Archive for December, 2018

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.