All posts by Cort Johnson

Could the Gut Cure Neuroinflammation? An MS and ME/CFS/FM Inquiry

Gut Neuroinflammation Connection Revealed

“There is something very critical about how the gut and brain are connected, and we’re starting to unravel the molecular threads behind that clinical observation. It’s a great example of how fast science can move.” Jen Gommerman – co-author

Limiting our attention solely to chronic fatigue syndrome (ME/CFS), fibromyalgia (FM) and allied disorders might be a mistake. Recent studies indicate that ME/CFS and FM fit into the broad category of neuroinflammatory disorders which include multiple sclerosis (MS), Parkinson’s disease and others.

ME/CFS and FM neuroinflammatory

ME/CFS and FM may fit into a broad spectrum of neuroinflammatory disorders.

The same parts of the brain may not be affected in each disease, but it’s possible that each is undergirded by a similar inflammatory milieu. If the goal is to reduce neuroinflammation, then an approach that works in one disease could work in another.

The immense amount of research being devoted to these other neuroinflammatory disorders suggests they could provide critical insights into ME/CFS and FM as well.

A recent multiple sclerosis gut study provided a prime example of how progress in one neuroinflammatory disease may benefit others. It underscored the gut’s long reach and illuminated a potential treatment approach – not just for MS, but possibly also for other neuroinflammatory diseases.

It raised the possibility that manipulating one’s gut bacteria may at some point become an effective treatment approach in the fight against neuroinflammation.

Cell. 2018 Dec 21. pii: S0092-8674(18)31560-5. doi: 10.1016/j.cell.2018.11.035. [Epub ahead of print] Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10. Rojas OL1, Pröbstel AK2, Porfilio EA1, Wang AA1, Charabati M3, Sun T1, Lee DSW1, Galicia G1, Ramaglia V1, Ward LA1, Leung LYT1, Najafi G1, Khaleghi K1, Garcillán B4, Li A5, Besla R6, Naouar I1, Cao EY1, Chiaranunt P1, Burrows K1, Robinson HG7, Allanach JR7, Yam J1, Luck H5, Campbell DJ8, Allman D9, Brooks DG10, Tomura M11, Baumann R2, Zamvil SS12, Bar-Or A13, Horwitz MS14, Winer DA6, Mortha A1, Mackay F4, Prat A3, Osborne LC7, Robbins C15, Baranzini SE16, Gommerman JL17.

Their study started in the head and moved downwards. Researchers wondered where the heck the plasma cells (IgA antibody producing B-cells) showing up in the central nervous systems of MS patients were coming from. It turned out they were coming from the gut.  They found that B-cells were making their way to the gut where gut bacteria where flipping their switch – and turning them into IgA producing plasma cells. Now their one and only goal was to produce IgA antibodies.

IgA antibody gut chronic fatigue

IgA antibody producing cells that are formed in the gut appear to play a major role in tamping down inflammation in the brain

Eventually they made their way up the body to the brain, where (in the presence of IL-10) they were tamping down inflammation. Interestingly, the guts of the mouse model for MS were deficient in these cells. These plasma B-cells were so effective at reducing brain inflammation that boosting their levels in the mice’s guts returned them to health.

The levels of these plasma cells are also reduced in the guts of humans during MS relapses – presumably because they’re being recruited to the brain to fight the inflammation.

This finding cleared up a conundrum – why knocking out B-cells tended to help people with MS while knocking out only the IgA-producing cells made them worse. B-cells were believed to promote neuroinflammation and autoimmunity and they do. The B-cell inhibitors used are believed to reduce T-cell activation and suppress autoantibody production.

No one suspected, though, that specialized B-cells might also play a critical role in suppressing inflammation. Knocking those cells out resulted in the patients getting worse.

Gut Modification

“Showing that IgA-producing B cells can travel from the gut to the brain opens a new page in the book of neuroinflammatory diseases and could be the first step towards producing novel treatments to modulate or stop MS and related neurological disorders.” Sergio Baranzini – co-author

The next steps seem clear: find a way to increase the number of IgA-producing plasma cells in the guts of people with neuroinflammatory disorders in the hope that they will knock down inflammation in the brain. Because some bacteria – which ones is unknown at the moment – trigger B-cells in the gut to change to IgA producing plasma B-cells, the next step is to identify that microbe and find a way to increase its numbers.  In other words, find a way for the gut to naturally reduce inflammation in the brain.

“If we can understand what these cells are reacting to, we can potentially treat MS by modulating our gut commensals. That might be easier than getting drugs into the brain, which is a strategy that hasn’t always worked in MS.” Gommerman – senior author

Potential Relevance to Chronic Fatigue Syndrome (ME/CFS), Fibromyalgia, etc.

“As a clinician-scientist, it is exciting that our experiments linking preclinical animal models to the biology we see in real MS patients may have uncovered a general mechanism for how the immune system counteracts inflammation.” Pröbstel – co-author

Chronic fatigue syndrome (ME/CFS) is not MS but the two diseases might be more closely related than one might think. Having mononucleosis/glandular fever increases the risk of coming down with either ME/CFS or MS and infections often trigger relapses in both diseases. The most disabling symptom in MS tends to be fatigue and both diseases mostly affect women. Plus pregnancy often brings a (temporary) respite in both diseases.

A Simmaron Research Foundation sponsored spinal fluid study found similar levels of immune alterations in ME/CFS and MS, and pointed to a major, almost MS-like, alteration of immune factors in ME/CFS.

Simmaron’s Spinal Fluid Study Finds Dramatic Differences in Chronic Fatigue Syndrome

Jarred Younger, who knows neuroinflammation as well as anyone in this field, believes that MS and ME/CFS could turn out to be close cousins. Younger believes the neuroinflammation present in both diseases may be similar, with the notable distinction that the immune cells in MS have been tweaked to attack the neurons, while those in ME/CFS, thankfully, have not. (Younger has begun a low dose naltrexone trial in early stage MS patients to see if he can stop the neuroinflammation before it has irrevocably damaged the nerves.)

 

Jarred Younger III : Treatments – A Better LDN and the Hunt for Microglia Inhibitors

What works in MS could work in ME/CFS and it already has – at least in two cases. A MS drug called Copaxone was very effective in two ME/CFS patients who’d been misdiagnosed with MS. In fact, it was much more effective in those patients – resulting in significant reductions in fatigue –  than it ever was in MS.

The really exciting thing about this study is its potential relatability to other diseases.  These researchers appeared to have stumbled upon a basic gut induced anti-inflammatory pathway that may help with other neuroinflammatory diseases including, who knows, perhaps ME/CFS and FM.

It’s clear that we can’t view MS as strictly a brain disease. Yes, the overt physical damage occurs in the brain, but gut issues play a role as well. In fact, this study suggests the possibility that gut damage – in the form of a dysregulated microbiome – might even play a critical role in allowing MS to progress.

Could the Gut Be a Potential Drug Factory?

Given the possibility that harnessing an as yet unknown microbe in the gut could reduce inflammation in the brain, one has to wonder if the gut, with its trillions of microbes, is a potential reservoir of drugs.  Could we tweak the microbes in the gut to provide other factors that reduce disease? Will gut manipulation ultimately play an important role in treating chronic diseases?

Immune Factor May Jump Start Chronic Fatigue Syndrome (ME/CFS)

December 31, 2018

“For the first time, we have shown that people who are prone to develop a CFS-like illness have an overactive immune system, both before and during a challenge to the immune system. Our findings suggest that people who have an exaggerated immune response to a trigger may be more at risk of developing CFS.” Alice Russell

This British study is interesting in so many ways. Most importantly, it draws a link between an overactive immune system and CFS-like chronic illness in Hepatitis C patients who were studied before and after treatment with an immune stimulant. The authors believe it may tell us why some people come down with chronic fatigue syndrome (ME/CFS) after an infection. If so the Brits have found the first predictive blood factor for ME/CFS.

Psychoneuroendocrinology. 2018 Dec 14. pii: S0306-4530(18)30196-3. doi: 10.1016/j.psyneuen.2018.11.032. Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of chronic fatigue syndrome. Russell A1, Hepgul N2, Nikkheslat N3, Borsini A4, Zajkowska Z5, Moll N6, Forton D7, Agarwal K8, Chalder T9, Mondelli V10, Hotopf M11, Cleare A12, Murphy G13, Foster G14, Wong T15, Schütze GA16, Schwarz MJ17, Harrison N18, Zunszain PA19, Pariante CM20.

It is interesting in one way, because it comes out of King’s College London – the longtime home of Simon Wessely, the British psychologist who developed the cognitive behavioral therapy (CBT) and graded exercise therapy (GET) approach to chronic fatigue syndrome (ME/CFS). Wessely, a leader of the biopsychosocial approach to ME/CFS, championed the idea that psychological and social factors largely perpetuate ME/CFS.  Psychiatrists Trudy Chalder and Mathew Holtorf also hail from King’s College.  (Anthony Cleare, another psychiatrist from King’s College, has done substantial research into the HPA axis in ME/CFS over the past 20 years. Cleare’s 1995 paper used cortisol tests to differentiate ME/CFS from depression.)

Kings College Medicine

King’s College London has been the home of several prominent pyschiatrists studying ME/CFS (By Stephen Craven, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=13848828)

Six years ago Medical Express reported that the PACE Trial – which Kings College researchers participated in – proved that CBT/GET practices “provide good value for the money“. Three years ago Queen Mary College of London and King’s College London dug their feet in to prevent the release of the raw PACE data.  It was King’s College that called the attempt to get the data “vexatious,” which in legal terms basically means without merit. The PACE findings are now in the throws of being discredited.

The study is also interesting because it was funded by the Medical Research Council (MRC), a United Kingdom based governmental agency that funds medical research. The MRC, which helped fund the PACE trial, has been a mixed bag. Funded studies on ethnicity, risk factors (biopsychosocial risk factors) and CBT speak to a strong behavioral thrust. However, the MRC has also funded studies on the mitochondria, the autonomic nervous system and now on an immunological model of ME/CFS.

A new generation of psychiatrists from King’s College appear to be taking a different tack. Carmine Pariante, who has focused for years on the physiological roots of depression, has been using hepatitis C patients to try and understand how immune mediated fatigue and depression arise.

A Model for ME/CFS?

It turns out that when hepatitis C patients are given interferon-alpha (IFN-a) about a third of them develop severe fatigue and/or become depressed. The realization that an immune activating drug was causing fatigue and depression in those who were not fatigued or depressed before was a revelation to the medical community. That led to the idea of sickness behavior, which posits that during an infection, the brain and immune system induce symptoms (flu-like symptoms) that force individuals to isolate themselves, stopping the spread of the infection.

trigger ME/CFS

Did high IL-10 levels jump start ME/CFS?

