Dr Markov CBIS Theory of ME/CFS - General Discussion

[Garz]

interesting - thanks Hip

i am having trouble getting clarity on how far into the structure the mucous membrane reaches

here is a diagrammatic representation of the filtration membrane inside the bowman's capsule - it doesn't look to me like there is a mucosa there as such - just the specialised filtration membrane at the boundary between the blood flow and the urine side

its clear that the ureters and bladder all have true mucous membranes - so zooming out to the broader structure of the kidney and working in from the urine side - the ureters branch into the the renal calyces which are chambers of the kidney through which urine collects from the passes.

these are little cup shaped voids that collect and i think pump the urine out down the ureters to the bladder. they are of interest to us here as they are the usual site of standard kidney infections so these are perhaps the prime candidates for the location of Markov's proposed biofilm infection

its not clear to me yet how much further into the structure of the kidney the mucosa might reach - this image shows the proximal tubule where the urine comes out of the bowman's capsule - that may also have a mucosal membrane - but there doesn't seem to be any physical barrier between that space and the insde of the bowmans space - so any bacterial there could presumably make it inside the bownam's space also

 

[Hip]

its clear that the ureters and bladder all have true mucous membranes

In the context of the Markov theory of ME/CFS, perhaps the crucial event which turns a healthy person into an ME/CFS patient is when the epithelial layers in the kidney become leaky (analogous to leaky gut), which then allows toxins to pass through the epithelium and enter the bloodstream.

Epithelial layers (mucous membranes) in general leak when the tight junctions between epithelial cells open up. Various factors can open the tight junctions, including: viruses, bacteria, bacterial toxins, mycotoxins and other factors (a list of leaky gut causes in this post).

Viral infection (not bacterial infection) triggers something like 90% of cases of ME/CFS, so somehow we have to factor in viruses to the Markov theory. Perhaps these viruses trigger ME/CFS when they infect the kidney epithelium, and then cause the epithelium to become leaky.

It's possible the kidney bacteria were happily living in the kidneys for years or decades without any problems, and without leaking their toxins into the bloodstream; but once a leak was created in the kidneys by viral infection, that's when the toxins start entering the blood, causing the symptoms of ME/CFS. That's one possible scenario anyway.

A variation on the theme would be that a viral infection of kidney epithelium weakens mucosal immunity (which viruses are known to do), and this then allows existing bacteria in the kidneys to grow in population, thus becoming more of a problem. Both of these scenarios could occur together.



When looking into this possible viral connection to the Markov theory, I found that some of the classic viruses linked to ME/CFS are able to infect the kidney glomeruli:

Coxsackievirus B can infect mesangial cells in the kidney glomerulus. Ref: 1

Cytomegalovirus can infect the glomerular vascular unit in the kidney. Ref: 1

Note that the glomerular vascular unit = mesangial cells + glomerular endothelial cells + podocytes.

Cytomegalovirus can infect glomerular epithelial cells, glomerular mesangial cells, tubular epithelial cells, and endothelial cells in the kidneys Ref: 1

Parvovirus B19 can cause acute glomerulonephritis with mesangiolysis. Ref: 1

So I started to hypothesise that if Dr Markov's theory is right, then perhaps the crucial event which causes ME/CFS is when the acute viral infection enters the kidneys, and makes the kidneys leaky; and/or causes a worsening of an existing kidney bacterial dysbiosis.



From the ME/CFS treatment perspective, if a leaky kidney epithelial layer is the root cause of ME/CFS, then drugs which can close the tight junctions may be helpful. There is one such drug called larazotide acetate, which some ME/CFS patients I know have been experimenting with; but unfortunately larazotide is not systemically absorbed, it only works locally, so when you take it orally, it can address leakiness in the intestines, but it cannot travel to the kidneys.

