ME/CFS in the Era of the Human Microbiome: Persistent Pathogens Drive Chronic Symptoms...

ljimbo423

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Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in the Era of the Human Microbiome: Persistent Pathogens Drive Chronic Symptoms by Interfering With Host Metabolism, Gene Expression, and Immunity
Amy Proal
* and
Trevor Marshall


Autoimmunity Research Foundation, Thousand Oaks, CA, United States

The illness ME/CFS has been repeatedly tied to infectious agents such as Epstein Barr Virus. Expanding research on the human microbiome now allows ME/CFS-associated pathogens to be studied as interacting members of human microbiome communities.

Humans harbor these vast ecosystems of bacteria, viruses and fungi in nearly all tissue and blood. Most well-studied inflammatory conditions are tied to dysbiosis or imbalance of the human microbiome.

While gut microbiome dysbiosis has been identified in ME/CFS, microbes and viruses outside the gut can also contribute to the illness. Pathobionts, and their associated proteins/metabolites, often control human metabolism and gene expression in a manner that pushes the body toward a state of illness.

Intracellular pathogens, including many associated with ME/CFS, drive microbiome dysbiosis by directly interfering with human transcription, translation, and DNA repair processes.

Molecular mimicry between host and pathogen proteins/metabolites further complicates this interference. Other human pathogens disable mitochondria or dysregulate host nervous system signaling.

Antibodies and/or clonal T cells identified in patients with ME/CFS are likely activated in response to these persistent microbiome pathogens. Different human pathogens have evolved similar survival mechanisms to disable the host immune response and host metabolic pathways.

The metabolic dysfunction driven by these organisms can result in similar clusters of inflammatory symptoms. ME/CFS may be driven by this pathogen-induced dysfunction, with the nature of dysbiosis and symptom presentation varying based on a patient's unique infectious and environmental history.

Under such conditions, patients would benefit from treatments that support the human immune system in an effort to reverse the infectious disease process.
 
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Belbyr

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Interesting article, lots of reading. I had a recent relapse and unfortunately I'm still in it. Started to run low grade fever, ached really bad all over like a flu, and all my symptoms were pretty bad.

I told myself, my body is fighting something!
 
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This is an excellent review.

Any suggestions regarding:

“treatments that support the human immune system”?
Mel, the author alludes to the kind of immunotherapy they’re using for cancer patients where they re-engineer the t-cells to attack the tumors- this can be done for pathogens as well. I saw a recent publication about MS patients receiving an immunotherapy that activated cells to attack EBV virus- although early, study cited exciting developments (vision, mobility improvements) Here is link to that article: : https://neurosciencenews.com/immunotherapy-ms-10238/amp/
 
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S-VV

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Authors webpage: http://microbeminded.com

Trevor Marshall, co-author, is the creator of the Marshall protocol, ie, vit (25) D is immunosuppressive, and stimulating the VDR is good for the inmune system.

He does this with olmesartan. In fact, he has one study about inmunostimulation for CFS patients.
 
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Honestly, this vitamin D protocol sounds dubious. I'm going to put it on the shelf right next to methylation.
It’s only referenced to provide example of a protocol that used immunostimulation as its basis - not at all advocating.
 
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I'm skeptical too. Has anyone here actually tried this protocol? I would think that, if it was actually effective, the word would be out by now.
Protocol takes years to complete and works by putting the majority of CFS symptoms into overdrive(not always, but very often) to aid the immune system in eventual systemic inflammation resolution. There are a lot of stories of successful recoveries from CFS(along with other diseases) on their support forum.
 

bertiedog

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There are a lot of stories of successful recoveries from CFS(along with other diseases) on their support forum.
Some people reported that they nearly died from trying his theory and what put me off was that everything was cloaked in secrecy and anybody who reported negative findings were accused of not doing the protocol properly. I remember it very well as something to avoid.

Pam
 
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Some people reported that they nearly died from trying his theory
Probably they were moving too fast with antibiotics.

reported negative findings were accused of not doing the protocol properly.
Negative findings of what? Side effects of immune activation? Well, yeah, they can be rather unpleasant at times. :) Especially for those with a history of managing CFS with immune suppressing supplements(O-3, Curcumin, ALA, NAC, NAG, Pred, D3, B-vits, etc).

I remember it very well as something to avoid.
It becomes somewhat easier to tolerate once one realized that the other side of the coin is an endless queue of various anti inflammatory drugs/vitamins and nothing else...
 
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ukxmrv

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I'm skeptical too. Has anyone here actually tried this protocol? I would think that, if it was actually effective, the word would be out by now.
It's been done to death many years ago. Some of the proponents joined online CFS groups way back when it was Vit D and sunlight aversion and then drugs.

There was in-fighting even within the group of people pushing the theory and a lot of nastiness.

Personally I take a big pinch of salt whenever this is mentioned.

I am guessing that this is a "low impact" journal?
 