Since many people with chronic fatigue syndrome (ME/CFS) are by definition caught in a chronic case of “sickness behavior” (a chronic illness state triggered by an infectious event), hepatitis C patients provide the possibility of real insights into ME/CFS.  If researchers can determine how immune activation triggers flu-like symptoms and/or depression in people being treated for hepatitis, they may get clues to what is going on with ME/CFS.

In an action that proved enormously helpful, the group took baseline measures of immune activation prior to the introduction of the interferon drug, and then afterwards. They also assessed psychological factors and metabolites associated with the kynurenine system.

THE STUDY

Psychological Factors Play No Role

In a finding that must have disappointed Trudy Chalder and Mathew Hotopf – who were also part of the study – psychological factors struck out on all counts. Neither a history of depression, stressful life events in the prior six months or early life trauma had any effect on  those who became ill following the IFN-a administration.

Cytokines Not Perpetuating Fatigue

Cytokines weren’t, strictly speaking, perpetuating fatigue in the ill hepatitis C group either. The cytokine levels in both the recovered and the still fatigued hepatitis C patient were similar.

They may, however, have triggered it.

Possible Predisposing Factor Identified

The hepatitis patients who came down with severe fatigue demonstrated increased IL-10 and IL-6 levels early on – very early on.  In fact, hepatitis C patients who became ill had high IL-10 levels BEFORE they received the drug. High levels of IL-6, a pro-inflammatory cytokine which has been associated with fatigue, were found early in the illness.

IL-10

High Il-10 levels at baseline may be a biological risk factor for coming down with ME/CFS.

The researchers speculated that patients’ immune systems were primed to take off prior to their receiving the drug – and it was this immune priming which lead them to become ill after taking the drug.

Six months later their IL-10 levels, interestingly, were normal – suggesting that IL-10 had done it’s work quickly and then faded into the background, leaving behind a chronic state of fatigue.

The beauty of this study is that it identifies possibly the earliest blood factor yet – increased IL-10 levels – that may set someone on the path to developing ME/CFS.

While the authors didn’t attempt to explain how these factors produce ME/CFS, some possibilities immediately present themselves. Higher than normal IL-10 levels could suppress one’s ability to quickly clear an infection.  High IL-10 levels and several IL-10 polymorphisms have also been associated with the development of lupus, an autoimmune disorder.

Andrew Miller of Emory University has some ideas of his own.

Miller Time

Andrew Miller, PhD also believes that the ‘sickness behavior’ he finds in hepatitis C patients given IFN-a is similar to what’s happening in ME/CFS.  Miller, however, came to that conclusion, by looking at the brain.

He found reduced activation of the striatum – a part of the basal ganglia that produces dopamine – in fatigued hepatitis C patients and people with ME/CFS. This finding suggested that reduced dopamine levels in ME/CFS may be producing problems with motor activation (physical activity) and fatigue. Indeed, primate studies indicate that immune activation in the presence of low dopamine levels results in enormous fatigue, motor slowing, and depression.

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

Another study, taking a deeper look at what happens to a brain on IFN-a, found it took just four hours for IFN-a to produce microstructural changes in the left striatum – changes that were “strikingly correlated” with the development of fatigue. The authors reported that increased levels of lactate and altered pH – two problems found in ME/CFS –  may set the stage for these microstructural abnormalities.

Microstructural Havoc: The Immune System, Fatigue and the Brain – An ME/CFS and FM Scenario

Immune Hypersensitivity Syndrome?

This presents the possibility that infection-produced inflammation could knock out dopamine production permanently, leaving behind – and this may be the important part – a hypersensitized reaction to inflammation. Miller believes that dopamine deprivation causes the basal ganglia to over-respond to inflammatory signals, resulting in the fatigue and other symptoms associated with “sickness behavior”.

That sickness behavior includes mood changes. The British group found that a “biological sensitivity”, or over-reaction to IFN-a, predicted who would come down with depression while on the drug.

When Anthony Cleare of King’s College trashed Montoya’s cytokine findings last year because they didn’t show cytokine elevations, he missed the point that Montoya’s results may have pointed to a possible exquisite sensitization to cytokines in ME/CFS.

Conclusion

It was very good to see an MRC-funded physiological study pan out and get such abundant media coverage.  Thankfully, Lenny Jason is in a good position to follow up on this study result to see if IL-10 is indeed raised in young people who fail to recover from infectious mononucleosis. If that pans out, the first predisposing factor for ME/CFS in the blood will have been found.

That finding will then give us an entry point to determining how ME/CFS comes about. Avindra Nath’s and Derya Unutmaz’s studies of short-duration post-infectious ME/CFS patients would hopefully be able to piggyback on the British finding and begin to unravel the genesis of ME/CFS.

The basal ganglia/hepatitis connection is fascinating because it suggests that the Brits’ hypothesis, that fatigued hepatitis C patients present a good model for ME/CFS, may be correct. Andrew Miller’s and other studies suggests that the brain changes in ME/CFS replicate those of the fatigued hepatitis C patients. Interestingly, they affect the basal ganglia – a part of the brain involved in motor activation (physical movement), learning, cognition and fatigue.

Miller’s hypothesis that inflammation may knock out dopamine production in the basal ganglia resulting in a hypersensitization to immune signals in ME/CFS is compelling. Neuroinflammation has been linked to microglial activation and reduced dopamine levels.  Plus two studies have found reduced basal ganglia activation in FM. One study suggested the basal ganglia could be causing the movement problems in FM.

Spinning Fibromyalgia: Brain Findings Suggest Dopamine May Be Key

Given that the basal ganglia affects movement, fatigue and reward, it would seem to present a rich vein for ME/CFS researchers to mine.  In other fields, researchers would probably be vigorously digging away at a vein with this much potential ore in it, but in ME/CFS researchers are just scratching the surface. Getting  more out of the research community will require that the federal government fulfill its promise to invigorate this field.

In the meantime, it’s good to see the MRC and the Brits, psychiatrists most of them (!), make good on a physiological study, hopefully set the stage for more to come.

The Probiotic Paradox: When Probiotics Fail or Even Do Harm – an ME/CFS Perspective

December 18, 2018

Our guts are teeming, just teeming, with bacteria that provide many useful functions. They break down food, knock down pathogens, regulate the immune system and hormone release, and even affect brain functioning. Several serious diseases including cancer, diabetes and rheumatoid arthritis have been associated with what are considered unhealthful assemblages of gut bacteria.

probiotics

These studies indicated that pounding the gut with probiotics isn’t always a good idea.

Studies suggest that something is off, though, in the guts of people with chronic fatigue syndrome (ME/CFS). Pro-inflammatory and anaerobic species are more dominant and diversity -an important component of a healthy gut –  is low.  Plus bad gut bacteria may be gnawing away at our gut linings when we exercise, allowing the bacteria to spill into our blood, causing systemic inflammation.

The solution seems clear – pound the gut with good bacteria, get it back into balance, turn the immune activation off, and who knows, maybe even conquer ME/CFS and fibromyalgia (FM). Certainly it’s worked for some people but for many others it hasn’t. That’s really no surprise, nothing works for everyone in these diseases, but some people have experienced really negative effects from good bacteria. How could that have happened?

We’re beginning to learn how. Two studies that are turning upside down our notions of using probiotics to replenish our gut flora are indicating that the gut, like every other part of the body, is more complex than we knew, it seems.

The Studies

Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features. Zmora N, Zilberman-Schapira G, Suez J, Mor U, Dori-Bachash M, Bashiardes S, Kotler E, Zur M, Regev-Lehavi D, Brik RB, Federici S, Cohen Y, Linevsky R, Rothschild D, Moor AE, Ben-Moshe S, Harmelin A, Itzkovitz S, Maharshak N, Shibolet O, Shapiro H, Pevsner-Fischer M, Sharon I, Halpern Z, Segal E, Elinav E. Cell. 2018 Sep 6;174(6):1388-1405.e21. doi: 10.1016/j.cell.2018.08.041.

These Israeli researchers did something rather simple – at least in design – which, in retrospect, should have been done long ago. They took 25 healthy people, used endoscopy and colonoscopy to assess the bacteria found in their upper and lower guts, then gave them a standardized dose of probiotics twice a day (Lactobacillus acidophilus, L. casei, L. casei sbsp. paracasei, L. plantarum, L. rhamnosus, Bifidobacterium longum, B. bifidum, B. breve, B. longum sbsp. infantis, Lactococcus lactis, and Streptococcus thermophilus) and measured the bacteria in their guts. Their stools were sampled throughout the study.

Resisters and Persisters

Two groups emerged: the persisters – a group whose guts accepted the new bacteria and changed in a positive way, and the resisters whose guts rejected the bacteria and didn’t change at all.

Their interest piqued, the researchers then transferred the bacteria from the resisters and persisters into mice with no gut bacteria, and then gave probiotics to them. The same thing happened – indicating that the bacterial makeup of a person’s gut, at least in part, determines whether probiotics will help them or not. Something about the ecological makeup of the resisters’ bacterial populations made it impossible for the good bacteria to catch hold.

That was an intriguing finding, but the Israeli researchers didn’t stop there. Adding the participants’ gene expression – which genes were active or not in the blood – into the mix, they hit a home run.  Even though they were healthy, the resisters had something extra going on – an autoimmune gene signature – that was somehow not allowing their gut to accept good bacteria.

If you’re not benefiting from probiotics, then, both your immune system and your gut bacterial makeup may be keeping the probiotic bacteria from taking hold. The problem may be worse than that, though.

Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT.

Suez J, Zmora N, Zilberman-Schapira G, Mor U, Dori-Bachash M, Bashiardes S, Zur M, Regev-Lehavi D, Ben-Zeev Brik R, Federici S, Horn M, Cohen Y, Moor AE, Zeevi D, Korem T, Kotler E, Harmelin A, Itzkovitz S, Maharshak N, Shibolet O, Pevsner-Fischer M, Shapiro H, Sharon I, Halpern Z, Segal E, Elinav E.Cell. 2018 Sep 6;174(6):1406-1423.e16. doi: 10.1016/j.cell.2018.08.047.

When gut problems are suspected, a standard protocol among some doctors is to wipe the slate as clean as possible by killing the bacteria with antibiotics and then re-populating the gut with probiotics. Of course no probiotic combination can approach the immense diversity found in our guts, but anecdotal reports suggest the protocol does seem to work in some people.

This study suggested, though, that there are much better ways to go about replenishing one’s gut after a nuclear attack by antibiotics. The researchers wiped out the guts of three sets of people, then recolonized one group with fecal transplants of their own gut bacteria, another with probiotics, and the last they let recover naturally.

The guts of the participants recolonized with transplants of their own fecal material recovered at lightning-speed: within a week their gut composition was back to normal. The participants whose guts were allowed to heal naturally took about three weeks to return to normal, but the people taking probiotics took up to six months for their gut composition to return to normal, and some of them were still not normal even then.