It's interesting that stress can open up the tight junction and cause increased leakiness in the mucous membranes. Perhaps this explains why in some very rare cases, ME/CFS patients have improved by psychological therapy that addresses unconscious stresses the patient may have in their mind. Although I don't believe that stress is generally involved in ME/CFS; but suspect stress may be an issue for a tiny subset of ME/CFS patients.

 

[Atlas]

i am having trouble getting clarity on how far into the structure the mucous membrane reaches

I've also looked a little into kidney anatomy.

Summarizing what I've learnt:

The hollow part in the kidneys where the urine comes out is called the renal pelvis. The surface layer of the mucosa/mucous membrane in the renal pelvis is called the urothelium, also known as the transitional epithelium. This transitional epithelium is continuous in lining the renal pelvis, the ureters, and bladder.

Traveling downstream through the renal pyramids, the transitional epithelium begins to be seen in the papillary ducts, which channel fluid out through the renal papilla (the tip of the renal pyramid) into the minor calyx (the entry point to the renal pelvis).

The simple columnar epithelium of the collecting duct system transitions into urothelium near the junction of a papillary duct and a minor calyx.

Thus, the transition to urothelium mucous membranes occurs at the entry point into the renal pelvis.

According to encyclopedia Britannica, the thickness of this lining increases as it enters the renal pelvis and proceeds to thicken further in the ureters and the bladder:

The mucous membrane lining increases in thickness from the renal pelvis downward. Thus, in the pelvis and the calyxes of the kidney the lining is two to three cells deep; in the ureter, four to five cells thick; and in the bladder, six to eight cells.

It's on this mucous membrane lining the renal pelvis that I presume Dr. Markov theorizes has a bacterial dysbiosis (including in the calyxes like you noted @Garz).

What I'm wondering about is, what advantages might there be for bacteria living in the mucosa of renal pelvis/calyxes...

...is there any reason why bacteria wouldn't colonize the upstream renal tubules which are lined differently?

...is there any survival advantage of living on the mucosa of the renal pelvis as opposed to living further downstream in the ureters or the bladder?

And if not, how would an infection be limited to the kidneys?


Edit: It looks like it's possible for simple columnar epithelium to also secrete mucous, but not sure if the renal tubules do that or not. So, not sure whether the lining of the renal tubules is also considered a type of "mucous membrane"
...

 

[Atlas]

The kidneys do contain an epithelium (epithelial cell layer), though I am not sure if these secrete mucous like other mucous membranes.

The transitional epithelium (urothelium) does apparently secrete mucous. See here, last paragraph.

Also here:

The surface of all transitional epithelial cells is covered by a fibrillar mucous coat

 

[Garz]

@Atlas thanks for the info - it helps

What I'm wondering about is, what advantages might there be for bacteria living in the mucosa of renal pelvis/calyxes...

...is there any reason why bacteria wouldn't colonize the upstream renal tubules which are lined differently?

i was thinking in the same direction

as far as we understand it - for a non-invasive but persisting biofilm of pathogenic bacteria to exist in the kidney long term we only know of one model by which this would occur - and that is the gut model - where mucous layer is generated by the epithelium and grows at a rate equal to or outstripping the rate at which the bacteria can grow through it -

this would explain the lack of bacterial clearance by the immune system and also a lack of gross morphological changes in the kidney over time.

but there are puzzling aspects also - as you point out -

it seems the mucous producing lining goes at least as far as the calyces - making these spaces perhaps the most likely location for a biofilm colony

but this raises questions -

since there is a clear path with no membranes to block it from travelling further the organisms could in theory simply grow further up the linings of the fluid channels into the proximal tubule - and into the bowman's space itself.
here they do meet a membrane / barrier of sorts - but it is a very thin and delicate one little more than a single row of epithelial cells and so its hard to imagine this would stop pathogenic bacteria growing into this space and beyond

indeed - as opposed to the relatively austere conditions in the mucous layer on the ureter and bladder and the urine surrounding it - it would seem like the kidney tissues themselves with their available nutrient supply - might be a more suitable location.

