ME/CFS Buzz (March 19th) – the Gut, the Brain, the Immune System and more

March 22, 2012

Posted by Cort Johnson


A Biological Cause of ‘Poor Stress Management’ Found in ME/CFS?

Brain Behav Immun. 2012 Mar 6. Stress management skills, neuroimmune processes and fatigue levels in persons with chronic fatigue syndrome. Lattie EG, Antoni MHFletcher MAPenedo FCzaja SLopez CPerdomo DSala ANair SFu SHKlimas N.

Its certainly not clear that everyone with ME/CFS reacts poorly to stress but anecdotal reports suggest that many people with ME/CFS are more vulnerable to stressors after the getting the disorder than they were before they had it. Noting that stress often worsens symptoms this study looked for physiological components that might be able to explain part of the stress response problem in ME/CFS. In this study these Miami researchers looked at self-report measures of fatigue, emotional distress and their ability to manage their stress and sought to link them to cytokine and cortisol measures.

They found that patients with better ‘perceived stress management skills’, not surprisingly, tended to be less fatigued and have less emotional distress and have a greater cortisol fluctuations over the day and lower levels of Il-2. The lower levels of diurnal cortisol in the more stressed out patients suggested a less ‘dynamic’ stress response system was present and brought into question whether damage to HPA axis was responsible for some of the difficulties some people have in handing stress.

Low diurnal cortisol levels have been found in rheumatoid arthritis but have mostly been studied, not surprisingly, since cortisol is a ‘stress hormone’ in stress disorders They’ve been found in fibromyalgia, post traumatic stress disorder, RA and other disorders.

One ME/CFS study found that behavioral therapies could return cortisol levels to normal in some patients while another suggested that those types of therapies didn’t work as well in people with low cortisol levels.

The fact that patients with high levels of IL-6 tended to rate themselves as being poor at stress management and suffered from increased fatigue suggested that high levels of this cytokine, long known to be associated with increased pain levels, may result in increased distress and inhibit an individuals ability to manage stress.

This study suggested that problems in two areas, the HPA axis and the immune system exacerbate symptoms and may impact the ease with one deals with stress.

The Body/Mind Connection: Do Bad Gut Bacteria Cause Depression (?)

J Affect Disord. 2012 Mar 11. Increased IgA and IgM responses against gut commensals in chronic depression: Further evidence for increased bacterial translocation or leaky gut.

Maes MKubera MLeunis JCBerk M.

Bacterial translocation with immune responses….commensal bacteria may play a role in the pathophysiology of depression, particularly chronic depression.

In the study just reviewed we saw that high levels of an immune factor called IL-6 might cause increased pain and increase the difficulty of managing stress. Now Dr. Maes shows that the immune system may be involved in causing depression as well. Dr, Maes has been focusing on the physiological causes of fatigue and depression for years and in this study he zeroed in on the gut.

Some researchers believe leaky gut linings in people with IBS, CFS and other disorders allow gut bacteria to ‘translocate’ out of the gut and make their way into the blood stream where they prompt an immune reaction and symptoms of fatigue, pain, etc. In this followup study Maes found that people with chronic depression (but not recurring depression) had increased levels of antibodies to an array of pathogenic gram-negative gut bacteria. (The outer membranes of this type of bacteria contain an endotoxin which can trigger fever and alarming low levels of blood pressure and even in really severe cases, death. Given this it’s not surprising that the immune system jumps on these bacteria right away. )

Maes’s finding indicated that pathogenic bacteria may be making their way out of the gut of people with chronic depression but not in the healthy controls suggesting that depression in some people may be more in the gut than in the head.

Bacterial Toxin Makes Healthy People Look Rather Like CFS Patients

Nucl Med. 2012 Mar 13. Glucose Metabolism in the Insula and Cingulate Is Affected by Systemic Inflammation in Humans. Hannestad J, Subramanyam KDellagioia NPlaneta-Wilson BWeinzimmer DPittman BCarson RE.

In the last study Maes’s findings suggested that endotoxin triggered inflammation could be causing depression. Now these Yale researchers went so far as to inject healthy people with small amounts of endotoxin and then used a PET scan to see what parts of the brain were affected.

They found that endotoxin results in increased fatigue, reduced social interest, increased inflammatory cytokines levels, higher activation (glucose metabolism) of the insula and lower activation of the anterior cingulate.

This study suggested that systemic inflammation – the kind that probably occurs in CFS – produces ‘depressive symptoms’ (eg fatigue, mood swings, etc., poor sleep, etc.) and alters the functioning of brain regions involved in interoception (monitoring the body’s internal signals), positive emotions and motivation.

Recent (and upcoming studies) have targeted abnormalities in the insula and the anterior cingulate in ME/CFS. This study suggests that these abnormalities can be caused by inflammation triggered by bacterial toxins – which as Maes showed – could be present in the gut area.

Did They Miss a Disease? Chronic inflammation paper points way to ME/CFS?

