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Dr Chia finds Double-stranded RNA in stomach biopsies

thegodofpleasure

Player in a Greek Tragedy
Messages
207
Location
Matlock, Derbyshire, Uk
In 2007, Dr John Chia published a paper which showed that a high proportion of M.E patients were found to have a viral protein (VP1) expressed in biopsies taken from the tissues lining their stomachs. That paper can be found here: http://jcp.bmjjournals.com/content/61/1/43.abstract and the full version is also available in the Library: http://forums.phoenixrising.me/inde...ated-with-chronic-enterovirus-infection.3097/

Dr Chia & colleagues have now followed up that work with a new paper entitled "Functional Dyspepsia and Chronic Gastritis associated with Enteroviruses" a full version of which can be accessed here: https://app.box.com/s/tzqw9bu7w48rd037jvmlyzmbr3pedo7g

Abstract
After decades of research, functional dyspepsia (FD) remains one of the most elusive gastrointestinal
disorders. Endoscopic appearance of mild inflammation of the gastric mucosa without ulceration
and microscopic evidence of mild chronic inflammation are often considered as normal
findings since no etiology could be found other than H. pylori. Enteroviruses infect the gastrointestinal
tract and have been shown to persist in the stomach of symptomatic patients with myalgic
encephalomyelitis/chronic fatigue syndrome (ME/CFS). In this study, we evaluated FD patients
with and without the diagnosis of ME/CFS, and were able to support the viral protein staining with
finding of double-stranded RNA in 63% of the same stomach biopsies by immunoperoxidase
staining. Furthermore, we clarified the possible cross-reaction with creatine kinase brain subtype
(CKB), present in parietal cells, using antibody competition experiments and western blot analysis
of stomach proteins. Viral protein+ and dsRNA+ biopsies were infectious in SCID mice. More research
is needed to elucidate the mechanism of enterovirus infection of the stomach associated
with FD and chronic gastritis.

Having failed to capture the interest of the scientific community with his earlier work, Dr Chia has played down the "CFS" angle in the title of the paper and in finding the same rates of infection in Functional Dyspepsia patients, will engage with a much broader audience in the world of gastroenterology.

This could therefore be huge for us !

If you look at the Wikipedia page on Double-stranded RNA viruses http://en.wikipedia.org/wiki/Double- stranded_RNA_viruses and then follow some of the leads - for example to "DICER" http://en.wikipedia.org/wiki/Dicer, it doesn't take too much imagination to see that a genetic defect in the DICER1 gene could be at the root of the problem - both in FD/ Chronic Gastritis and in M.E. ........ the difference being that PwME go on to develop additional autoimmune problems.
 

Bob

Senior Member
Messages
16,455
Location
England (south coast)
I haven't had time to read this study in detail or to fully think through its potential implications, but my initial impression was that it may mean that enteroviruses are not associated with ME, per se, but they may be associated with ME patients who have gastrointestinal issues, and also people without ME who have gastrointestinal issues. (i.e. enteroviruses may be associated with gastritis etc, rather than ME itself.) This could mean that it's yet another opportunistic virus that takes advantage of our dysfunctional immune systems, leading to secondary symptoms/complications (or comorbid diagnoses), rather than it being a casual agent. But I may have missed some significant info, as I've only briefly skimmed the article. Anyone else have any thoughts about this after reading the paper?
 

Simon

Senior Member
Messages
3,789
Location
Monmouth, UK
Interesting stuff., Chia has demonstrated the presence of enterovirus in stomach biopsies in a new and very large cohort of mecfs patients (n=416, collected 2006-2012) - backing up his earlier findings from the 2007 paper.

Immunoperoxidase staining demonstrated:
  • enterovirus VP1 in 343/416 (82%) and 53/66 (83%) of the stomach biopsies from FD patients with and without ME/CFS, respectively,
  • dsRNA in 268/ 416 (64%) and 41/65 (63%) in the two patient cohorts, respectively (Figure 1). 9/47 (19%) and 5/46 (11%) of the controls stained positive for VP1 and dsRNA, respectively (p < 0.01, χ2 test with Yates correction).
The team also showed that potential cross-reaction of test antibody to a protein other than VP1 couldn't account for these results (this was a crticism raised about the original 2007 study).

However, the study also showed the same high rate of enterovirus in functional dyspepsia whether or not they have mecfs, suggesting that enterovirus infection alone is unlikely to be the cause of mecfs. We also don't know what proportion of mecfs patients have functional dyspepsia (it's 10-20% of the general population, the paper says). Presumably Dr John Chia sees patients with stomach problems.