so it does beg the question "why do these biofilm colonies not become invasive into the kidney tissue"

are they obligate anaerobes perhaps - such that any tissues with good oxygen supply will be uninhabitable for them

this does not seem to stop other anaerobic bacteria inhabiting wounds etc - where i think the tissue damage and inflammation stops blood flow causes necrosis and the bacteria can live there in the dead and dying tissues

or could the biofilm colonies be located on the other side of the bowman's space - this is possible as as far as we have theorised to date - the bacteria are getting into the kidney from the bloodstream in the first instance

but if they are there - and just showing up in the urine in small numbers due to damage to the filtering systems of the kidney - the question becomes again - "how come they are not invasive "- as, in the capillaries, there is no mucous layer to keep them away from tissues ....

if the Markov theory is correct - there is something going on here that is v unusual

 

[Hip]

so it does beg the question "why do these biofilm colonies not become invasive into the kidney tissue"

A far as I am aware, in healthy people, we don't generally observe mucous membrane biofilm infections becoming invasive and entering the body to any degree. You have bacteria living in biofilms on the mucous membranes: in the nose, sinuses, oral cavity, intestines, urinary tract, but these generally are kept in place by the immune system.

So I think the answer to your question is that the healthy immune system is designed to stop these bacterial biofilm communities living on the the body's mucosa from spreading into the body.

Although in certain disease like Crohn’s, you can get some bacteria translocation across the intestinal lining and into the interior tissues and organs of the body.

And nonalcoholic fatty liver disease is a common condition (found in 25% of adults) which is associated with bacteria translocating from the gut and into the liver.



When I caught the virus which triggered my ME/CFS, coxsackievirus B4, I noticed that all of a sudden, I started develop lots of brown plaque on all my teeth. Plaque of course is just a bacterial biofilm that grows on the teeth.

Not only that, but a few other people who caught my CVB4 virus also had this sudden onset of dental plaque.

Before catching CVB4, I never observed any brown plaque on my teeth.

This I think is an example of how viruses can compromise mucosal immunity, and allow bacterial infections to proliferate on the mucous membranes.

The bacteria and the biofilm may not translocate into the body, because systemic immunity may still be functioning normally; but mucosal immunity may be compromised by the viral infection, leading to bacterial dysbiosis on the mucous membranes.


So if my CVB4 virus facilitated the growth of biofilm bacteria on my teeth, due to compromising oral mucosal immunity, then perhaps the virus also caused a biofilm dysbiosis to appear in my kidneys.

 

[MartinK]

Hi guys, today I found we in Czech Republic have one clinic, which prepares customized autovaccines (perhaps in the same way as Dr. Markov - I don't know, that's why I'm writing this here, whether it's something of the same quality or not.)

- https://www.paracelsiumpraha.cz/terapie/#SIAB

"Our vaccines (SIAB), which are produced from the biological material of a specific client, are suitable for you, and therefore a high degree of treatment success is guaranteed here. Vaccines are dripped under the tongue always before meals and several times a day. The production process is approved by the Ministry of Health. The vaccines are tasteless and are suitable for everyone from small children or even for clients with diabetes."

I would like to call to paracelsium - I can find out the details. Maybe you can suggest some questions.

I'm preparing my Uricult Plus right now because I want to get the vaccines made - I want to send them to Ukraine, but this might be a game changer for EU patients?

