The first blog in a couple of weeks is different – it’s not on ME/CFS/FM or long COVID per se – and that may be a good note to start out on. It’s a reminder that ME/CFS is not alone – that it shares broad themes with other diseases – some of them major diseases that are getting much more research. If we’re looking at how to end ME/CFS/FM and long COVID, some of the answers will likely come from them.

Of those diseases, multiple sclerosis (MS) must be near the top of the list. MS is a major fatiguing illness and the fatigue is unusual: it’s often the first symptom to show up and it doesn’t track with the demyelination found; i.e. something else associated with MS is causing it.

Some studies suggest that something could be happening in ME/CFS as well. A recent study, “Regional microglial activation in the substantia nigra is linked with fatigue in MS, pointed an arrow at the same part of the brain – the basal ganglia – that studies suggest play a major role in ME/CFS. Plus, the authors suggested the same cause – microglial activation/neuroinflammation – that Jarred Younger and other researchers have proposed is at play in ME/CFS is also at play in MS.

Unrewarding Reward: The Basal Ganglia, Inflammation and Fatigue In Chronic Fatigue Syndrome

In fact, the authors proposed that,

“Future research studies are needed to compare the fatigue-related microglial changes in MS with other diseases such as CFS and Parkinson disease and identify common and disease-specific mechanisms of fatigue in neurologic disorders.”

A Fatigue Nucleus in Multiple Sclerosis… and ME/CFS and Fibromyalgia?

This “identify common and disease-specific mechanisms of fatigue” is where the juice lies for us. Could at least some similar mechanisms of fatigue be present in all these diseases? If they were, that would be a huge boon for diseases like ME/CFS/FM and long COVID.

Of course, there’s also the MS and ME/CFS Epstein-Barr virus (EBV) connection. EBV may be the cause of MS, and it’s a clear trigger for ME/CFS. Now comes the coronavirus which, like EBV, can quickly trigger an ME/CFS state. Will it trigger MS as well? We don’t know.

EBV, in the form of infectious mononucleosis or glandular fever, rapidly triggers ME/CFS but takes years to trigger MS – so the coronavirus-MS connection will take some time to sort out. Just as with ME/CFS, though, MS researchers are looking to long COVID to help them better understand MS:

“We believe that the “research rush” triggered by the novel Coronavirus may propel studies on MS; vice versa, deepening our knowledge on MS pathogenesis and its relationship with viral infections could guide the investigations on COVID-19 immunopathogenesis.”

The Study

Now comes another intriguing MS study which is not focused on fatigue but on demyelination; i.e. the loss of the protective covering of the neurons that occurs in MS. Various studies have suggested that some demyelination may occur in ME/CFS, but if it does, it’s orders of magnitude lower than found in MS. Nevertheless, the study points to intriguing connections between three major players in both MS and ME/CFS: the brain, the vagus nerve and the gut.

In “Key role of the gut–microbiota–brain axis via the subdiaphragmatic vagus nerve in demyelination of the cuprizone-treated mouse brain,” the researchers gave mice an MS-like condition, then cut the connection between their vagus nerve and their brain. The longest nerve in the body, the vagus nerve is the conduit between the immune system in the body and the brain, and a regulator of both the immune and the autonomic nervous system.

gut-brain axis

Severing the connection between the gut and brain helped both the brain and the gut. Whether the problem lies in the gut, the brain, and/or the vagus nerve is, however, unclear.

The mice responded to the rather dramatic intervention positively – both the neuroinflammation and nerve demyelination declined. That was noteworthy, but the study didn’t stop there – and fact that it didn’t is emblematic of the increasing number of tools researchers have to throw at a disease. It seems like the era of the “one-shot” study is drawing to a close. More and more, we’re seeing complex studies that assess multiple systems which almost invariably show how linked together those systems are.

Citing the ever-increasing literature regarding the gut-brain connection and the vagus nerve’s role in that connection, the researchers turned to the gut. (Gut studies suggest the gut may be “off” in similar ways in MS and ME/CFS (impaired short-chain fatty acid/butyrate production, leaky gut). Could severing the vagus nerve positively affect the gut as well?

It did. Cutting the vagus nerve connection to the brain restored the bacterial diversity that had been lost when the researchers plunged the (poor) mice into their MS-like state. Plus, it normalized the levels of six of the metabolites that had gone wonky. Statistical analyses suggested that the recovery of the bacterial flora, changes in gut metabolite levels, and myelin recovery were all associated with each other. In other words, the brain-gut connection held – the two appear to be inextricably linked.

Why would cutting the vagus nerve help? Because it constitutes the “immune superhighway” between the body and the brain. Signals regulating the immune systems of the brain and the body whiz up and down the vagus nerve. Once that dysfunctional nerve was cut, the inflammatory signals it was transmitting stopped, the inflammation died down, and the gut started to repair itself.