Any ecologist  (the gut is an ecological system) probably wouldn’t have been surprised at this result. Trying to reinstitute a complex ecosystem by giving a few species a boost can allow them to block others from establishing themselves, resulting in a low diversity ecosystem. That’s basically what happened. Even months later the guts of probiotic-receiving participants had low bacterial loads and dysregulated gut ecosystems. It turned out it was far better to let mother nature take its course and allow the gut ecosystem to repopulate naturally.

It’s possible, then, that taking probiotics when you have a dysregulated gut ecosystem could help, but it could also throw things off. One wonders if some of the negative responses to probiotics result from adding good bacteria into the wrong ecosystem.

Laboratory studies suggest that factors secreted by the Lactobacillus species often found in yogurt preparations might actually be inhibiting other bacteria from colonizing. The probiotic species found in store-bought preparations, it should be noted, are not necessarily the ones that are needed – they’re the ones easily grown in the lab.

“We’re talking about an entire rainforest in the gut that’s being affected in different ways by different antibiotics, and you can’t just patch that up by giving a probiotic. Because, let’s face it, a probiotic has maybe seven or eight strains. There’s a lot in the literature about some of these bacteria being beneficial, and it’s interesting, but they are really some of the few microbes in the gut that are fairly straightforward to culture. And I think that drives the probiotic industry more than it would like to admit.” Allen-Vercoe

The Poop on Stool Samples

But then came some more bad news. Putting stool samples in your body may not be your idea of fun, but at least it’s easy to do and relatively inexpensive. However, despite the fact that stool samples are regularly used to assess gut bacterial composition, they provide a pretty inaccurate snapshot of what’s going on in the gut.  The bacteria actually found in the gut (obtained through endoscopies and colonoscopies) were markedly different from those found in stool samples.

Lactobacillus bacteria

Factors secreted by some Lactobacillus bacteria may prevent other bacteria from colonizing

Finding the probiotics you took via your mouth in your stool was supposed to be a sign of success, but this study found that wasn’t necessarily true.  It’s quite possible for probiotics to show up in your stool without recolonizing your gut at all.

The stool samples failed at predictiveness as well. While the gut mucosal samples (and the gene expression results) could be used to determine whether someone was a “resister” or “persister” – the stool samples could not.

It turns out that the most widely used snapshot of the gut – the stool sample – is the least representative. Gut mucosal sampling – a sampling of the bacteria found in the gut lining via two invasive procedures (endoscopy and colonoscopy) is the only way to truly determine the state of your gut, because the samples are obtained from where the gut bacteria actually reside.

There are, of course, other less invasive ways to assess the effectiveness of probiotics or fecal transplant. Improvement in symptoms: gut issues, fatigue, mood, etc. could indicate that whatever gut manipulation you’re doing is working.

The news in these studies wasn’t all bad, though. The fact that the probiotics were better able to colonize the guts of the healthy controls who had lower levels of good gut bacteria suggested that people with poor gut flora – such as people with ME/CFS – have a better chance of benefiting from probiotics. (That has to be considered alongside the fact that people with autoimmune tendencies tended to resist probiotic colonization.)

Still, the fact that probiotics may be more effective in those with more impaired guts wasn’t really a surprise. There is certainly a place for probiotics in medicine. A recent review of two ME/CFS probiotic studies concluded that probiotics had a “significant effect on modulating the anxiety and inflammatory processes “. Repeated studies have found them helpful in irritable bowel syndrome (IBS), metabolic syndrome, diabetes and obesity. The situation is just a bit more complex now.

That we’re not at the prescriptive phase of treating most diseases with probiotics isn’t exactly shocking, either.  ME/CFS researchers Ian Lipkin and Maureen Hanson, a member of Simmaron Research’s Scientific Advisory Board, have been tackling the gut, and both have been wary about providing any prescriptions for gut manipulation in ME/CFS yet. Given the huge differences in gut bacteria from person to person, a personalized approach – matching personal gut weaknesses with specific probiotics – was always probably going to be necessary.

Ian Lipkin alluded to this earlier:

As we learn more about ME/CFS, we are beginning to define subtypes. This is critical to understanding how people become ill and developing practical solutions for management. The challenge is not unique to ME/CFS. It is representative of the Precision Medicine initiative that is sweeping clinical medicine and public health. Just as there is no one cause or cure for all cancers, all forms of heart disease, or all infections, there will be more than one path to ME/CFS and more than one treatment strategy.

The good news is that gut research is exploding in ME/CFS. Ian Lipkin introduced an  gut-associated subset (ME/CFS patients + IBS) with unique metabolic problems, and remarkably enough, found that differences in gut bacteria were more effective than metabolites in differentiating people with ME/CFS from health controls.  Derya Unutmaz – whom Lipkin is now collaborating with – has found strong evidence that T-cells  associated with bad bacteria are playing a role in ME/CFS.  Plus, a recent hypothesis put forth by Jonas Blomberg proposes that leaky gut may set the stage for ME/CFS. Finally, Maureen Hanson is overseeing the first fecal transplant trial in ME/CFS.

“The Subset Maker”: Lipkin Chronic Fatigue Syndrome Study Highlights Energy Issues In Gut Subset

Simmaron Research is an active collaborator in microbiome and immune-related studies with Dr. Lipkin, Dr. Hanson, Dr. Mady Hornig, Dr. Elizabeth Unger, and others to deepen the field’s understanding of disease subsets and to identify and study treatment options for patients.

Immune Study Adds to Evidence Of Body-Wide Problems With Energy Production in Chronic Fatigue Syndrome (ME/CFS)

Increased expression of CD24 …could thus reflect abnormalities in maintaining appropriate ATP generation (in ME/CFS). The authors

Numerous studies suggest problems with energy production exist in chronic fatigue syndrome (ME/CFS). The huge energy needs exertion places on the muscles and brain suggest they’re an obvious place for energy production problems to show up. Ramping up to fight off pathogens also places extreme demands on energy production in immune cells. Now comes a study which suggests that energy production problems in a subset of B-cells could be setting people with ME/CFS up for problems with inflammation and autoimmunity.

B-cells and ME/CFS

The first couple of successful Rituximab trials brought renewed interest in the immune cells most effected by the drug – the B-cells. The last, large Rituximab trial unfortunately failed – the drug does not work in ME/CFS – but the Rituximab effort succeeded in other ways.

First off, it brought two creative and dedicated researchers, Oystein Fluge and Olav Mella to the field and energized ME/CFS research in Norway.

B-cell

A B-cell producing antibodies to fight pathogens

Secondly, the B-cells – which play a huge role in immunity (and autoimmunity) – finally got some study in ME/CFS.  Keeping with ME/CFS’s time-honored tradition of falling between the cracks in medicine, several studies found no indication of altered levels of “classical B-cell markers”.

Something unusual did, however, pop up, in an extended analysis, which went well beyond the classical markers usually explored. In 2015 a study found that a molecule called CD24 was highly expressed in a group of B-cells.

CD24 is an adhesion molecule which turns on various signaling networks – it basically tells cells what to do. It is most highly expressed on early stage or transitional B-cells as they emerge from the bone marrow.

During the normal transition from immature to mature metabolically active B-cells, early B-cells are tested again and again for evidence that they may be turning into autoantibody producing cells and many are removed.  Over time, as these cells transform themselves into mature B-cells, the CD24 molecule gradually disappears from their surfaces. High levels of these molecules in people with ME/CFS suggested that a problem with B-cell maturation might be present.

Since antibody producing B-cells play a major role in fighting off infections, having a bunch of immature B-cells hanging around the immune systems of ME/CFS patients could constitute a problem.

Plus there’s evidence that the CD24 molecule plays a role in several diseases.  CD24 polymorphisms (genetic variants of CD24) have been associated with increased risk for and accelerated progression of autoimmune diseases including multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematous. CD24 can also be over‐expressed in many cancers, including B cell lymphomas.

In short, it’s not a molecule you want to ignore.

Energy Production Problems in the Immune System

Front Immunol. 2018 Oct 22;9:2421. doi: 10.3389/fimmu.2018.02421. eCollection 2018. CD24 Expression and B Cell Maturation Shows a Novel Link With Energy Metabolism: Potential Implications for Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Mensah FFK1, Armstrong CW2, Reddy V1, Bansal AS3, Berkovitz S4, Leandro MJ1, Cambridge G1.

In a 2018 study, a UK and Australian group took B-cells from ME/CFS patients and healthy controls, stimulated them and then monitored what happened.  As before, they found an increased frequency of CD24+ B-cells in ME/CFS patients.

What made the increased frequency of these naïve CD24 packed B cells in ME/CFS so interesting, though, was their mode of energy production.

Examining the metabolism of the ME/CFS patients’ cells, the researchers found a “strong(ly) positive” association between the amount of glycolysis and lactate produced and the expression of CD24 molecules on ME/CFS patients’ B-cells. Put another way, the more glycolysis was used to produce energy and the greater the lactate production (a by-product of glycolysis) – the more the CD24 molecule showed up on ME/CFS patient’s B-cells.

energy production me-CFS

Findings suggesting that a body-wide problem with energy production are present in ME/CFS are piling up.

Lower levels of mitochondria in these cells suggested one reason ME/CFS patients’ B-cells may be stuck in this mode.  Not surprisingly, the authors found this more prominent B-cell subset in ME/CFS was also largely unresponsive to stimulation.

That suggested that not only do the energy problems in ME/CFS extend to the immune cells but that they could be impacting immune functioning – in this case by keeping ME/CFS B-cells in a naïve state – that may be associated with disease.

Plus increased levels of the CD24 molecule have also been associated with a damaging state called “senescence”.  Instead of undergoing a process called autophagy during which a cell’s contents are safely recycled, during senescence – which is often associated with aging –  damaged mitochondria cause cells to slowly deteriorate while producing scads of pro-inflammatory factors.

An exercise physiologist, Graham Salmun, recently reported that his exercise study results suggest senescence is indeed occurring in ME/CFS.  He believes problems with aerobic energy production are a) impairing ME/CFS patients ability to produce energy and b) creating a senescent state that is causing chronic inflammation.

Anaerobic Thresholds, Fatty Acid Problems and Autophagy: Dr. Klimas’s Exercise Study

Conclusion

This study provided an intriguing metabolic snapshot of the immune system. The fact that increased expression of the CD24 molecule has been associated with autoimmune disorders and cancer makes the CD24 finding in ME/CFS interesting, but the metabolic connection the researchers found may be more important.

Their findings suggest that the same problems producing energy found elsewhere in ME/CFS may also be occurring in their immune cells.  Plus the findings suggest that a state of senescence, chronic inflammation and cellular unresponsiveness may be present as well. The possible penalties of having an immune system with a broken aerobic energy production system could go beyond fatigue and pain and extend to problems with autoimmunity, and perhaps in rare cases, cancer.

Studies finding an increased reliance on anaerobically produced energy in the muscles, the brain, in neutrophils and now in some of the B-cells all suggest that a body-wide disruption in energy production may be present in ME/CFS.

