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Convergence

The authors showed how gut, immune and metabolic issues might come together to produce post-exertional malaise in ME/CFS.

We know the gut is in play in some way in ME/CFS. Gut symptoms are common and studies have evidence of dysregulated gut flora and leaky gut (gut bacteria in the blood).

The big question, though, is what it all means. We know that gut issues have the potential to affect the immune system, but do they? What effect does exercise-induced leaky gut have on the immune system? Do the metabolic problems that have been found during exercise have any effect on the gut? How might the gut, the immune system and the metabolism be intertwined in a way to produce post-exertional malaise?

Any answer to ME/CFS, fibromyalgia, long COVID, etc. is going to have find ways to link these different systems together.

This study, “Suppressed immune and metabolic responses to intestinal damage-associated microbial translocation in myalgic encephalomyelitis/chronic fatigue syndrome”, attempted to do that, but it was unusual in another way.

Led by an unusually determined researcher, Armin Alaedini PhD, it re-analyzed samples that had been gathered during a large 2014 XMRV study and a smaller 2015 study, and kept at -80°C in the Solve M.E. Biobank. The smaller study had assessed the degree of leaky gut that occurred during and after an exercise study in people with ME/CFS and healthy controls. Not only did it find a higher incidence of leaky gut in ME/CFS but it found that the gut bacteria had persisted in the blood much longer in the ME/CFS patients.

The study examined a wide range of immune factors (plasma levels of IgG, IgA, and IgM anti-endotoxin (LPS)-core antibodies, lipopolysaccharide (LPS)-binding protein (LBP), soluble CD14 (sCD14), intestinal fatty acidbinding protein (FABP2) (R&D Systems), IgG, IgA, and IgM antibodies to the gliadin protein fraction of dietary wheat IgM antibodies to casein, IgG, IgA, and IgM antibodies to bacterial flagelli, IL-10, IFN-γ, and TNF-α cytokines, LPS concentrations) as well as metabolomics.

Findings

FABP2 elevations in ME/CFS

Note that not everyone with ME/CFS had elevated FABP2 – a sign of damage to the gut lining – but enough did to produce a statistically very significant difference (p<.006).

A dramatic increase in antibody responses to both microbial and dietary antigens in the ME/CFS patients suggested that their immune systems were responding to higher levels of bacteria and gut particles in the blood. The higher expression of FABP2 – fatty acid binding protein expressed in the epithelial cells linking the small intestines suggested that the epithelial cells lining the gut were damaged, allowing gut contents to spill into the blood in ME/CFS.

That made sense given what we know about ME/CFS, but the next finding did not. Given the evidence of increased leaky gut, they expected to find elevations in two early immune response factors (lipopolysaccharide (LPS)-binding protein (LBP), sCD14) normally associated with it but did not.

IgA IgM antibodies bacterial toxins

Similarly dramatically increased IgA and IgM antibodies to bacterial toxins in the ME/CFS cohort indicated that one part of their immune system was highly aroused.

Lipopolysaccharides (LPS) are proteins found on bacteria that present a red flag to the immune system, indicating that foreign bacteria are present in the bloodstream. LBP and sCD14 are immune factors that help to quickly rally the immune system to quickly remove the bacteria, yet both were low in ME/CFS.

Given the evidence that more bacteria had leaked into the bloodstream of the ME/CFS patients, their early or innate immune response should have been going gangbusters. Their LBP and sCD14 levels indicated it was not.

The authors noted that another study had, to the authors’ surprise, failed to find increased levels of another early immune response protein called c-reactive protein. Inflammation seemed to be present in ME/CFS, but important early markers associated with the inflammatory response were not. What was going on?

THE GIST

  • Talk about convergence. We’re used to hearing about how the gut can affect the brain through the gut-brain axis, but how about a study which shows how problems in the immune system, the gut, and the metabolism may be “conspiring” together to produce post-exertional malaise in ME/CFS?
  • Using samples stored in the deep freeze from two studies done in 2014/2015 (thanks to Solve M.E. Biobank), one of which examined the effects of exercise on leaky gut, they 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. One side of the immune system – the antibodies – leapt into action. Another side – the early inflammatory immune response that’s designed to quickly neutralize the invaders – did not, however.
  • Plus, an anti-inflammatory factor called IL-10 that both knocks down the early immune response and interferes with glucose metabolism in the gut was elevated in ME/CFS.
  • That set the stage for the last finding involving impaired energy production. We usually think of energy production in terms of exercise, but when the immune cells find an invader, they need to ramp up their energy levels dramatically in order to combat it.
  • This study found, though, that while exercise did indeed significantly increase 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. Instead, the levels of those factors remained flat. Once again, we see a strange non-response to exercise in this disease.
  • That suggested that the early immune response against the bacterial invaders simply didn’t have the energy to get going in ME/CFS. That, in turn, allowed the toxic bacteria to persist in the bloodstream.
  • The findings suggested 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.