@Hip @Garz

 

[Garz]

Hi Martin,

Happy New Year to you - and hope you are doing OK

i have been following the theory with interest - but i am not really close to the details on what the Markov vaccines actually contain or how the treatment is done

i think they are just heat sterilised bacterial cultures - but don't know the details of how much vaccine is given on what schedule etc

Hip is you man for that

since they seem to be doing similar things - it would be interesting to hear if the Czech clinic is aware of Markov's clinic and his theory of CFS - and any views or feedback they may have on it.

do they also currently treat CFS with autovaccines from patients urine?

if they do - what are their findings / experience - eg treatment durations, recovery rates?

all the best!
G

 

[Hip]

- https://www.paracelsiumpraha.cz/terapie/#SIAB

"Our vaccines (SIAB), which are produced from the biological material of a specific client, are suitable for you, and therefore a high degree of treatment success is guaranteed here. Vaccines are dripped under the tongue always before meals and several times a day. The production process is approved by the Ministry of Health. The vaccines are tasteless and are suitable for everyone from small children or even for clients with diabetes."

Interesting find. Though I am not sure if these Paracelsium Clinic autovaccines are made from actual bacteria taken from the patient. Perhaps you can ask the clinic that question.

On this page, the clinic say:

biological material is taken in a certain, specific state of the organism, or stage of the disease

I am not sure what they mean by "biological material", and whether biological material means bacteria taken from the patient.



Note that the autovaccines the Paracelsium Clinic make are sublingual mucosal autovaccines, rather than injected vaccines.

Assuming these autovaccines can be made from bacteria taken from the patient's urine, I am not sure how the efficacy of mucosal versus injected vaccines compares.

But Dr Markov said good things about mucosal vaccines. Dr Markov does not make his own mucosal autovaccines from his patients' bacteria, because he explained that requires a good lyophiliser machine, which are very expensive.



We know from the results of the Uromune studies that sublingual vaccines like Uromune are able to target the urinary tract, and help prevent recurrent UTIs.

So these sublingual autovaccines from the Paracelsium Clinic could be effective in treating ME/CFS, if they are made from bacteria isolated from the urine.

You might like to explain to the Paracelsium Clinic the method Dr Markov uses to culture bacteria from ME/CFS patients' urine, and ask the clinic if they can make autovaccines from this bacteria.


It looks like these autovaccines are inexpensive, the price list states they cost about €12 each, plus the consultation and examination fees of abut €40.

 

[MartinK]

@Hip thank you, I will write a mail to them today.
will post new info soon I hope!

 

[Atlas]

Not getting any bacteria growth on this round of dipslides. The slides are expired but a bit concerning. Maybe his last round wiped out bac.

@bensmith Were you able to get any growth with new dipslides?

 

[wastwater]

These post viral syndromes maybe caused by a viral hit to the liver lowering complement C3 leaving C5 uncleaved for immune activation creating an immunodeficiency that’s under reactive to bacteria and over reactive to viruses
It may only occur in the genetically vulnerable and the bacteria under reaction is worse in childhood

 

[Atlas]

I asked Dr. Markov for his thoughts on the extent of where the bacteria might be living within the kidneys. Basically, he considers this question unanswered — his clinician's guess is that the main problem site is in the pyelocaliceal system (the renal pelvis and calyxes) — but he emphasized this is just a guess and he had hoped that by now researchers would have been looking into it.

As for why the kidneys are believed to be the likely site of the intoxication problem, I understand the reasons include:

1. The data suggested that patients who had these bacteria in urine were far more likely to subsequently develop measurable kidney inflammation. Based on clinical data, he concluded that "in the vast majority of cases, both acute and chronic inflammation in the kidneys (pyelonephritis) is preceded by a stage of bacterial carriage, mainly enterobacteria and staphylococci. It is this condition that we called nephrodysbacteriosis".

2. "Based on 25 years of clinical observation and experiences, we found that children, being treated with bacterial autovaccines for Nephrodysbacteriosis, when growing up, as a rule, [do not develop] classic pyelonephritis and CBIS."

3. The absorbent surfaces within the filtration network in the kidneys could possibly be a vector for toxins to leak. These tubule surfaces are intended to reabsorb desirable nutrients from the urine back into the blood, but presumably they are not foolproof at preventing toxins from reabsorption. They are inherently permeable, so potentially more likely to leak large quantities of toxins than say a leaky renal pelvis epithelium or leaky gut epithelium (which also has the first-pass liver filter).