 

Could “Junk DNA” Be Causing Chronic Fatigue Syndrome / Myalgic Encephalomyelitis?

Carmen Scheibenbogen

Dr. Scheibenbogen continues to successfully plough new ground

It seems like every time you turn around another part of the genome pops up. It’s amazing how far our knowledge of the human genome has progressed since the Human Genome Project was completed just 15 years ago. Thankfully the small band of researchers involved in chronic fatigue syndrome / myalgic encephalomyelitis (ME/CFS) seem to be keeping up with the latest findings.

Dr. Scheibenbogen seems intent on ploughing new ground. First she re-energized the search for autoantibodies in ME/CFS. Then she examined the effectiveness of a promising treatment called immunoadsorption. With her latest study she and her colleagues at Institute for Medical Immunology, Charité-Universitätsmedizin in Berlin became the first in this disease to examine a peculiar part of our genome called long non-coding RNA’s.

Hope for an ME/CFS Autoimmune Subset: A German Researcher Steps Forward

When most people think of RNA they’re probably thinking of the messenger RNA (mRNA) which carries the genetic code from the DNA in the nucleus of our cells to ribosomes. The ribosomes then translate the mRNA into proteins – which then do the work of our cells.

pre mRNA

pre-mRNA -(Wikipedia—httpsupload.wikimedia.orgwikipediacommonsthumbaa4Pre-mRNA-1ysv-tubes)

Not all RNA produces proteins, however. Formerly termed “junk DNA“, non-coding RNA’s – RNA’s which do not encode proteins –  make up a substantial part of our genome.  (They lack the “reading frames” necessary for the process of translation from RNA to protein to begin). Long non-coding RNA’s (lncRNA) are particularly long pieces of RNA (>200 nucleotides long) which do not encode proteins.

While their presence has been known for decades, it wasn’t until the 1990’s that the first hint of the role they play in regulating gene expression and epigenetics  appeared. Research since then has shown that lncRNA’s play an important role modulating the activity of transcription factors which turn the expression of our genes on and off.

Epigenetics –  heritable changes in gene expression that do not involve changes in the underlying DNA sequence – is all the rage now. The ability of infections and other stressors to turn genes on or off via epigenetics presents an intriguing explanation for how an infection could result in ME/CFS. Because lncRNA’s can regulate the epigenetic process, they could provide even more basic insights into how ME/CFS began.

LncRNA’s can also catalyze biological reactions and respond to cellular signals. Their extreme flexibility allows them to interact with proteins, DNA and RNA to affect many physiological processes. One review stated they, “can impact almost all physiological functions.” Another review called them, “a new and crucial layer of biological regulation”.

They’re certainly providing a fresh look at complex diseases. Search for long non-coding RNA’s in PubMed and you’ll get a long list of diseases they may be implicated in. A recent review of the role lncRNA’s may play in cancer called them, “new players in the old battle against cancer”. Some regulate mitochondrial synthesis and energy production.  Pathogens can induce the production of lncRNA’s in humans that then promote viral survival.

It’s become increasing apparent that they can play a role in fundamental developmental processes that can produce chronic disease states. One review called them “arguably the hottest area of RNA research” today.  Still much remains to be learned about the roles they play.

“Remarkable” Finding

The expression signature of very long non‑coding RNA in myalgic encephalomyelitis/chronic fatigue syndrome. Chin‑An Yang1,2,3,4 , Sandra Bauer5, Yu‑Chen Ho3, Franziska Sotzny5, Jan‑Gowth Chang1,3,4† and Carmen Scheibenbogen. Transl Med (2018) 16:231 https://doi.org/10.1186/s12967-018-1600-x

In this study – the first of its kind in ME/CFS – Dr. Scheibenbogen examined the expression of ten very large lncRNAs (> 5 kb) involved in immune regulation, or which influence genes involved in the stress response and/or metabolic and neurologic processes.

The authors were clearly surprised by their findings.  After all, they’d simply taken ten lncRNA’s that they thought, based on findings in other diseases, might play a role in ME/CFS.

In a finding they called “remarkable”, the expression of those ten lncRNA’s was enough to distinguish ME/CFS patients from healthy controls. In fact, the expression of any two of three of these lncRNA’s (NTT, MIAT and EMX2OS) was all that was needed to pick out most ME/CFS patients.

Diagnositic accuracy

The elevated expression of just three lncRNA’s was enough to identify most ME/CFS patients

Then seeking to understand if the chronic illness state present in ME/CFS could be turning these lncRNA’s on by exposing them to biological stressors known to be present in ME/CFS. They found that punishing cell lines with oxidative stress did, in fact, increase the expression of the lncRNA’s. Subjecting the cell lines to a viral stressor also increased expression of one of them. Doing it increased the expression of a gene associated with chronic inflammation and blood vessel dysfunction – two problems that are believed to be present in ME/CFS.

ME/CFS seems to revel in producing findings that baffle researchers and this study was no exception. The enhanced expression of one lncRNA (EMX2OS) was something of a mystery as it is rarely found in the cells (peripheral blood mononuclear cells) they examined. It is, however, increased in brain hypoxia; i.e. low oxygen levels in the brain – which Dr. Shungu’s studies suggest may be present in ME/CFS.

Study Suggests “Bad Energy” is Core Problem in Fibromyalgia and Chronic Fatigue Syndrome (ME/CFS)

Finally, the authors noted that it took just three lncRNA’s (NTT, MIAT, and EMX20s) to do what it took Kerr 88 genes and Naviaux 8-13 metabolites to do – differentiate ME/CFS patients from healthy controls. One wonders if Scheibenbogen’s examination of lncRNA’s is getting at some basic components of ME/CFS.

Treatment Implications

No direct treatment implications were mentioned. In the short-term they’re viewed more as providing excellent diagnostic biomarkers. For instance, lncRNA’s are now being used to one of most difficult diagnostic scenarios of all – prostate cancer. They’re now being used in men with high PSA levels and negative biopsy results.

Direct treatments based on lncRNA’s are probably years away but should be noted that lncRNA’s are a very active area of research for a good reason: turning down their expression could turn off basic processes that cause disease. The author of a recent study which found that LncRNA’s play a role regulate fat metabolism reported:

“We are still in the early stages of figuring out how lincRNAs function in human disease, but what used to be considered ‘junk’ in the genome may actually point us towards the jackpot of developing effective therapeutic approaches for cardiometabolic diseases,” Jennie Lin, MD, MTR

This new exploration of ME/CFS patient’s genomes further substantiates the notion that ME/CFS is a disease of immune dysregulation. Given the study’s strong results surely more lncRNA study in ME/CFS is on the way.

 

Could Crippled Herpesviruses Be Contributing to Chronic Fatigue Syndrome (ME/CFS) and Other Diseases?

We provide evidence…. that herpesviruses dUTPases…(have) unique immunoregulatory functions that can alter the inflammatory microenvironment and thus exacerbate the immune pathology of herpesvirus-related diseases including myalgic encephalomyelitis/chronic fatigue syndrome, autoimmune diseases, and cancer. Williams et. al.

Most people are exposed to herpesviruses such as Epstein-Barr virus (EBV) early in their lives and carry the viruses in latent form in their B cells. Sometimes – particularly when the body is under stress – the immune system slips a bit and the viruses reactivate, causing anything from no symptoms at all to – more rarely – being associated with such devastating disorders as autoimmune diseases and cancer.  One study suggests that glucocorticoids released during stress tell EBV to come out of hibernation.

EBV virions leukemia

EBV infected (green) leukemia cells

Herpesviruses have a long enough history in ME/CFS for the disease to have been referred to as chronic Epstein-Barr virus syndrome by some in the 1980’s. However, over thirty years later, the role herpesviruses play in ME/CFS is unclear. Are they simply a common trigger of ME/CFS or do they play a more fundamental role? Several studies have found no evidence of herpesvirus reactivation while others suggest immune problems exist that could allow the virus to wreak havoc in some patients.

The Ohio State University team lead by Maria Ariza and Marshall Williams believes researchers have missed an obvious possibility. They don’t believe the virus per se is the problem. (If they’re right, you can basically throw out all the viral load studies.)

It’s not that the virus is reactivating; in fact, they believe the virus may be most dangerous in ME/CFS when it fails to reactivate properly and produces kind of a very low-level, smoldering infection. Even as the immune system in people with ME/CFS is mostly smothering EBV, the virus is producing a protein that’s causing harm.

“Surprisingly, none of these studies have approached the possibility that virus encoded proteins, rather than the viruses themselves, may act as drivers of/contribute to the pathophysiological alterations observed in a subset of patients with ME/CFS.” Authors

It turns out that in herpesviruses a failure to replicate produces something called “abortive lytic replication”.  As it does that, it produces proteins that get ejected into the blood stream or get inserted in vesicles called exosomes, which then travel through the blood. These exosomes are now believed to play important roles in cell to cell communication.  (Maureen Hanson is now studying exosomes in ME/CFS).

The protein released during abortive lytic replication is an enzyme called deoxyuridine triphosphate nucleotidohydrolase or EBV-dUTPase. The unusual herpesvirus dUTPase saga at Ohio State University began way back in 1985 with a Williams/Glaser study. It gathered force in the mid-2000’s with a series of papers suggesting the protein might be a good target for chemotherapy, produced “sickness behavior” in mice, and triggered pro-inflammatory cytokine production.

In 2010 Ronald Glaser won an NIH grant to study the protein titled STRESS EFFECTS ON VIRUS PROTEIN INDUCED INFLAMMATION AND SICKNESS BEHAVIOR and the hunt was on to determine dUTPase’s effects in ME/CFS.  (This long standing grant continues today under Ariza and Williams’ name.)

A 2013 paper suggested dUTPase might provide a way to reconcile the studies which had not found herpesvirus reactivation in ME/CFS with others suggesting that the virus could be having profound effects. It found that even under conditions of low viral load, herpesvirus dUTPases were able to trigger a pro-inflammatory response strong enough to promote atherosclerosis and perhaps even precipitate a heart attack. In 2012, Williams, Ariza , Glaser and Martin Lerner and Lenny Jason produced the first direct evidence that dUTPases may be producing problems in ME/CFS. The small study found a prolonged antibody response to the protein in a large subset of ME/CFS patients.

A 2014 study indicated that during EBV’s last gasp while undergoing lytic replication, the virus was pouring enough dUTPase into exosomes to produce major immune effects that supported or promoted the establishment/maintenance of further EBV infections.

The 2017 ME/CFS Study

J Med Virol. 2017 Mar 17. doi: 10.1002/jmv.24810. [Epub ahead of print] Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Gulf War Illness patients exhibit increased humoral responses to the Herpesviruses-encoded dUTPase: Implications in disease pathophysiologyHalpin P1, Williams MV1,2, Klimas NG3,4, Fletcher MA3,4, Barnes Z3,5, Ariza ME1,2.