Semin Cancer Biol. 2012 Feb 24. [Epub ahead of print]New insights into chronic inflammation-induced immunosuppression. Kanterman JSade-Feldman MBaniyash M

Chronic inflammation is present in a variety of chronic illnesses and some researchers are convinced it plays a key role in CFS but the idea that inflammation is driving an illness rather than being a product of one is probably fairly new. In this paper focusing on ‘new insights’ these Israeli researchers state that chronic inflammation results in a kind of complicated steady state of immune functioning that is just beginning to be understood. The most interesting thing about this steady state is how closely it may mimic what is happening in CFS.

These Isreali researchers state that chronic inflammation results in reduced natural killer cell functioning and immune suppression – two factors that appear to be present in ME/CFS. How intriguing it is that a state of chronic inflammation (ie immune activation) appears to produce a state of immune suppression as well.

There are more intriguing intersections here….The NFkB and STAT transcription pathways that play a key role in producing immune suppression have both been implicated in ME/CFS . The immune suppression present in chronic inflammation blunts the impact of immune based therapies and suggests that immune treatments must be ‘fine(ly) tuned’ to be effective. We’ve heard similar considerations from Dr. Klimas and others regarding the delicate balancing act needed to promote the under-active portions of the immune system and tamp down the over-active ones in ME/CFS.

It’s not clear if this situation does apply to CFS but it does hold out the promise that similar patterns of immune activation/immune suppression might occur elsewhere and researchers in other disorders could be developing tools that might be helpful in CFS.

Gene Linked to CFS Pops Up In Chronic Pain Study

Eur J Pain. 2012 Mar 13. doi: 10.1002/j.1532-2149.2012.00131.x. [Epub ahead of print]Genetic variation in the beta-2 adrenergic receptor is associated with chronic musculoskeletal complaints in adolescents. Skouen JSSmith AJWarrington NMO’ Sullivan PBMcKenzie LPennell CEStraker LM.

The beta-adrenergic receptor- 2 showed up big time in the Light gene expression studies and now its appearance in a fibromyalgia study suggests that problems with this gene contribute to fatigue and pain in a variety of disorders. This western Australia study examined polymorphisms in beta adrenergic 2 receptors and the COMT gene to see if FM patients with more pain happened to have unusual forms of these genes.

This study found that being female (once again :)) and poor mental health (?) was associated with an increased risk of having disabling neck and low back pain and widespread pain and having an unusual form of the beta-adrenergic gene.

According to the Lights this gene dilates the blood vessels that feed the muscles. Its not clear what this particular variant does but it sounds like problems with it could impair blood flows causing metabolite buildup and perhaps widespread muscle pain….. perhaps even after exercis

Its good to see similar findings crop up in different studies in allied disorders

In the Bulls-eye: Cochrane Reports Focus on Milnacipran in Fibromyalgia Cochrane Database Syst Rev. 2012 Mar 14;3:CD008244. Milnacipran for neuropathic pain and fibromyalgia in adults. Derry SGill DPhillips TMoore RA.

Drug companies must shiver whenever they hear that the Cochrane reports are lasering in on one of their drugs. The Cochrane reports take a therapy or drug, do an intensive analysis of studies involving it, and then pretty much tell the world whether its any good or not.

This time they had Milnacipran, a drug approved for neuropathic pain and fibromyalgia, in their sights. Their report was pretty much in line with Dr. Clauw’s general prescription of pain drug effectiveness…it worked fairly well (30% reduction in pain) in some patients (about 40%)and not at all in others. (It was just above placebo in effectiveness with about 30% more people getting relief). (Dr. Clauw noted that the placebo effect is surprisingly strong in pain drug trials).

This highlights a couple of things…one – pain relief is a tricky process that is still little understood and is quite variable across the population and two…there are few magic bullets out there…three – placebo ie mindfulness interventions do reduce pain moderately (30%) in a subset of patients.




Dr. Lerner Video and Treatment Guide Released

Dr. Lerner has been treating ME/CFS patients for a long time and he has just released a two part video called a ‘Primer for CFS’ as well as a Treatment Resource Guide which is chock full of heretofore difficult to find information.

Check out the Forum Thread here:>

Phoenix Rising Looking for Recovering/Recovery Stories 

Yes it does happen! And we’d like to find how and to who. As part of an upcoming series on Treatment we’re looking for stories of people who have recovered significantly or fully. Some of the things we’d like to know are

  • date of illness
  • Type of onset
  • How sick you got
  • What worked
  • How long it took
  • Resources You suggest
  • Advice for others

Please send your stories to No stories/accounts will be made public without your permission.