The Toxicon detoxification tests suggest that the kidneys typically are not the best at filtering out these toxins.

Spoiler

The Toxicon lab test found that the detoxification and elimination of toxic proteomes from the blood of CBIS patients was mainly carried out through macrophages of mesenchymal origin in 75% of patients, through the liver in 23% of patients, and via the kidneys in 2% of patients.

4. The high flow rate of the kidneys was also previously mentioned. If the quantity of toxins pumped into the blood by the filtration system exceeds the quantity that it removes from blood then a higher flow rate could mean a higher toxin buildup in blood.

 

[Hip]

his clinician's guess is that the main problem site is in the pyelocaliceal system (the renal pelvis and calyxes) — but he emphasized this is just a guess and he had hoped that by now researchers would have been looking into it

This is very interesting. So Dr Markov speculates the kidney bacterial dysbiosis may be located in the calyxes and renal pelvis.

Looking at the location of the calyxes and renal pelvis on the diagram below, these appear to be hollow areas in the kidney where the urine collects. The urine collects in the pelvis, and then runs down to the bladder via the ureter tube (a tube which is about 7 mm in diameter, and about 20-30 cm long).

Kidney Calyxes and Pelvis

I wonder whether the mucous membranes surfaces on the calyxes and renal pelvis would be actually accessible to topical antibacterial or anti-biofilm treatment?

If you emptied your bladder by going to the toilet, and then instilled into your bladder some antibacterial solution, and then perform a headstand against a wall so that you invert your body, that solution might run down the ureter tube, and into the kidney calyxes and renal pelvis, where the solution can work topically.

 

[Atlas]

and then perform a headstand against a wall

@Hip you come up with the best most interesting and craziest ideas. Picturing this made me laugh out loud.



However, the Ureters have a valve at the site of bladder entry which prevents backflow of urine.

Moreover, if backflow happens, it's not a good thing. It's called Vesicoureteral reflux which can damage the kidneys.

Also, when looking a little into mechanisms by which bacterial toxins could make it from the renal pelvis into the bloodstream, I recently learned that one possible way is pyelorenal backflow. This is when the contents of the renal pelvis can flow backwards by various routes and make it back into the blood circulation. One such route is called pyelotubular backflow — where the urine flows backwards up the kidney tubules and is pushed out into the bloodstream.

As far as I know pyelorenal backflow is not considered a normal occurrence but it takes only a very small pressure increase in the renal pelvis to trigger it. So if one did manage to trigger backflow from the bladder into the renal pelvis, or even if one injected a solution directly into the renal pelvis, this would trigger pyelorenal backflow and if that's where the dysbiosis is then a significantly greater than usual amount of toxins would be flushed out into the blood.

So while this standing on head idea is creative I would highly recommend not trying it.

 

[Hip]

@Hip you come up with the best most interesting and craziest ideas. Picturing this made me laugh out loud.

However, the Ureters have a valve at the site of bladder entry which prevents backflow of urine.

Moreover, if backflow happens, it's not a good thing. It's called Vesicoureteral reflux which can damage the kidneys.

Well I do like to entertain!


I was not aware there is a one-way valve in the ureter. That sends my plans back to the drawing board!

And as you say, it might be risky instilling a substance into the kidney calyxes and renal pelvis.

I was thinking in terms of instilling things like a glutamine solution, which is known to help leaky mucous membranes heal (glutamine is considered the best leaky gut healing supplement). My guess is that the calyx and renal pelvis mucous membranes may be leaky — analogous to a leaky gut which allows bacterial toxins in the gut to enter the bloodstream.

Various factors are known to cause a leaky gut, including chronic viral infections of the intestinal mucous membranes, as well as certain bacteria and mycotoxins.