Then, in an expanded version of the 2012 study, the group in 2017 (which also included Nancy Klimas and Mary Fletcher) presented stronger evidence that herpesvirus produced dUTPases were present and could be causing harm in a subset of ME/CFS patients. The study looked for evidence that herpesvirus produced dUTPases were tweaking the immune systems of 74 ME/CFS patients – and found it.

The fact that antibodies to dUTPases produced by both EBV and HHV-6 were found in almost fifty percent of the ME/CFS patients in the study suggested that the two herpesviruses may be reactivating each other in ME/CFS – a feature also found in immune suppressed states such as organ transplant patients and drug induced hypersensitivity syndrome (DRSS).

Plus, for the first time, autoantibodies to the human dUTPases (humans produce a dUTPase as well) were found in ME/CFS – at much higher levels than in healthy controls (39% vs. 5%).

The authors suggested the Loebel’s 2014 study, which uncovered problems that ME/CFS patients’ T cell’s were having in suppressing EBV, could account for the evidence of multiple herpesvirus reactivations.

EBV I: A Deficient Immune Response, Increased Levels of Epstein-Barr Virus Opens Up EBV Question in Chronic Fatigue Syndrome Again

The immune system does ultimately jump in and suppress the virus in most people with ME/CFS, but it takes its time to do that. That delay appears to give herpesviruses the time they need to spill immune altering dUTPases into the bloodstream and slip them into exosomes to travel through the body.

EBV smoldering infection

EBV is halted from fully reactivating but the authors believe the smoldering infection present in ME/CFS could have significant consequences for some.

Besides the immune alterations possibly caused by herpesvirus produced dUTPases, they may be contributing to numerous symptoms including flu-like symptoms, fatigue, cognitive problems, anxiety, etc. in ME/CFS.

Plus, because failed herpesvirus reactivations commonly occur alongside actual herpesvirus reactivations, herpesvirus encoded dUTPases could end up being an excellent biomarker for herpesvirus reactivations.

This strange model of partial viral reactivation could end up playing a role in ME/CFS, Gulf War Syndrome and other diseases in several ways. It could be actually driving ME/CFS in a subset of patients, or it could, along with other possibly related immune issues, be exacerbating it.

Next Steps

However it all works out, it’s clear that the Ohio State University team’s long embrace of this novel protein is paying off. The more work they do with herpesvirus-encoded dUTPases, the more evidence they seem to find of its role in ME/CFS and other diseases. They have an 8-year continuing NIH grant under their belts – a grant that looks like it and the herpesvirus-dUTPase-ME/CFS saga will likely continue in the foreseeable future.

If the findings hold up, it may even provide a treatment option – the authors have published a paper alerting drug-makers to the potential this escaped protein may hold in treating herpesvirus infections.

Dr. Williams reported that the group has “some exciting data” concerning the potential role dUTPase plays in autoantibody production and the neurological effects the protein may be having in people with ME/CFS. The manuscripts are being written up now and will be submitted shortly.

 

Post Treatment Lyme Disease Unmasked? Immune Hole in the Illness Identified

It’s one of the bigger puzzles in medicine and one that has obvious implications for chronic fatigue syndrome (ME/CFS): why some people given oral antibiotics recover from Lyme disease while others sometimes remain sick for decades. Given the infectious trigger often seen in ME/CFS, any post-viral or post-bacterial illness is of interest. For the most part, researchers don’t know why some people fail to recover fully from an infection; they’ve hardly touched the subject, but an answer in Lyme disease may be coming.

The Study

The study was not large, containing 32 patients and 18 healthy controls, but the results were exciting, providing for the first time a possible biological explanation for the puzzling problem of post-treatment Lyme disease syndrome (PTLDS).

targeted approach Lyme

The ability to target a specific part of the immune system was the key to this studies success.

It’s not taking away anything from the researchers that the study wasn’t particularly innovative. In fact, it did something rather obvious, something that’s been done and is being done in ME/CFS (by Lenny Jason). The study took people with early Lyme disease (n=32) and healthy controls (n=18) and then (after providing the standard antibiotic regimen) followed them over two years, measuring their immune status.

The difference between this successful Lyme disease study and the less successful ME/CFS studies that measured cytokines, gene expression, and autonomic functioning is that the Lyme researchers had a clear target. Mouse studies have shown that the Borrelia burgdorferi bacteria that cause Lyme disease hammer the B-cells, and that’s what the study focused on.

Results

We herein identify plasmablasts as a key B cell population that correlates with resolution of Bb infection and Lyme disease in humans. The authors

They found that B-cells called plasmablasts were elevated prior to antibiotic treatment in patients who returned to health.  Plasmablasts are activated B-cells which circulate for a time in the blood in response to an infection.  The higher level of plasmablasts in the recovered patients suggests that these patients simply mounted a stronger immune response to the infection. That was kind of a no-brainer, but the strength of the study was that they were able to specify what part of our amazingly complex immune system the problem was in.

They also determined that the patients who returned to health also exhibited significantly greater clonal expansion: their activated B-cells produced more clones designed to target and get rid of the bacteria. Again, in retrospect, not a surprising finding, but one that does open up a possible treatment option that hasn’t previously been available.

b-cell Lyme disease

A type of B-cell called a plasmablast turned out to be the key.

Along the way this group also produced a possible diagnostic test which may a) be able to identify Lyme disease infections very early on and b) have high rates of accuracy.  The current Lyme tests do neither; they’re only about 50% accurate during the early stages of infection when studies show treatments are most effective.

They also demonstrated that Lyme disease prompts the expansion of a type of memory B-cell (CD27−) associated with some infections and, more commonly, with autoimmune diseases (rheumatoid arthritis, lupus and multiple sclerosis).

Possible Therapy

Finally, the results point to an unexpected potential therapy – monoclonal antibody drugs. Monoclonal antibody drugs (the “mabs”, e.g. Rituximab) can be theoretically designed to trigger the immune system to target any cell in the body or to influence how the immune system works in other ways. In cancer, for instance, many monoclonal antibodies have been produced that target specific cancer cells. In autoimmune diseases such as rheumatoid arthritis, Crohn’s disease and ulcerative colitis, monoclonal antibodies bind to and inhibit the pro-inflammatory cytokine TNF-a.

Over 75 monoclonal antibody drugs have been approved by the FDA.  Only one, interestingly, specifically has targeted an infection (HIV).  These drugs have, however, recently been effectively used in Ebola and syncytial virus infections.

The authors suggested that Borrelia burgdorferi (Bb)specific monoclonal antibodies could whack the bacteria hard enough to allow doxycycline to work in all patients, not just those with more robust B-cell responses.  In fact, recent developments in monoclonal antibody production suggest that an anti-Lyme drug could be used prophylactically to provide protection against the bug.  The limiting factor may be expense, but recent developments may bring the cost of these drugs down.

Prospecting in Chronic Fatigue Syndrome (ME/CFS)

This study indicates that prospective studies – studies which follow a population over time as some fall ill – can work really well if the study target is focused correctly.  Starting back with Dr. Lloyd’s Dubbo studies several have been done in ME/CFS. None have achieved the results that this Lyme study did, but they have been illuminating.

The Dubbo studies followed 253 people for 12 months after they were infected with one of three pathogens (EBV, Ross-River Virus, Coxiella burnetii). That 11% met the CDC criteria for ME/CFS after six months indicated that long standing illnesses after serious infections were surprisingly common.  Attempts to figure out why a significant number of people remained ill were largely ineffective though.

Some of the studies were quite small and are probably not conclusive but they suggested that neither increased herpes viral titers (herpes virus reactivation) nor changes in 35 cytokines nor gene expression nor psychological factors played a role.

Dubbo studies

The Dubbo studies found that the severity of the initial infection played a role in who failed to recover from an initial infection.bo

The only finding that initially stood out was the severity of the initial infection. People with more severe symptoms initially were significantly more likely to come down with ME/CFS.  In 2008, however, the group found a possible genetic underpinning for the disease; it turned out that polymorphisms (unusual formations) in genes coding for two cytokines (IFN-y, IL-10) affected how ill a person got and how long they remained ill. The findings suggested that a genetic predisposition for an increased inflammatory response might be tipping some people over into prolonged illnesses.

In 2009 Vollmer-Conna, a member of the Dubbo group, working outside ME/CFS found more evidence that one’s immune status makes a difference. She found immune status prior to surgery significantly affected one’s immune functioning, distress levels and ability to recover after surgery.

Next Jason and Katz began a large study of adolescents that came down with infectious mononucleosis (IM). They found no evidence that reductions in peak work capacity, or activity levels, or problems with orthostatic intolerance,  or reductions in salivary cortisol or natural killer cell number and function played a role in an adolescents inability to recover from IM.  The study, however, did suggest that early damage to autonomic nervous system, to the ability to consume oxygen, as well as psychological factors and differences in cytokine networks  were present in those who failed to recover from IM.

Another Jason-Katz study which did not examine biological factors other than autonomic nervous system functioning found, as did the Dubbo study, that the severity of the initial infection – and the amount of bed rest it prompted – played the most significant role in who remained ill. Psychological factors such as “perceived stress, stressful life events, family stress, difficulty functioning and attending school, family stress, and psychiatric disorders” had no impact.

In 2013 Jason, Katz and others began an even larger study which tracked college students after coming down with infectious mononucleosis. They’ve collected blood samples from and have been following over 4,000 college students over the past couple of years. About 5%  contracted infectious mononucleosis, a common trigger for ME/CFS. Grants applications are being written to further assess autonomic functioning, as well as cytokine, metabolome and saliva biological risk factors..

If Jason et. al. have picked the right target, this fascinating study could tell us more about what goes wrong when someone gets ME/CFS. If it doesn’t then their samples –  banked in liquid nitrogen at -80 degrees C –  provide a potentially invaluable resource for the future.

By capturing the blood of people with ME/CFS before they got sick, as they were getting sick and then after the illness became established, Jason’s unique biobank could allow future researchers to quickly determine if the factor they believe plays a critical role in ME/CFS does – saving much time and money.

Small Non-profit Potentially Makes Big Difference

Showing that you don’t have to be large to potentially make a major difference, this potential Lyme breakthrough came not from the NIH or the CDC but from a small Lyme non-profit – The Bay Area Lyme Foundation  – that’s been in business for just over five years.  The study was the product of an 2014 award, The Bay Area Lyme Foundation Emerging Leader Award, that went to Lisa Blum, PhD, a former Stanford postdoc. That award specifically targets veteran researchers who have not previously worked in Lyme research.

The Simmaron Research Foundation is another non-profit that is seeking to scientifically redefine how a disease is understood and treated.  It is currently funding studies that are using proteomics and metabolomics to study cerebral spinal fluid in ME/CFS, that are assessing the effectiveness of underutilized treatments such as Ampligen, IVIG and Cidofovir, and that are seeking to understand why the rate of a lymphoma is increased in ME/CFS.