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There are still zero alternatives. Well there is one: wait a decade or so in a hope that symptoms will eventually come to a resolution ... or decline even further to a totally disabled state.
 

JES

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There are still zero alternatives. Well there is one: wait a decade or so in a hope that symptoms will eventually come to a resolution ... or decline even further to a totally disabled state.
There is a third possibility, decline even further following experimental treatments with little evidence. There is no win-win scenario, if it was that simple, everyone would already be onboard. At best you can luck into finding something that works. When you read about people that have recovered, there is not one treatment that is consistently mentioned. If you go through all recovery stories online, they are attributed to at least a hundred different treatments. What's worse, some of these recoveries might not have come from the treatment itself, but from some other factor, we don't simply know. We don't even know if ME/CFS is one disease or a cluster of diseases with similar symptoms.
 
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There is a third possibility, decline even further following experimental treatments with little evidence.
Attached is my blood test before and 3 months later after staying on the protocol. Only sick gets this kind of shift of immune cells on Olmesartan - for healthy ones it is identified as placebo. I've showed it to an immunologist and he told that they see this king of changes in blood work after commencing their own immune stimulation protocols on a patients with various deceases.

https://www.ncbi.nlm.nih.gov/pubmed/15291377
In the dose-finding study, 792 patients were randomized to olmesartan (2.5-80 mg) or placebo once daily…. The results of the clinical studies in >3000 patients receiving olmesartan showed that the frequency and profile of adverse events with olmesartan were generally similar to those with placebo; the frequency of adverse events was not dose related. Olmesartan, with or without hydrochlorothiazide, was well tolerated over two years of treatment.

There is a third possibility, decline even further following experimental treatments
Good points and basically yes, i agree. There are certain risks in every treatment.

We don't even know if ME/CFS is one disease or a cluster of diseases with similar symptoms.
There is enough research data presenting CFS as an inflammatory disease(against chronic infections such as Lyme, EBV, etc)

Some links from my personal collection of evidence:

Mean cytokine levels in ME/CFS patients(a table):
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576836/table/t03/?report=objectonly

From the following paper:

Cytokine signature associated with disease severity in chronic fatigue syndrome patients
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576836/
Although the inclusion of fatigue duration as an additional covariate was expected to result in a loss of statistical power, regression analysis by both disease severity and fatigue duration revealed that the upward linear trend across disease severity remained statistically significant for CCL11, CXCL10, G-CSF, GM-CSF, IFN-γ, IL-4, IL-5, IL-7, IL-12p70, IL-13, IL-17F, leptin, LIF, NGF, ICAM1, and resistin. The findings by severity for CXCL1, SCF, and TGF-α shifted slightly above the threshold for statistical significance (CXCL1, adjusted P = 0.0536; SCF, adjusted P = 0.0531; TGF-α, adjusted P = 0.0797), possibly because of variance inflation (18) by the independent covariate of fatigue duration. Only CXCL9 and IL-1α inversely correlated with fatigue duration but lost statistical significance after correction for multiple comparisons (SI Appendix, Table S2).
...
Remarkably, 17 cytokines were associated with severity in ME/CFS patients. Thirteen of these 17 cytokines are primarily proinflammatory: CCL11, CXCL1, CXCL10, IFN-γ, IL-4, IL-5, IL-7, IL-12, IL-13, IL-17, leptin, G-CSF, and GM-CSF.


By picking CXCL10(for example):

CXCL10/IP-10 in Infectious Diseases Pathogenesis and Potential Therapeutic Implications
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3203691/
Inflammation is associated with secretion of CXCL10 from leukocytes, neutrophils, eosinophils [1], monocytes, epithelia, endothelial and stromal cells, and keratinocytes in response to IFN-γ [2-3]. CXCL10 specifically activates CXCR3 receptor, a seven trans-membrane-spanning G protein-coupled receptor (GPCRs) [4], which is predominantly expressed on activated T, B lymphocyte [5], natural killer (NK), dendritic and macrophage cells. CXCL10 induces chemotaxis, apoptosis, cell growth inhibition and angiostasis. Abnormal levels of CXCL10 have been observed in body fluids of individuals infected with viruses [1, 6-7], bacteria [8-9], fungi [10] and parasites [11-13] indicating an important role in pathogenesis of these diseases.
 

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What I still dont get, is the inflammtion a result of a weak immune system triggered by a unknown pathogen or is the inflammation a result of an autoimmune reaction triggered by a unknown pathogen. Or is a pathogen confusing the metabolism and therefore the immunsystem is weak/over reacting? As far as i know, there is no evidence for any of thosehypotheses.
 
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Or is a pathogen confusing the metabolism and therefore the immunsystem is weak/over reacting
Basic evidence that intracellular pathogens lead to persistent inflammation(aka cytokines secretion):

https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(14)00140-1
Moreover, transinfected CD4+ T cells secrete more inflammatory cytokines than noninfected (but activated) ones.

There was a study of infected macrophages with similar findings i.e. dysregulation of the immune system due to constant cytokines secretion.
 
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