Rising about his research into ME, but first, check out what Suzanne Vernon – a co-author of the study – wrote on the Bateman Horne Center website about how the study happened. The genesis of this study, which dates back to 2009 – and the formation of the Solve ME/CFS Biobank – demonstrates why the Biobank and efforts like DecodeME can be so helpful.

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Suzanne Vernon on the Genesis of This Study

Suzanne Vernon PhD

Intrigued by Alaedini’s work on post-Lyme Disease, in 2009, Suzanne Vernon – one of the study co-authors – asked him to collaborate on an ME/CFS study. Alaedini used some of the samples from that study for the 2023 study.

I met Armin Alaedini in 2008 at a meeting in San Francisco that was about solutions for Lyme and other tick-borne diseases through cutting-edge science. I was fascinated by his presentation on immunological findings in post-treatment Lyme disease and I approached him about collaborating on ME/CFS.

 

At this time, I had just started as the scientific director at the CFIDS Association, now Solve, and had the idea to set up a biobank of ME/CFS samples as a resource to drive and advance cutting-edge ME/CFS science. One year later, the biobank was jumpstarted because Science magazine published the paper describing an infectious retrovirus in the blood of ME/CFS patients.

 

Within days of that paper being published, blood banks and pharmaceutical companies were in search of blood samples from ME/CFS patients in order to validate the findings, develop tests and treatments. This motivated a collaboration between Solve and 5 ME/CFS clinical centers to collect blood samples from their well-characterized patient populations for biobanking and distribution to blood banks and pharma.  Since that time, those precious blood samples have been used in multiple research studies (including this one).

 

In one of our first collaborations, Dr. Alaedini and his team at Columbia examined ME/CFS blood samples for signs of inflammationNot finding evidence of inflammatory markers in ME/CFS, he suspected a defect in specific acute-phase immune responses in ME/CFS or a lack of the instigating microbes at the time of the blood draw. 

 

To test this, he tapped into two different studies that had blood samples. The first were those 2009 blood samples from the SolveCFS BioBank that included 131 ME/CFS samples and 86 healthy control samples. The second were blood samples from a study led by Sanjay Shukla and Dane CookThis super cool study (“Suppresssed immune and metabolic responses to intestinal damage-associated microbial translocation in myalgic encephalomyelitis/chronic fatigue syndrome“)used an exercise challenge to show that there was an increase in bacterial translocation into the blood and slower clearance from the blood following exercise in ME/CFS patients.

 

The result of this impressive collaborative research study is a compelling explanation for what could be causing PEM.

Check out the earlier study that this one built on.

Exercise Triggers Gut Changes in Chronic Fatigue Syndrome (ME/CFS)

The Armin Alaedini Interview

  • Antigen – any foreign substance that evokes an immune response in the body. Dietary antigen – a food particle that sparks an immune response; bacterial antigen – a bacterial particle that does the same. It’s usually the immune response that does the damage.
  • Increased gut permeability – leaky gut; where the barrier between the gut and body breaks down – releasing bacteria and food particles into the bloodstream – causing an immune response.
  • Bacterial and dietary translocation – the movement of gut bacteria and food particles through the gut wall into the bloodstream.
  • Innate immune responses – the quickest immune response to damage or pathogen entry. Often associated with inflammation.

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 an NIH-funded project, which resulted in our recent publication that demonstrates how microbial translocation links gastrointestinal, immunologic, and metabolic defects in ME/CFS.

2) In the paper you co-authored, “Suppresssed 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 at 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.

3) Your study also noted you found an ‘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.

4) People with ME suffer from post-exertional 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.

Exercise Triggers Gut Changes in Chronic Fatigue Syndrome (ME/CFS)

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.

Our data pointed to defects in specific metabolic responses involved in energy production, as well as in specific acute-phase innate immune responses that are supposed to counter microbial translocation by removing circulating LPS and other microbial components from blood.

But more interestingly, the suppression of these responses (metabolic and immunologic) correlated, suggesting a relationship or interaction between them that gives potential clues regarding causality. There is, in fact, prior data showing that suppressed glucose and citrate metabolic responses have a direct negative impact on innate immune responses.

Interestingly, those same metabolic responses in our study participants also correlated negatively with IL-10, an immunoregulatory cytokine that is known to be expressed in response to microbial products through different signaling pathways and to be particularly important as a key mediator of intestinal immune homeostasis.

We believe that the observed increase in IL-10 levels in ME/CFS during exercise limits the inflammatory reaction triggered by circulating microbial products, while enhancing the antibody-mediated clearance of translocated microbial and dietary antigens, as was clearly seen in our study.

There is also data from previous studies indicating that glucose deprivation can upregulate IL-10 production. So, there seems to be a mechanism here whereby the suppression of metabolic responses involved in energy production not only directly dampens the innate immune cell function, but it also enhances IL-10 production, which further limits the expression of acute-phase immune responses that are meant to counteract microbial translocation.

There is data from other studies indicating that uncontrolled microbial translocation is associated with neuroinflammation and cognitive dysfunction in the context of other conditions. This is important, because brain imaging studies in ME/CFS are in fact suggestive of low-level neuroinflammation and altered brain function in conjunction with impaired cognitive performance and other associated symptoms, including in response to exercise.

Major Study Links Gut Bacteria to Fatigue in Chronic Fatigue Syndrome (ME/CFS)

5) 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 (movement) 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.

Indeed, it may include medications directed at the targets I previously mentioned, such as specific immunomodulatory agents, or inhibitors of intestinal barrier dysfunction, or activators that reverse the observed metabolic dysfunction.