Could the Brain’s Mast Cells Be Causing Chronic Fatigue Syndrome (ME/CFS)?

“We propose that stimulation of hypothalamic mast cells by environmental neuroimmune pathogenic and stress triggers activates microglia leading to focal inflammation in the brain and disturbed homeostasis.” Theoharides et. al., 2018

Dr. Theoharis Theoharides is an MD and PhD who has published almost 400 papers. A pioneer in the field of mast cell research, Theoharides runs the mastcellmaster.com website and has produced a line of dietary supplements to tamp down mast cell activity. Just a couple of days ago he led an NIH sponsored workshop “Mast Cell Triggers and Mediators Beyond Allergy and Tryptase”.

Recently he took up the subject of chronic fatigue syndrome (ME/CFS), energy metabolism and mast cell activation in a paper “Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Metabolic Disease or Disturbed Homeostasis?

First Theoharides examines the idea that problems with energy metabolism are causing ME/CFS. He agrees that the energy problems ME/CFS patients experience are due to problems with energy depletion, stating that, “Much evidence suggests that the pathophysiology of ME/CFS is highly associated with alterations in normal energy metabolic processes and abnormalities in cellular bioenergetics”, but then spoils it a bit by suggesting that deconditioning could be the cause.

Similarly, in his section on metabolic syndrome and ME/CFS, Theoharides proposes that problems with blood pressure regulation and insulin resistance, “most probably reflect the lack of physical activity and prolonged lack of muscle use in ME/CFS patients”.

low energy production ME/CFS

Theoharides agrees the energy production problems in ME/CFS are real and posits a new cause for them.

But then Theoharides agrees that a hypometabolic state which reduces energy production (ATP) is probably present.  He also agrees that the typical ME/CFS phenotype, i.e. the way the disease presents itself clinically, largely matches that found in people with mitochondrial diseases. He notes that muscle biopsies do show signs of mitochondrial problems.

On the other hand, people with ME/CFS don’t have the mitochondrial DNA mutations, enzyme issues or drops in ATP production typically found in those diseases.

He suggests that free radicals produced by pro-inflammatory cytokines could be whacking the mitochondria in ME/CFS so hard so as to blunt their ATP production, but then notes that no consistent evidence of cytokine upregulation, has been found.

After basically concluding that energy production is a problem in ME/CFS but that none of the usual suspects are the likely answer, and citing the fact that physical, mental and/or emotional stress tends to do people with ME/CFS in, Theoharides, like the Cortene group, turned to the HPA axis.

Many ME/CFS studies, after all, have found problems in the HPA axis – one of the two stress response systems in our bodies – and the axis does affect metabolism. Could it be ground zero for ME/CFS?

Mast Cell Activation

Theoharides thinks so. He proposes that mast cell activation, smack dab in the heart of the HPA axis – the hypothalamus – is occurring in ME/CFS.

If mast cells are involved in ME/CFS it wouldn’t be that much of a surprise.  They are, after all, extraordinarily versatile immune cells which have the capability to produce the extraordinary number of symptoms found in ME/CFS.  Containing hundreds of immune mediators, they can respond to a wide range of stimuli – from pathogens (including mold) to hormones to toxins to immune and neuronal factors.

Best known as mediators of allergic reactions, they’re also “sensors of environmental and psychological stress.” These “sensors” can secrete localized “danger signals” which stimulate the microglia in small pockets of the body/brain.  Theoharides proposes that a mast-cell induced inflammation in the hypothalamus could be causing chronic fatigue syndrome (ME/CFS).

The Mast Cell / Hypothalamus Inflammation Connection

Several studies suggest that inflammation is present in the brains of people with ME/CFS and/or fibromyalgia and Theoharides thinks he knows how this occurs.

It turns out that most of the brain’s histamine is located in the hypothalamus. Plus mast cells are also found in the pituitary gland (as well as the thyroid, the thalamus and the pineal gland).

Theoharides’ mast cell ME/CFS hypothesis begins with a hormone – corticotropin releasing hormone (CRH) – which is released by the hypothalamus during stress and which has been implicated in a series of neuroinflammatory disorders.

hypothalamus chronic fatigue syndrome

Theoharides believes that mast cell activation in the hypothalamus – a key hormone regulator with connections to the limbic system- could play a key role in ME.CFS.

Theoharides believes CRH stimulates the mast cells in the hypothalamus (and elsewhere) to produce something called vascular endothelial growth factor (VEGF), which then increases the permeability of the blood-brain barrier (BBB). That leaky BBB then allows more immune cell (e.g. mast cell) and perhaps pathogen infiltration into the brain and bingo, you have inflammation.

Once in the hypothalamus those activated mast cells produce more CRH, further tweaking the hypothalamus and producing compounds such as histamine, tryptase and mtDNA which send the microglia into a frenzy, causing them to release inflammatory cytokines/chemokines (IL-1B, IL-6, CCL2) that further disrupt hypothalamic functioning.

While the pro-inflammatory cytokines are busy doing that, Theoharides also believes they’re likely whacking the mitochondria in the brain and body, causing centrally (brain induced) as well as peripherally produced (body induced) fatigue, sleep problems, etc.

The main problem, though, is a not an overt threat but hyper-sensitized microglial cells pouring out inflammatory factors in response to the slightest stressors.

(Meanwhile, mast cell activation in the pineal, pituitary and thyroid glands may also be disturbing sleep and producing more fatigue.)

And there you have it. Mast cells – which just happen to be concentrated in several of the brain areas implicated in ME/CFS – have gone off the rails. They’re causing microglial cells to produce pro-inflammatory factors which are producing inflammation in key parts of the brain that are involved in the stress response, fatigue, sleep, etc.

The Hypothalamus – A Central Player

A couple of years ago, though, Dr. Bateman of the Bateman-Horne Center came to a similar conclusion: she believes that inflammation in the lower part of the brain containing the thalamus, hypothalamus and pituitary plays a key role in ME/CFS.  The hypothalamus, which sits just above the brain stem, regulates blood pressure, temperature, and hormone and water content.

Dr. Bateman noted that these organs control the hormones (the hypothalamus is the hormonal control center of the brain) and much of the autonomic nervous system, and then pointed out a long list of hormonal problems (corticotrophin releasing hormone (CRH), growth hormone, thyroid, LH/FSH, vasopressin, oxytocin) that have been uncovered in ME/CFS and fibromyalgia.

She believes that a “limbic encephalitis” is causing a cascade of problems going both ways; up into the cortex and down into the thalamus, pituitary and the autonomic nervous system.

A Mystery No Longer? The Big Picture Emerging In Chronic Fatigue Syndrome? Dr. Bateman Talks

Treatment

Theoharides blasted through several possible mitochondrial enhancing treatments (bezafibrate, angiotensin II inhibitors, CoQ10, Losartan) which he didn’t find all that much promise in, before focusing on magnesium, which he noted plays a “critical role in energy metabolism and in maintaining normal muscle function(ing)”.

Theoharides cited studies indicating that magnesium supplements are able to significantly increase muscle strength and endurance and did so, interestingly enough, by enhancing glucose availability in the brain (possibly low in ME/CFS) and muscles, and by delaying and/or reducing lactate accumulations (possibly high in some people with ME/CFS/FM).

Then it was on to flavonoids, which Theoharides reported have anti-inflammatory, anti-oxidant and neuroprotective effects. Genistein can reduce muscle fatigue while epigallocatechin, naringin and curcumin have been shown to ameliorate ME/CFS symptoms in experimental models.   Astragalus flavonoids, olive extract, and quercetin may have similar effects.

Luteolin was the highlight of the bunch.  With its mast cell inhibiting, anti-oxidant, anti-inflammatory, microglia inhibitory and neuroprotective properties, luteolin is very high on Theoharides’ list, and in 2015 he produced a paper extolling its benefits.  (One study found that tetramethoxyluteolin or methlut appears to be the most effective mast cell inhibiting form of luteolin and is more effective than cromolyn.) Theoharides cited studies that luteolin improved symptoms in autism spectrum disorder (ASD), post-Lyme Syndrome and brain fog in (the not particularly rigorous) open-label trials.

Theoharides has hailed fatigue and mast cell inhibiting properties of flavonoids before and has even produced his own line of supplements, but his statement that, “novel treatment approaches are required to address the central pathogenic processes” in these diseases indicates that, in their current form, these flavonoids are not the answer.

One of the problems has been that it’s hard to get these substances into the brain.  At the end of the paper, though, Theoharides proposes a different way of supplement administration that may be more effective.

Intranasal Administration

“Intranasal administration of select flavonoids may reduce inflammation in the hypothalamus and correct the central pathogenesis of ME/CFS.”

Intranasal administration – basically a shot of volatilized factors into the nose and hopefully eventually into the hypothalamus- is getting more and more attention. Theoharides even suggested if it worked it could even correct the problem.

intranasal spray chronic fatigue syndrome

Theoharides proposes that intranasal sprays may be able to get at the inflammation in the brain

No studies have been done, but since the hypothalamus sits behind the amygdala, which is right behind the nose, it’s possible intranasal supplementation could help dampen down inflammation there.

Flavonoids are just the beginning of the intranasal administration story, though. Over the last couple of years more and more people with ME/CFS/FM have been experimenting with intranasal administration of insulin and glutathione.

Plus, Theoharides mentioned another intranasal option -microvesicle trapped curcumin – that is emerging. Curcumin is perhaps the most scintillating of all the natural anti-inflammatories, but bioavailability has been a challenge.

In 2015 Theoharides proposed that intranasal administration of tetramethoxyluteolin might be useful as well.

A blog on intranasal administration is coming up.

Conclusion

Dr. Theoharides agrees that problems with energy metabolism are likely present in ME/CFS but proposes that their genesis probably lies in mast cell activation in the hypothalamus and other brain organs. Theorharides suggests that corticotropin releasing hormone produced by the hypothalamus activates masts cells to produce substances that activate the microglia, causing the production of pro-inflammatory substances which produce centrally or brain induced fatigue and autonomic nervous system issues. Mast cell activation in the pituitary and thyroid produces further problems with sleep, fatigue and cognition.

Theorharides also proposes that intranasal application of anti-inflammatory substances such as cucurmin and luteolin may be able to access the hypothalamus thus tamping down the neuroinflammation he believes may be at the heart of ME/CFS.

 

 

 

Autoimmune Model Proposes Chronic Fatigue Syndrome (ME/CFS) Begins in the Gut

Jonas Blomberg’s paper “Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model” was published in “Frontiers in Immunology”, an apt journal for a paper featuring an “explanatory model” of chronic fatigue syndrome (ME/CFS). Autoimmunity is definitely a new “frontier”; as Blomberg points out, it’s possibility not a reality yet, but like other frontiers it evokes new vistas – new opportunities and some new challenges.