The Phantom Struck Down by ME/CFS

Phantom of the Opera star Michael Crawford developed a bad enough case of ME/CFS that he was forced to retire for some years…Lots of rest helped him to eventually recover and he began to talk about it last year. Recently he did a radio interview in which he mentioned it.

and check out another story here

Anesthesia WARNING Wallet Card for ME/CFS & FM Patients

The New Jersey CFS Association offers a printable card you can carry in your wallet ( regarding precautions in case you should need anesthesia in an emergency. It is based on advice to doctors/patients who are about to be hospitalized or have surgery, developed by Dr. Charles Lapp and Dr. Paul Cheney
Easier Form of Gamma Globulin Making the Rounds

Gamma Globulin Come to Your Home- – Some patients do very well on gamma globulin but its always had to be administered intravenously. Now several ME/CFS docs including Dr. Lapp and Dr. Peterson are using a subcutaneous version by Hizentra that uses a windup pump which slowly pushes the IVIG in under your skin .

If this works out it will make a useful treatment much easier (and hopefully less expensive) top access.


{ 11 comments… read them below or add one }

Cort March 23, 2012 at 6:56 am

Thank Claire! I appreciate it.


Rachael March 23, 2012 at 9:20 am

I am very interested in the gut/ brain/ immune system connection in ME/CFS and how it seems to cross-over into illnesses like autism and autoimmune conditions (many of these conditions reporting IBS as problematic). The second brain, technically known as the enteric nervous system contains some 100 million neurons, more than in either the spinal cord or the peripheral nervous system. The enteric nervous system uses more than 30 neurotransmitters, just like the brain, and in fact 95 percent of the body’s serotonin is found in the bowels. Serotonin can have a stimulatiing effect on the immune system.

Some foods, along with some antidepressant medications called SSRIs increase serotonin levels in the gut/brain. It’s little wonder that meds meant to cause chemical changes in the mind often provoke GI issues as a side effect, such as irritable bowel syndrome. This is probably one of the reasons SSRI’s affect some ME/CFS sufferers so badly; those who already suffer from irritable bowel, nausea and an up-regulation of the immune system and are not in need of more serotonin, or an immune system boost.

Think Twice: How the Gut’s “Second Brain” Influences Mood and Well-Being


Cort March 23, 2012 at 3:00 pm

Thanks Rachel, I agree the gut or the ‘second brain’ is a fascinating area. Sometime this year we should get the outcome of the CAA funded study to characterize the gut flora of CFS patients before and after exercise…..:)


Arnar March 23, 2012 at 11:01 am

Great post, Cort. Very interesting summaries altogether.Your work is much appreciated. Greetings from Sweden.


Cort March 23, 2012 at 3:12 pm

Thanks Arnar – from the home of my ancestors (some of them anyway) :). Hope you’re doing well.


Tony Mach March 23, 2012 at 1:32 pm

Two remarks:

The studies by Kathleen and Alan Light find an direct association with the alpha-2a receptor, not the the beta-2a receptor (unlike the study by Skouen et al.). Now, there may be an indirect connection (that a mutation in the beta-receptor leads to an differential expression in the alpha-receptor). But the studies do not map one to one.

Personally, I find the conclusions of Michael Maes (in all of his studies) too good to be true. Until there are others who independently confirm his findings, I personally will take his studies with a lot of grains of salt.


Cort March 23, 2012 at 2:57 pm

Sigh…this stuff is tough…Thanksy – lot’s of adrenergic receptors there. I got the Light stuff from a book chapter they wrote

In addition to the mean differences, we found strong correlations between increases in mRNA of ASIC3, P2X4, P2X5, TRPV1, adrenergic α2Aα2A, adrenergic β1, β2, COMT, IL10, TLR4, and CD14 in the CFS patients and their reports of increased mental fatigue during the 2-day time period following exercise.

I hope that the adrenergic B2 RNA corresponds to the “beta-2 adrenergic receptor ” mentioned in the title of the study – this is a complicated field :(…

In the book chapter ( the lights suggest that this group of receptors all do figure in muscle activity (muscle relaxation) and blood flows (blood vessel dilation).

“This increased blood flow serves to reduce metabolites, terminating the signals underlying sensory muscle fatigue. The sympathetic output signal is mediated by adrenergic β2 receptors on vascular smooth muscle in the working muscle and by adrenergic α receptors in non-working muscles, and by adrenergic β1 receptors in heart muscle.”

Given how involved these receptors are in muscle relaxation ( (which is probably what I should have focused on) the fact that they’ve popped up in this chronic pain states ifs fascinating..and given all my problems with muscle stiffness, particularly after exercise. (Thanks for getting me to ‘dig deeper’ :))

I tried to find out what the particular polymorphism did but have been unsuccessful so far.


Claire Castell March 23, 2012 at 2:07 pm

Excellent report on the latest research. Thanks, Cort, for keeping us up to date.


Phoenix Rising March 23, 2012 at 2:55 pm

Thanks Claire – I appreciate it.


MishMash March 24, 2012 at 7:18 pm

Thanks Cort. Six articles, all pointing to diametrically opposing etiologies for our illness. We still have failure to launch. Oh well…


Cort March 25, 2012 at 6:15 pm

Ha! I wonder if there’s anyway to connect the dots…


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