The authors concluded:

“Given the crucial role of the vagus nerve in the gut–microbiota–brain axis, vagus nerve stimulation may be a promising therapeutic option for MS patients, it will be of great interest to investigate whether vagus nerve stimulation can improve clinical symptoms.”

There’s no doubt that vagus nerve stimulation has a way to go but it’s potential is clearly large.

Vagus Nerve Stimulation in ME/CFS, FM, POTS and Long COVID – Is its Promise Being Fulfilled?

The Gist

  • ME/CFS/FM and long COVID are not alone. Besides the usual suspects (post-treatment Lyme disease, Gulf War illness, irritable bowel syndrome), similar themes pervade other illnesses – some of them major illnesses that get bountiful research funding. If we’re looking forward to the end of ME/CFS and similar diseases, it’s likely some answers will come from these other diseases.
  • Multiple sclerosis with its high degree of fatigue, its Epstein-Barr virus trigger, and basal ganglia, gut, and autonomic nervous system findings, stands at the top of that list. 
  • A recent mouse study explored the effect of the gut-brain axis on MS by severing the communication link – the vagus nerve – between the gut and the brain. Not only did the degree of nerve demyelination reduce, but the diversity of the gut flora, several gut metabolites, and some gut bacteria returned to normal.
  • It wasn’t clear exactly why this happened, but a dysfunctional vagus nerve, or an overheated gut, or an overheated brain (or all three) could be responsible. The study showed in spades how inextricably linked these systems can be: the gut can spark inflammation in the brain, the brain also affects the gut, and the vagus nerve is the conduit between the two.
  • The authors zeroed in on the vagus nerve, suggesting that vagus stimulation was the next logical step to try.
  • The solutions to diseases like MS and ME/CFS could come together; once we get to the heart of one, the pathway to the other will show up. That would be possible if a common disease state (gut issues, sympathetic nervous system activation, neuroinflammation, infectious trigger?) gives birth to different manifestations of the core problem.
  • The coronavirus pandemic and long COVID have opened up tremendous opportunities in this regard. Finally, medical research has been tasked with precisely understanding how an infection affects the body and how it can cause chronic diseases. It’s in that interface that we stand to learn so much. 
Given the huge interest in the role the gut plays in MS, in particular (dozens of papers over the last couple of years), the high levels of fatigue, and the similar gut findings in ME/CFS and MS, MS is a good disease to keep an eye on regarding the role the gut plays in disease and possible treatments. Probiotics, keto diets, fecal transplantation, antibiotics and mindfulness-based therapies (to improve vagus nerve functioning) are all being explored.

It’s not just MS, though, as a great deal of attention to the gut-brain axis is being given to other major neurological diseases. A recent review article stated:

“it is clear that changes in microbiota composition play a vital role in the pathogenesis of various neurodevelopmental and neurodegenerative disorders, such as Autism Spectrum Disorder, Alzheimer’s disease, Parkinson’s disease, Multiple Sclerosis, Amyotrophic Lateral Sclerosis, anxiety, stress, and so on.”

The gut-brain axis may not stop at neuroinflammation either. One review paper that focused on how gut issues may be able to impact the mitochondria in the brain reported: “In this review, we focus on how exogenous agents, i.e., viral pathogens, or unbalanced microbiota in the gut-brain axis can also endanger mitochondrial dynamics in the central nervous system (CNS).”

Similar problems in the gut-vagus-nerve-brain axis appear to be in play not just in neglected diseases like ME/CFS, fibromyalgia, and Gulf War Syndrome – and long COVID – but also in major diseases like MS and other neurological disorders – something that bodes well for progress in this potentially vital area.

In fact, it’s possible that the solutions to diseases like MS and ME/CFS could come together; that once we get to the heart of one, the pathway to the other will show up. That would be possible if a common disease state (gut issues, sympathetic nervous system activation, neuroinflammation, infectious trigger?) gives birth to different manifestations of the core problem.

Avindra Nath certainly thinks so with regard to the ME/CFS/CFS/GWI/Long-COVID constellation of diseases. He believes if you solve one, you’ll be able to solve the others. Time will tell about these other diseases.

Avindra Nath on ME/CFS and Long COVID – “We’re Going to Learn a Lot”

Whatever happens, the coronavirus pandemic and long COVID have opened up tremendous opportunities to relook at the role infections and pathogens play in chronic disease. The medical field can no longer stop at trying to fight off an infection – it now must learn how infections can cause long-term problems. Not since the HIV/AIDS epidemic – and probably not even then – has the medical community focused so closely on a pathogen. That new turn bodes well for all of us.

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