European ME/CFS reseachers

Jonas Blomberg headed up a European group which produced an autoimmune model of ME/CFS

Blomberg has recently been immersed in a study designed to validate (or not) Dr. Scheibenbogen’s autoantibody findings in chronic fatigue syndrome (ME/CFS). The lead role the Europeans are taking on in exploring autoimmunity in ME/CFS is evident: Blomberg and Gottfries are Swedish, Scheibenbogen is German, and Mella and Fluge – of the Rituximab trial – are Norwegian.

(Carl-Gerhard Gottfries’ story is so unusual that it warrants a short retelling. Gottfries, a Swedish psychiatrist, recovered from ME/CFS using, of all things, a staphylococcus vaccine.  Gottfries opened an ME/CFS clinic, published his findings and treated patients with the vaccine for several decades until it was withdrawn from the market. Find out more about Gottfries’ fascinating story here.)

There are so many ideas floating around concerning the cause ME/CFS that one is tempted to throw up one’s hands. Is cellular energy production in the dumps? Are the autonomic nervous system problems keeping people wired and exhausted at the same time? Is an autoimmune process pummeling the body? Are hidden infections tormenting ME/CFS patients with never ending flu-like symptoms? Or as Cortene suggests, are problems in the HPA axis wreaking havoc on the rest of the body.

We could go on and on (ion channel dysfunction (Griffiths University); whacked out basal ganglia (Miller/Japanese); microbiome dysregulation (Lipkin & Hornig, Unutmaz, Lombardi), “traveling genes”  (RCCX – Meglathery); atypical sepsis (Bell); neuroinflammation (Younger), (mast cell activation in the hypothalamus – Theoharides. ).

The fact that so many people have proposed so many interesting hypotheses is encouraging, but the downside to such a munificence of possibilities is a kind of inertia. Until the ME/CFS field settles on one or a few models of disease, this small field is inevitably going to progress more slowly that we would wish.

In fact, the two Davises at Stanford (Ron and Mark – not related) have questioned whether the field should devote time and money to chasing down hypotheses at all.  Better, they have suggested, to gather more and more data and see what emerges. That said, something has been emerging – an explanatory model in which autoimmunity plays a key role.

An Autoimmune Model of Chronic Fatigue Syndrome 

Basically, the authors propose that it all starts with your genes and your leaky gut. Not the leaky gut you necessarily associate with ME/CFS but the leaky gut you had before, perhaps long before you came down with ME/CFS.

A Genetic Predisposition

Autoimmune diseases typically feature a strong genetic component and run in families. It’s not that rheumatoid arthritis shows up in family member after family member. It’s that a range of other autoimmune diseases do. Blomberg picks out three intriguing autoimmune diseases – thyroid disease, Sjogren’s Syndrome (SS) and lupus – which studies suggest run in ME/CFS families.

genetic predisposition to chronic fatigue syndrome

Evidence of a genetic predisposition is one of several factors suggesting ME/CFS could be an autoimmune disease.

ME/CFS itself is also associated with diseases Blomberg considers to be emerging autoimmune diseases including hypothyroidism, fibromyalgia and POTS, each of which has been associated with increased levels of autoantibodies. Blomberg clearly believes an autoimmune cluster containing many of the diseases associated with ME/CFS is emerging before our eyes.

High rates of two of those diseases (thyroid, SS) also recently showed up in a postural orthostatic tachycardia syndrome (POTS) study (along with antiphospholipid syndrome).

Blomberg then ploughed through genetic, immune and epigenetic data in ME/CFS, highlighting some findings suggesting autoimmunity might be present.

For instance, autoimmune diseases often occur when HLA molecules improperly display self-antigens to cytotoxic or helper T-cells.  T-cells, it turns out, are often huge drivers of autoimmunity, and when they produce autoimmunity, HLA issues are often prominent. Guess what: an HLA issue has been found in ME/CFS. (Ron Davis is studying HLA genes in ME/CFS.) Another study found that increased prevalence of genetic alteration (a SNP) in a T-cell receptor gene known to play a role in autoimmunity suggested that a T-cell based autoimmune process could be present.

Infections, EBV, Autoimmunity and ME/CFS

Infections often trigger autoimmunity. In fact, the infectious trigger that has sparked ME/CFS for many is one big clue that an autoimmune process may be present. With regard to autoimmunity, the more severe the infection, the better, and several studies show that deficiencies in IgG subclasses may have left people with ME/CFS more vulnerable to a severe infection.

Several gene expression studies showing alterations in T-cell and innate immune response genes suggested that ME/CFS patients’ immune systems could be fighting off an infection.

The Autoimmune Virus

EBV is especially interesting as a facilitator of autoreactivity. Blomberg et. al.

If you’re unlucky enough to first meet up with the Epstein-Barr virus (a common trigger of ME/CFS) during adolescence, it’s likely to trigger your immune system to produce a massive number of antibodies, including autoantibodies.  EBV also produces antigens with highly repetitive structures (e.g., Gly–Ala–Gly–Ala repeats in EBNA1) which tend to confuse the immune system and trigger the production of autoantibodies.

It’s no wonder, then, that infectious mononucleosis (glandular fever) significantly increases the risk of later coming down with at least two autoimmune diseases: multiple sclerosis (MS) and lupus. That’s an interesting enough intersection for Blomberg to assert that the immune responses that ME/CFS, MS and lupus have to EBV should be compared.

The Key Organ – the Gut

Anyone have gut symptoms (cramping, bloating, loose bowels, constipation) prior to ME/CFS?  I did – they weren’t major, but if one area of my body was a little bit off back then, it was my gut.

Blomberg believes your leaky gut may be the key to your illness. Not the leaky gut you necessarily have now, but the leaky gut you had before you got ME/CFS.

gut chronic fatigue syndrome

Blomberg believes a genetic predisposition and a leaky gut set the stage for ME/CFS

The gut is such a potential hotspot for autoimmunity because it contains so much foreign material. In fact the gut has been posited as something of a training ground for the immune system- it provides the immune system with the foreign materials it needs to learn how to distinguish self from non-self.

Gut disturbances are fairly common in autoimmune diseases, and the idea that alterations in gut flora are touching off autoimmune processes is being examined in a host of autoimmune diseases (multiple sclerosis, type 1 diabetes, RA, ankylosing spondylitis). The common occurrence of irritable bowel syndrome (IBS) – and the leaky gut that often comes with it – in ME/CFS presents a potential pathway for autoimmunity.

Blomberg proposes that the breach of your gut barrier created a state of low level chronic inflammation prior to you getting ME/CFS. The gut barrier is important because it’s a place in the body where tolerance (the ability to distinguish between self and non-self antigens) is more difficult to maintain. Given the extraordinary diversity and sheer number of gut bacteria, it’s easy to see how the immune system could be overwhelmed and lose it’s way.

Blomberg believes that slow leakage from the gut created a population of auto-reactive B-cells that remained mostly inactive or quiescent (in a state of anergy), almost like undercover agents infiltrating a city, waiting for the signal to pounce.  At some point a “decisive” immune event flipped them into action, and an autoimmune disease – ME/CFS – was born.

He bases his hypothesis of pathogenic autoantibody creation in ME/CFS on a process that appears to be occurring in lupus. The first step occurs when a genetically predisposed person meets up with bad gut bacteria. First, abnormal but not pathogenic B-cells, which have a “weak autospecificity”, appear. These weakly targeted B-cells are not strongly directed against a specific antigen or part of the cell and don’t appear to be particularly dangerous at first, but the body should still eliminate them. Blomberg proposes that it doesn’t.

Over time exposure to the bad gut bacteria causes the specificity of the B-cells to change – making them more targeted and dangerous. At some point an infection turns them on and they start producing clones of themselves which begin attacking the body. ME/CFS is born.

One possible sign that tolerance – the ability of the body to remove autoantibody-producing cells  – has been breached in ME/CFS are the TFG-B (and IL-10) findings. IL-10 and TGF-B, in particular, are the rare cytokines that are more or less consistently found dysregulated in ME/CFS cytokine studies. It turns out that T-helper cells use both these cytokines to regulate tolerance and anergy at the gut mucosa – the very place Blomberg believes the process of autoimmunity in ME/CFS begins.

Ian Lipkin’s recent study found a significant difference in gut composition between ME/CFS patients with IBS and those without. Some of those differences appeared to affect energy production.

Autoantibodies

It turns out that autoantibodies by themselves are not necessarily indicative of autoimmunity. Some “natural autoantibodies – (mostly IgM antibodies) are simply designed to rid the body of dead/apoptotic, damaged and infected cells and rarely cause autoimmune diseases. Other more dangerous autoantibodies need to be turned on by “cell danger” signals before they do harm. (This is why autoantibodies can often be found in healthy people.)

Autoantibodies have, of course, been found in ME/CFS and related diseases like POTS. At the Montreal conference Blomberg reported that his team was validating Scheibenbogen’s autoantibody findings in ME/CFS. They are one clue that autoimmunity is happening in ME/CFS but they provide, Blomberg reported, only circumstantial evidence of autoimmunity.

It’s the “erroneously activated” B-cells, he reported, that are “the root of the evil”, and it’s these cells that need more focus. Blomberg asserts that an in-depth sequencing of these deranged B-cells is needed. By sequencing the variable immunoglobulin chains found in them it should be possible to trace back to how they turned bad.

Other Possible Evidence of Autoimmunity

As noted earlier, Carl-Gerhard Gottfries successfully used a staphylococcal vaccine for years to treat himself and others with chronic fatigue syndrome (ME/CFS). That approach may have worked because the immune stimulation it provoked may have been able to induce tolerance; i.e. induce the body to remove the bad B-cells.

Since Rituximab knocks down B-cells, thereby removing misbehaving ones, it would seem to fit into Blomberg’s hypothesis. Unfortunately, the Rituximab trial failed, and if anecdotal reports are correct, more completely than we could have imagined.

Another possible indication that autoimmunity is present in ME/CFS are studies suggesting the incidence of Hodgkin’s lymphoma is increased in ME/CFS as it is in other autoimmune diseases.

In the end, though, Blomberg reports that the evidence that autoimmunity is at work in ME/CFS is circumstantial. It relies on the fact that people with ME/CFS often have other autoimmune diseases such as thyroiditis or diseases suspected of involving autoimmunity such as POTS, FM and IBS, that autoantibodies are present, and that immunostimulation (IVIG, staphyloccocus vaccine) may work.

Most of the work, though, needed to fulfill the Witebsky–Rose criteria for autoimmunity, remains to be done.

Primary Biliary Cirrhosis – An Autoimmune Roadmap for Chronic Fatigue Syndrome (ME/CFS)?

At the start of their paper, Blomberg et. al. proposed that their model could explain many of the facets of ME/CFS that have emerged – the most prominent of which are the energy production problems.