But if there is a one-way valve, no amount of standing upside down will help!

 

[BrightCandle]

I saw this and thought these two techniques might be of interest to investigate.

https://www.extremetech.com/extreme...dney-stones-painlessly-and-without-anesthesia

 

[Atlas]

@Garz I found a really intriguing paper relevant to our questions about possible locations of bacteria. It's super dense so I haven't been able to cover it all yet.

It discusses how renal tubule epithelial cells have unique functions in the innate immune response. This is potentially relevant to the elevated levels of IFN-a found in ME in preliminary findings by the itaconate shunt hypothesis team.


But relevant to the question of "where":

Chassin et al. have shown that [E. Coli] strains colonizing kidneys preferentially adhere to the apical surface of collecting duct tubules (34) which consist mainly of intercalated cells.

So... far from being off limits, the renal tubules are evidently fair game for urinary tract bacteria, and are even a preferential site for some. The study mentions that even non-pathogenic strains can make it into the renal tubules.

I did a calculation of the inner surface area of the collecting ducts alone, which estimated approximately 2m² per kidney. This is only for the collecting ducts, the lowest part of the renal tubules.

It also mentions strains of these E. Coli that can:

• Invade the epithelial cells and survive intracellularly.
• Disrupt the integrity of cell layers.
• Translocate through collecting duct cell layers without altering the tight junctions.

Other highlights:

Bacterial attachment to mucosal epithelial cells by fimbrial adhesins is the initial step in the pathogenicity of uropathogenic E. coli (UPEC).(59) The binding of adhesins to epithelial cell receptors results in tissue specificity, and allows UPECs to ascend into the lower urinary tract and the kidney.

In recent years, much attention has been paid to the urinary tract pathogenicity of Escherichia coli (E. coli), the emergence of highly-virulent, antibiotic-resistant strains of E. coli, (8) the ability of uropathogenic E. coli (UPECs) to form biofilms,(9) the development of intracellular bacterial communities of UPECs,(10,11) and the long-term consequences of complicated UTI (i.e acute pyelonephritis, APN) for renal graft function (4,5,12) The renal mucosal inflammation that results from the interaction between uropathogenic bacteria and/or epithelial bladder or renal tubule cells can lead to asymptomatic bacteriuria, urethritis, cystitis, and acute and chronic pyelonephritis.

When activated, TLR4 signaling may initiate the symptomatic disease process, while in the absence of TLR4 signaling, the infected host may instead develop an asymptomatic carrier state.

It is a similar "carrier state" that I imagine could bring the possibility of CBIS.

That while it may be locally asymptomatic, it may not always be systemically asymptomatic.

...
Link to the paper:
https://pubmed.ncbi.nlm.nih.gov/20584500/

 

[Atlas]

After the third autostrain shot yesterday I developed a light fever, and began feeling abnormally fluey and restless with a front-of-head headache in a way that felt different from normal ME symptoms.

According to the Markov vaccine instructions sheet fever is a common response and indicates bacteria die-off. It could also be my body's response to these inoculated bacteria in the vaccine. I am getting noticeable redness and swelling at injection sites, which was much less noticeable when I was taking the Staphylococcus shots. (The current shots are my autostrains of E. Coli and Enterococcus faecalis)

I can't remember the last time I had a fever. I certainly haven't had one since becoming severe 18 months ago. I don't think I've had one since 2017 when I had the infection which I suspect put me into mild.

Today fever is gone and I'm not feeling great but not super crashed either. Although my HRV hit an all time low and my resting/sleeping HR is elevated. Certainly my body has been fighting something anyway, so I'm taking it as a good sign.

 

[MartinK]

Hi guys, I just recieved message from dr. Markov with some recommendations.

Please, know anyone good EU source of some phytopreparation for the kidneys (dr. Markov recommend Krenfors, or Canephron, or Urolesan, or Phytolysin)

All alternatives welcome!
thx, Martin