Dr Markov CBIS Theory of ME/CFS - General Discussion

Hip

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Thanks. Any verdict on horsetail?
Horsetail does not seem to do much for me now, but it fixed my recurrent UTI when I had that issue.


@Hip...I recall Hip that you have another thread on selenium and that you take that daily too.As there is selenium in horsetail how do you balance that dosage?...Thanks.
I did not know there was selenium in horsetail, but after a quick Google, I see it is only 5 mcg per 500 mg, which is much less than the 400 mcg of selenium I take daily.
 

Dufresne

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I am interested in hearing any skeptical scientific opinions about Dr Markov's theory. I have been disappointed by the lack of scientific skepticism and scientific discussion on this theory. In particular, the question of whether a set of bacterial toxins leaking into the systemic circulation could really be the cause of ME/CFS, as Dr Markov believes.
I'm pretty sure bacterial translotcation is not the primary cause of my ME/CFS. However I think it interesting that IL-6 seems to be a central cytokine in both sepsis and exercise. It can see increases up to 100x with exercise, and in this context it's working in an anti-inflammatory capacity; on the other hand it's considered inflammatory in diseased states, as it is in sepsis. The following is from the Wikipedia entry for IL-6:

"In general, the cytokine response to exercise and sepsis differs with regard to TNF-α. Thus, the cytokine response to exercise is not preceded by an increase in plasma-TNF-α. Following exercise, the basal plasma IL-6 concentration may increase up to 100-fold, but less dramatic increases are more frequent."

Could it be that our systems are primed by TNF-a or some other aspect of the disease (or even a mild, chronic sepsis) and that IL-6 released in large amounts from physical exercise is acting to increase inflammation and leading to PEM?

IL-6 fits nicely into a model of sickness behavior. Indeed there are rodent studies on the subject. It's also worth noting that IL-6 can cross the BBB without too much trouble.
 
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I'm pretty sure bacterial translotcation is not the primary cause of my ME/CFS. However I think it interesting that IL-6 seems to be a central cytokine in both sepsis and exercise. It can see increases up to 100x with exercise, and in this context it's working in an anti-inflammatory capacity; on the other hand it's considered inflammatory in diseased states, as it is in sepsis. The following is from the Wikipedia entry for IL-6:

"In general, the cytokine response to exercise and sepsis differs with regard to TNF-α. Thus, the cytokine response to exercise is not preceded by an increase in plasma-TNF-α. Following exercise, the basal plasma IL-6 concentration may increase up to 100-fold, but less dramatic increases are more frequent."

Could it be that our systems are primed by TNF-a or some other aspect of the disease (or even a mild, chronic sepsis) and that IL-6 released in large amounts from physical exercise is acting to increase inflammation and leading to PEM?

IL-6 fits nicely into a model of sickness behavior. Indeed there are rodent studies on the subject. It's also worth noting that IL-6 can cross the BBB without too much trouble.
Yeah, that's very interesting. I just wanted to chime in and say I've had my cytokines tested (was last year though) and the only one that was out of range was IL-6, which was high (30 % above the top of the range or something IIRC).
 

Hip

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However I think it interesting that IL-6 seems to be a central cytokine in both sepsis and exercise. It can see increases up to 100x with exercise, and in this context it's working in an anti-inflammatory capacity
Interesting that IL-6 is involved in sepsis. IL-6 is definitely one of the three main sickness behavior cytokines, which are IL-6, TNF-alpha and IL-1beta. So high IL-6 could cause some of the symptoms of ME/CFS.

However, this old post details a study which found that in ME/CFS patients, blood levels of the soluble IL-6 receptor were no higher than normal, even after exercise (the soluble IL-6 receptor is what drives the pro-inflammatory trans-signaling IL-6 pathway).


As you say, massive amounts of IL-6 are released via exercise, but the exercise-induced IL-6 pathway is not the same as the infection-induced IL-6 pathway.

I spent some time reading about IL-6 a few years back, as I thought it might be involved in ME/CFS.

I discovered that IL-6 can operate by two pathways: the classical signaling IL-6 pathway which is anti-inflammatory and instigates tissue repair (this is the pathway induced by exercise); and the trans-signaling IL-6 pathway which is pro-inflammatory (this is the pathway induced by infection).



I'm pretty sure bacterial translotcation is not the primary cause of my ME/CFS.
In Dr Markov's theory, it is not actually translocation of bacteria which is taking place. In his theory the bacteria remain in one place (usually in the kidney, though he says in some patients the bacteria are in the nasopharynx).

But Dr Markov says these bacteria are secreting toxins which then leak into the systemic blood circulation, thereby affecting every cell and every organ in the body.


Some bacterial toxins are well studied, and their pernicious effects are known. For example:

Enterotoxin B secreted by Staphylococcus bacteria plays a critical role in the pathogenesis of autoimmune disorders, according to this study.

Another toxin made by Staphylococcus, alpha toxin, interferes with the immune response by polarizing macrophages towards the M2 type. Ref: 1
 

Dufresne

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Yeah, that's very interesting. I just wanted to chime in and say I've had my cytokines tested (was last year though) and the only one that was out of range was IL-6, which was high (30 % above the top of the range or something IIRC).
I imagine IL-6, because of the correlation to exercise, would be a hard one to draw conclusions from. "Did the subject take the elevator or the stairs on their way in, or even 5 hours ago?" But for this reason might have real implications for ME/CFS research.