An autoimmune disease exists in which an attack on the energy producing processes in the body produces symptoms and findings similar to those found in ME/CFS.  In primary biliary cirrhosis  (PBC) antibodies attack a small fatty acid molecule (lipoic acid) that’s part of the energy producing machinery on the surface of the mitochondria.

pyruvate dehydrogenase

Pyruvate Dehydrogenase -By Jonathanmott09 – Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=18520937

The antibodies in PBC attack the pyruvate dehydrogenase (PDH) enzyme complex which regulates the transition from glycolysis (anaerobic energy metabolism) to the tricarboxylic acid cycle (aerobic energy metabolism). The same issue -the transition from glycolysis to aerobic metabolism – has shown up repeatedly in ME/CFS studies.

Even though PBC is considered a liver disease, it produces enormous amounts of fatigue as well as cognitive problems, orthostatic intolerance and sympathetic nervous system hyperactivity. In fact, Julia Newton, who studied PBC before she studied ME/CFS and started a Rituximab trial in PBC two years ago, stated back in 2013 that,

“…at this stage the muscle and cardiac abnormalities that we have seen in patients with ME/CFS are exactly the same as those that we have seen in patients with PBC.”

Another fascinating aspect of PBC is that the autoantibodies are attacking a molecule, lipoic acid, which is added to the PDH enzyme using a rare process called lipoylation. Because some gut bacteria (Novosphingobium) also use lipoylation, it’s possible that bacterial leakage initiated the autoimmune process causing PBC.

Blomberg suggested that pathogenic, as yet unidentified immunoglobulins directed against mitochondrial proteins could be the source of ME/CFS and exhorted researchers to compare the post-exertional malaise in ME/CFS to other diseases such as fibromyalgia, PBC, etc.

Autoimmunity or Oxidative Stress? 

Finally Blomberg et. al. suggested that oxidative stress could be producing the same energy depleting issues as autoimmunity. That’s an intriguing idea given the comforting consistency oxidative stress study results have had in ME/CFS.  The authors noted that it was recently shown that the oxidation of a critical part of the pyruvate kinase enzyme can effectively block the transition of glycolysis to aerobic metabolism.

Dr. Shungu believes the lactate accumulations and glutathione reductions his studies have validated in the ventricles of the brains of ME/CFS patients are associated with oxidative stress.

Conclusion

Blomberg’s autoimmune model proposes that the seeds for ME/CFS were lain possibly long before the disease appeared and only “sprouted” once a decisive immune event occurred. He believes that a genetic predisposition plus a leaky gut laid the groundwork over time for what eventually became an autoimmune disease.

Autoantibodies provide circumstantial evidence of autoimmunity in ME/CFS but are not nearly enough to validate it.  Blomberg asserted that an intensive study of the abnormal B-cells in ME/CFS could both help to validate that diagnosis and identify the precipitating event which triggered this illness.

If ME/CFS is an autoimmune disease targeting the mitochondria it may have a close cousin called primary biliary cirrhosis (PBC) which produces similar symptoms including enormous fatigue. In PBC autoantibodies disrupt the transition from anaerobic to aerobic energy production – the same process, interestingly enough, that appears to be affected in ME/CFS.

While autoimmune processes could produce the energy problems in ME/CFS, oxidative stress – which studies have found to be consistently high in this disease – could produce the same result.

System Reset? Study Suggests Pro-Inflammatory / Autoimmune Reset Occurred in Chronic Fatigue Syndrome (ME/CFS)

Epigenetics research holds the fascinating possibility of figuring out what shifted at the very beginning of chronic fatigue syndrome (ME/CFS).  For many with ME/CFS a sudden change occurred – some sort of biological reset quickly happened – which never relinquished itself.

epigenetic reset ME/CFS

Something triggered ME/CFS. Could it have been an epigenetic reset?

Finding out what “reset” occurred is what epigenetics is all about.  Epigenetics identifies changes in the expression of our genes that occur after we meetup with biological stressors such as pathogens, drug, toxin or even foods.

Most of our genes that produce proinflammatory cytokines, for instance, have a kind of a lock on them. Removing that lock leaves them free to express themselves and leaves us open to poor health.

Epigenetics explores how the biological challenges we encounter in life can remove those locks (or add to them) resulting in an entirely new genetic landscape – one that could perhaps cause something like ME/CFS.

Many people’s ME/CFS/FM starts with an infection, and viruses can exert major epigenetic changes to our genome.  Herpes simplex virus (the virus Dr. Pridgen is targeting in fibromyalgia) engineers changes to our genome which help the virus avoid destruction and enhance its replication. Those changes include a suppression of our immune system, which can result in an increased risk of cancer.

What goes around comes around, though.  Epigenetic News recently reported that an epigenetic modifying cancer drug was able to return the parts of the immune system that the  herpes simplex virus had disturbed to normal. The drug was able to effectively fill in the immune hole created by the herpes virus by boosting a number of immune factors (IFN-a, IL-8, IL-6, transcription factors, stress response factors). Mouse studies revealed that the drug also reduced reactivation of the virus.

That suggests that some similar drugs now in clinical trials could help in the fight against herpes and other viruses or could perhaps simply return to normal epigenetically modified genes that have suppressed immune functioning.

 “A new class of antivirals based on this study might be useful for patients who are resistant to existing antivirals like acyclovir and ganciclovir….. (or in) viral infections for which there aren’t pharmaceuticals to boost an individual’s immune response.” Dr Kristie

If epigenetics turns out to play the major role in ME/CFS that it does in cancer and other diseases, a cancer drug could someday be in store for ME/CFS treatment.

Epigenetics Study Highlights Immune Alterations in ME/CFS

The epigenetics story begins with gene transcription – the first step in the process of translating our genes into proteins.  Gene expression gets enabled by the removal of methyl groups that block transcription and/or by the addition of methyl groups that stop genes from being expressed.

Malay Trivedi and Lubov Nathanson at Dr. Klimas’s Institute of Neuroimmune Research at Nova Southeastern University recently published the most comprehensive study yet on epigenetics in chronic fatigue syndrome .

Just a few epigenetic studies have been done in ME/CFS and none like this one. For one, the group took advantage of a new breakthrough in genetic testing (an advanced Illumina array) to almost double the number of testing sites (from 450,000 to 850,000 sites). For another, the larger sample size (64 participants from two geographically distant locations) ensured a more comprehensive look at the epigenetic changes in ME/CFS. This allowed the group to produce what they called “consensus hypomethylated sites” they believe could be used in future studies.

The general findings of the study agreed with those from past ME/CFS epigenetic studies. Hypomethylation – the deletion of methyl groups, which make it easier for the genes to be expressed – was the theme, with 98% of differentially methylated sites in ME/CFS hypomethylated compared to controls. (Only 2% were hypermethylated compared to controls.)  The hypomethylation was most prominent in genes associated with immune cell regulation.

The high degree of hypomethylation was intriguing for several reasons. For one, Epstein-Barr Virus – presumably a common trigger in ME/CFS – overwhelmingly triggers hypomethylation and almost no hypermethylation of genes. Hypomethylation is also associated with pro-inflammatory gene expression in autoimmune diseases as well as in cancer promotion.

Multiple Sclerosis Breakthrough

A “global” hypomethylation, for instance, is also found in lupus and rheumatoid arthritis. The hypomethylation of a promoter gene for IL-6 in rheumatoid arthritis causes an overexpression of pro-inflammatory cytokines and other immune factors which ultimately results in joint damage.

Epigenetic changes to the HLA genes may have triggered MS. (HLA Gene Expression – by ZionLion77 – https://en.wikipedia.org/wiki/Human_leukocyte_antigen#/media/File:MHC_expression.svg)

The recently uncovered hypomethylation of an HLA gene in multiple sclerosis (MS) prompted researchers to state that epigenetic changes may even be “caus(ing) the disease”. That bold statement reflected the findings of a recent large study, which indicated that epigenetic changes were directly causing the largest risk factor found yet for MS.

That finding may have implications that go far beyond MS and could conceivably reach ME/CFS/FM.  Since the HLA region of the genome is associated with almost all autoimmune diseases, the authors believe their finding will impact other autoimmune diseases.

(Several years ago Ron Davis pegged the HLA region as a potential study area for ME/CFS. His Stanford Genome Lab has developed new methods of assessing this complex region of our genome, and he and Mike Snyder at Stanford are doing an intensive analysis of that HLA region in ME/CFS.)

Back to Chronic Fatigue Syndrome (ME/CFS)

The highest degree of hypomethylation in a genetic region in ME/CFS occurred in gene promoters associated with natural killer cell functioning, no less – the most consistent finding in ME/CFS.  That suggested that some sort of epigenetic reset – perhaps triggered by an infection – occurred in the NK cells of ME/CFS patients.

With regard to single genes, the authors highlighted the hypomethylation of genes associated with muscle hypotonia (low muscle tone) and cognitive impairment (MED13L), problems with protein synthesis (metabolism), and glucocorticoids (SGK3 gene – inflammation).

It was the immune genes, though, where the hypomethylation really came to the fore. Immune genes that regulate the adaptive immune response (T & B cells) and the production of immunoglobulins were hypomethylated. The authors asserted that those findings were in sync with reports of improvement from Rituximab.

Promoters (MMP14, MAP4K4, MAPK12 and CREB5), which may be activating tumor necrosis factor signaling pathways and thus contributing to the pro-inflammatory problems believed present in ME/CFS, were hypomethylated as well.

A gene (miRNA-148a) that impairs the innate immune response was also hypomethylated. Several of the hypomethylated genes were also found in prior ME/CFS studies.

Then there’s the IL21R gene. The hypomethylation of the IL21R gene promoter in ME/CFS could promote inflammation, autoimmunity, thyroid disease, intestinal inflammation, and others.  IL-21 also plays a critical role in triggering spontaneous experimental autoimmune encephalomyelitis – an animal model of brain inflammation.

Conclusion

IL-SR gene chronic fatigue syndrome

Unleashing the IL2R gene could contribute to inflammation (including neuroinflammation), thyroid disease and autoimmunity

Epigenetics is a relatively new science which is already proving to be a boon to the study of autoimmunity and cancer. Larger studies will be needed in ME/CFS for epigenetics to reach its potential, but the study from Dr. Klimas’s group suggested that, just as in some autoimmune diseases, enhanced hypomethylation may be increasing the expression of genes which promote inflammation and autoimmunity in ME/CFS.

The most encouraging thing about epigenetics is the possibility of reversing the epigenetic changes a pathogen, toxin or drug has caused. Much more study is needed to isolate any epigenetic culprits in ME/CFS, but epigenetic altering drugs are being developed for other diseases. One intriguing drug seeks to reverse the epigenetic changes caused by herpes simplex virus – thus returning the immune system to normal.  Another breakthrough suggests that epigenetic changes may be major drivers of multiple sclerosis.

This is clearly a field to keep an eye on.