As we don’t yet fully understand the cause-and-effect relationship between these potential immune, gut, and metabolic targets, more research is needed to better characterize the interaction between them in order to move this research toward the development of effective therapies.

Dietary approaches can certainly be envisioned to have a role in treatment because diet can impact the specific pathways involved. For example, dietary change alters the gut microbial population, which can lead to positive changes in gut barrier function, or it can lead to the production of certain metabolites by the gut bacteria that potentially counteract energy-producing metabolic dysfunction in the body.

6) 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.

The article suggested that endotoxemia (the presence of bacterial toxins in the blood) could be causing many symptoms in ME/CFS. If endotoxemia is present in ME/CFS, what would it take to show that?

We already have direct data pointing to low-grade endotoxemia in ME/CFS. In the recent study we published, we not only showed an increased immune response to microbial antigens but also increased levels of LPS in response to exercise in ME/CFS patients compared with healthy controls. Other groups have also shown increased microbial products, like bacterial DNA, in ME/CFS.

Taken together, the data point to low-grade endotoxemia that may explain many of the symptoms associated with ME/CFS, such as fatigue and flu-like symptoms.

The GIST

  • Thanks to Bronc from Phoenix RIsing for allowing Health Rising to post his interview with Dr. Armin Alaedini. Dr. Alaedini recently published a remarkable study suggesting that problems in the immune system, the gut, and the metabolism could be “conspiring” together to produce post-exertional malaise in ME/CFS
  • Using samples stored in the Solve ME Biobank, some of which dated back to 2009 and the XMRV saga,  this study took a deep dive into the immune system, the gut, and the metabolism.
  • The results made it clear that exercise was indeed causing ME/CFS patients’ guts to leak – spilling gut bacteria and food contents into the blood. As that happened, one side of the immune system – the antibodies – leapt into action. Another side, though, the early inflammatory immune response did not.
  • Plus an anti-inflammatory factor called IL-10 that knocks down the early immune response and interferes with glucose metabolism was elevated in ME/CFS – setting the stage for impaired energy production.
  • This study found that while exercise significantly increased the levels of two key energy factors (citrate, glucose) that power the early immune response in the healthy controls, it did not do so in ME/CFS.
  • That suggested that the early immune response against the bacterial invaders simply didn’t have the energy to get going in ME/CFS. That lapse in protection allowed toxic bacteria to persist in the bloodstream in people with ME/CFS.
  • The findings suggested, then, that a metabolic breakdown that hobbled the early immune response allowed high levels of bacteria to persist in the bloodstream of people with ME/CFS after exercise. That produced a condition called “endotoxemia” whose symptoms (fatigue, cognitive changes, headache, nausea, increases in heart rate, and decreases in blood pressure) bear some similarity to ME/CFS.
  • More study needs to be done, but Dr. Alaedini proposed that if his hypothesis is shown to be true immunomodulatory agents, inhibitors of intestinal barrier dysfunction, or drugs that reverse the observed metabolic dysfunction could be helpful.
  • Dr. Alaedini is currently attempting to secure funding in three areas: exploring defects in gut barrier function and gut immune response, developing an animal model that mimics the gut-immune-metabolic dysfunction they identified, and exploring the gut-immune-metabolic axis in post-infection syndromes such as long COVID and Lyme disease.

If metabolic problems are the driving force behind the IL-10 upregulation, the inhibited immune response to gut bacteria in the bloodstream, endotoxemia, and possibly neuroinflammation, what would be the next steps in figuring out what the metabolic problems are – and how to solve them?

Metabolic defects appear to be contributing to the dysfunction in the immune response to bacterial translocation and endotoxemia through the mechanism we describe in the paper. However, we believe that the root cause of the endotoxemia lies in gastrointestinal dysfunction.

Our data point to multiple potential therapeutic targets for ME/CFS to explore at the levels of metabolic, immune, and gut barrier function. Several previous studies have identified mitochondrial abnormalities in ME/CFS (which may underlie the metabolic dysfunction and energy deficits).

To move forward, we need better-controlled human studies and relevant animal models to replicate prior studies and better understand if and how they might contribute to ME/CFS symptoms. In other words, we need studies directed at delineating the cause-and-effect relationship between the observed metabolic dysfunction on the one hand and the ME/CFS-associated symptomatic response on the other.

These may include characterizing the potential genetic and proteomic underpinnings of the observed metabolic deficits, the integrity of the gut barrier function at the cellular and molecular level, and the mucosal immune response at the cellular and molecular level (both adaptive and innate).

What are your next moves? Have you tried to get a larger study funded, and if so, how did that go? Are you doing any other work on ME/CFS or related diseases?

We are currently seeking more funding for studies in three areas in particular. One is to focus on the gastrointestinal system and specifically on the defects in gut barrier function and gut immune response in ME/CFS through the direct study of the gastrointestinal tract in patients (i.e., going far beyond just blood work). As part of this, we’re also seeking to understand the relevance of food sensitivity/intolerance, given its high prevalence among ME/CFS patients.

Additionally, we would like to develop an animal behavioral model that recapitulates the specific gut-immune-metabolic dysfunction that we’ve identified in ME/CFS patients in our recent study. The development of a relevant animal model of ME/CFS may greatly advance our understanding of ME/CFS and aid in the development of therapeutics.

Finally, we’re interested in exploring how ME/CFS and post-infection syndromes, like those occurring after COVID and Lyme disease, are related by exploring the same gut-immune-metabolic axis in those patients. Ultimately, the mechanisms and the potential diagnostic tools and therapeutics developed for ME/CFS may be relevant and applicable to subsets of patients with various post-infection syndromes as well.

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