 

Since the researchers knew that exercise causes at least some gut bacteria to leak into the bloodstream of healthy people, exercise provided a nice way to chart the early immune response to gut bacteria in ME/CFS. Despite finding evidence of increased leaky gut in ME/CFS, including increased levels of lipopolysaccharides and antibodies to gut bacteria and foods, the same pattern prevailed – the rapid immune response to the gut bacteria remained flat in the ME/CFS patients.

The pattern was clear. Gut bacteria were invading the bloodstream of ME/CFS patients in large amounts. The antibody portion of the immune system was jumping into the action, but the early innate immune response that initiates a rapid inflammatory response (that was designed to neutralize the bacteria) was not. Given that, it was no wonder that the exercise study found that bacteria were hanging around longer in the ME/CFS patients’ bloodstream than in the healthy controls.

An Endotoxemia Disease?

Asserting that, “These data could be highly relevant to the clinical history and presentation of ME/CFS“, the authors suggested – for the first time that I can remember – that endotoxemia – which occurs when large levels of bacterial toxins are present in the bloodstream – could be producing the symptoms of post-exertional malaise (PEM). The symptoms of endotoxemia – “fatigue, cognitive changes, headache, nausea, increases in heart rate, and decreases in blood pressure” – are indeed, quite similar, to those seen in PEM.

The authors noted that if these bacterial toxins make their way to the blood vessels of the brain, they can turn on the microglia, producing neuroinflammation and problems with cognition. That was intriguing given that Cook – one of the co-authors of this study – found in 2017 that exercise “exacerbated symptoms, impaired cognitive performance and affected brain function in ME/CFS.” This new study suggests that an inability to clear bacterial toxins from the bloodstream could be contributing to the brain fog found in ME/CFS.

The increased levels of the IL-10 cytokine in the ME/CFS patients added an intriguing element. An anti-inflammatory, one would think, that elevated IL-10 levels would be welcome, but this and other studies suggests that the high IL-10 levels could be hobbling early inflammatory response to invaders.

The metabolomic results added another twist. We’ve almost always associated metabolic problems in ME/CFS with low energy and an inability to exercise. This study, though, suggested that the metabolic problems found (reduced utilization of glucose and fatty acids and increased utilization of amino acids to produce energy) could be having an effect on the immune system as well.

Immune cells need to quickly fire up their engines to fight off an invader or toxin, and the metabolomic results from the healthy controls indicated that during exercise they were able to access a significant increase in plasma glucose – the cleanest and most efficient form of energy available to our cells. Plasma glucose in the ME/CFS patients, on the other hand, remained flat. IL-10 – which was high in ME/CFS – is able to block glucose utilization in immune cells that protect the gut barrier.

The same pattern occurred with citrate – a crucial player in aerobic energy production – and the activation of the early immune response. Exercise triggered a rise in citrate in healthy controls but not in the ME/CFS patients.

Citrate / Glucose ME/CFS

Note how exercise increased the citrate and glucose levels in the healthy controls but not in the ME/CFS patients.

High IL-10 levels and reduced levels of two crucial players in energy production may, then, have impaired the ability of the immune system to: a) protect the gut lining; and b) quickly clean up the bacteria that escaped into the bloodstream during exercise. The endotoxemia that resulted could help explain the post-exertional malaise (PEM) that people with ME/CFS experience after exercise.

The authors hastened to say that because ME/CFS is a heterogenous disorder this process may be happening in a subset of patients. Bigger studies are needed to validate and expand on these findings, but the intersection between exercise, bacterial invasion of the bloodstream, and a suppressed early immune response – driven by metabolic problems – is really intriguing. I don’t remember many studies that have been able to bring so many different elements together in one package.

This study also highlighted the need to explore how the energy production problems in ME/CFS affect immune functioning.

The authors stated they hope to explore further why leaky gut is such a problem, how the immune system and metabolism play a role, and uncover biomarkers that can be used to assess treatments, and ultimately, to employ treatment strategies.

Check out an interview with the senior author of the study – Dr. Armin Alaedini

Immunosuppression Underlies Energy Deficits That Drive ME/CFS Symptoms Pt. II – The Armin Alaedini Interview

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