It's perhaps interesting to note that IL-6 is involved in Covid and might be an important marker in predicting long Covid.

"Four of the markers, analyzed via a data model, proved to be especially accurate in predicting long Covid: IFN-β, PTX3, IFN-λ2/3 and IL-6. Of these, IFN-β was the single most important indicator of long Covid, present 94% of the time when modeled in a set of four markers."

https://www.forbes.com/sites/willia...longed-inflammatory-response/?sh=4799b74b765c

This is more inline with what I think is happening in ME/CFS; that is, an upregulation of cellular immunity (interferons and such) in the brain that is then getting splashed with gasoline from the periphery. Interferons and cellular immunity in the brain due to infection followed by all kinds of stuff hitting the limbic system, from mast cells to IL-6 (from physical activity), and so on. Both interferons and IL-6 have been at times shown to be correlated with disease severity in ME/CFS. But perhaps where it gets even more interesting is in the individual response to these cytokines. This is where I think limbic health comes in. I like to think of this aspect along the lines of Dr Goldstein's work, where you have channels relating to sorotonin, dopamine, GABA, etc, that are impaired in ME/CFS patients. This is why you have such a myriad of treatments that can produce massive improvements in patients, though they often fall off after a while. It's as if the sickness behavior overturns the intervention. Some people are seeing this with Abilify, which is likely having its effect through the dopamine channel. Consider interferon-induced depression is not universally the case for those on interferon therapy, rather it tends to hit those with a history of mood issues, but that SSRI's and even fish oils can be employed to offset the induction of the syndrome. This would be an example of the serotonin channel.

I think the following is a good review of the cytokines in ME/CFS and I agree with the authors' conclusions:
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-019-1948-6
 

Dufresne

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Interesting that IL-6 is involved in sepsis. IL-6 is definitely one of the three main sickness behavior cytokines, which are IL-6, TNF-alpha and IL-1beta. So high IL-6 could cause some of the symptoms of ME/CFS.

However, this old post details a study which found that in ME/CFS patients, blood levels of the soluble IL-6 receptor were no higher than normal, even after exercise (the soluble IL-6 receptor is what drives the pro-inflammatory trans-signaling IL-6 pathway).


As you say, massive amounts of IL-6 are released via exercise, but the exercise-induced IL-6 pathway is not the same as the infection-induced IL-6 pathway.

I spent some time reading about IL-6 a few years back, as I thought it might be involved in ME/CFS.

I discovered that IL-6 can operate by two pathways: the classical signaling IL-6 pathway which is anti-inflammatory and instigates tissue repair (this is the pathway induced by exercise); and the trans-signaling IL-6 pathway which is pro-inflammatory (this is the pathway induced by infection).





In Dr Markov's theory, it is not actually translocation of bacteria which is taking place. In his theory the bacteria remain in one place (usually in the kidney, though he says in some patients the bacteria are in the nasopharynx).

But Dr Markov says these bacteria are secreting toxins which then leak into the systemic blood circulation, thereby affecting every cell and every organ in the body.


Some bacterial toxins are well studied, and their pernicious effects are known. For example:

Enterotoxin B secreted by Staphylococcus bacteria plays a critical role in the pathogenesis of autoimmune disorders, according to this study.

Another toxin made by Staphylococcus, alpha toxin, interferes with the immune response by polarizing macrophages towards the M2 type. Ref: 1
Yes, translocation was the wrong way to put it. I understand it's toxins being released from the bacteria into circulation that is the theory.

So there are two pathways for IL-6, but what I'm wondering is if one pathway could leak over onto the other. Could IL-6 from exercise also inflame a disease process happening at the same time?
 

Hip

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So there are two pathways for IL-6, but what I'm wondering is if one pathway could leak over onto the other. Could IL-6 from exercise also inflame a disease process happening at the same time?
Yes, that's an interesting idea, and it was what I was pondering in this post: could the IL-6 from exercise become pro-inflammatory, because of some dysfunction in the body? That could well explain PEM.

Basically, it is the amount of the soluble IL-6 receptor floating about in the blood that determines which of its two pathways secreted IL-6 takes.

The more soluble IL-6 receptors are present in the blood, the more the pro-inflammatory trans-signaling IL-6 pathway is activated when IL-6 is secreted. So if you had high amounts of soluble IL-6 receptor in your blood, then I think the IL-6 from exercise might become pro-inflammatory, rather than being anti-inflammatory.

But a study showed that ME/CFS patients have normal levels of soluble IL-6 receptors in the blood.

We can perhaps carry on this IL-6 discussion in that IL-6 thread if you like.
 

Dufresne

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Yes, that's an interesting idea, and it was what I was pondering in this post: could the IL-6 from exercise become pro-inflammatory, because of some dysfunction in the body? That could well explain PEM.

Basically, it is the amount of the soluble IL-6 receptor floating about in the blood that determines which of its two pathways secreted IL-6 takes.

The more soluble IL-6 receptors are present in the blood, the more the pro-inflammatory trans-signaling IL-6 pathway is activated when IL-6 is secreted. So if you had high amounts of soluble IL-6 receptor in your blood, then I think the IL-6 from exercise might become pro-inflammatory, rather than being anti-inflammatory.

But a study showed that ME/CFS patients have normal levels of soluble IL-6 receptors in the blood.

We can perhaps carry on this IL-6 discussion in that IL-6 thread if you like.
Damn, I should have known you'd already been there. :)