As @Bob says, maybe the enterovirus is opportunistic. Or maybe it's a trigger. Or something else... But still, interesting stuff.
 

thegodofpleasure

Player in a Greek Tragedy
Messages
207
Location
Matlock, Derbyshire, Uk
......my initial impression was that it may mean that enteroviruses are not associated with ME, per se, but they may be associated with ME patients who have gastrointestinal issues, and also people without ME who have gastrointestinal issues. (i.e. enteroviruses may be associated with gastritis etc, rather than ME itself.) This could mean that it's yet another opportunistic virus that takes advantage of our dysfunctional immune systems, leading to secondary symptoms/complications (or comorbid diagnoses), rather than it being a casual agent.

True. It could just be an opportunistic infection, but if you look further at the characteristics of these dsRNA viruses (and what they do - such as causing immunosuppression) then the likelihood that they are causative in ME starts to look more promising.

An interesting line of investigation would be to establish whether these dsRNA viruses are capable of causing infected cells to produce Heat-shock protein 60 (or epitopes of HSP60) which would perhaps help to explain a link between this type of infection and the development of autoimmunity in ME patients.
http://www.meresearch.org.uk/our-research/completed-studies/human-heat-shock-protein/
 

Sidereal

Senior Member
Messages
4,856
It is possible that a chronic enteroviral infection is associated with all "functional" disorders but that symptom expression depends on the viral load in various tissues. So you get functional dyspepsia if your GI is infected whereas to get full-blown ME/CFS you might need muscles and brain to be infected as well.
 

lansbergen

Senior Member
Messages
2,512
“Cpn 60 is ideally placed to play a central role in the initiation of the host immune response, whatever the actual nature of the immune system”

The idea of chaperonins as initiators of immune responses also fits in increasingly well, but in a different way, with another model of the immune system: the “danger” model.54 This idea proposes that, instead of the major function of the immune system being to discriminate between self and non-self, its function is actually to recognise “danger”; specifically, certain “danger signals” that emanate from the tissues of the body, rather than from pathogens. Thus, molecules released from stressed, damaged, and necrotic host cells would be seen by the immune system as signals of infection or wounding, and the appropriate response would be mounted. In this model, it is self Cpn 60 that is being recognised, not the Cpn 60 of the pathogen. Heat shock proteins such as Cpn 60 might be a good example of a danger signal, because they are themselves induced by stress or damage and would be present in large amounts in tissue containing stressed, damaged, or lysed cells. Thus, it would seem that Cpn 60 is ideally placed to play a central role in the initiation of the host immune response, whatever the actual nature of the immune system.


True. It could just be an opportunistic infection, but if you look further at the characteristics of these dsRNA viruses (and what they do - such as causing immunosuppression) then the likelihood that they are causative in ME starts to look more promising.

An interesting line of investigation would be to establish whether these dsRNA viruses are capable of causing infected cells to produce Heat-shock protein 60 (or epitopes of HSP60) which would perhaps help to explain a link between this type of infection and the development of autoimmunity in ME patients.
http://www.meresearch.org.uk/our-research/completed-studies/human-heat-shock-protein/
 

thegodofpleasure

Player in a Greek Tragedy
Messages
207
Location
Matlock, Derbyshire, Uk
Interestingly, Dr Chia reported finding chronic Chlamydia Pneumoniae infection in a small number of his ME patients as long ago as the late 1990's http://cid.oxfordjournals.org/content/29/2/452.full.pdf

That is a more interesting finding when viewed alongside the last paragraph from the ME Research Uk page describing Prof Blomberg's work on finding antibodies to epitopes of HSP60

The paper describes the identification of antibodies to heat shock protein 60 (HSP60), one of a number of “stress proteins” produced when cells undergo physiological stresses (e.g. excessive heat, disease, or infection). It seems that HSP60 is an element of the ‘cascade’ of danger signals which results in an immune response by the body. In a complicated series of experiments on blood sera from ME/CFS patients, other patients (including people with MS or systemic lupus) and healthy blood donors, the researchers measured immune responses to HSP60 peptides obtained from different kinds of infectious agents. Their main finding was that levels of antibodies to specific parts of HSP60 were relatively high, both in ME/CFS patients and in control samples. However, significant levels of antibodies to Chlamydia pneumoniae-derived HSP60 were present in around a quarter (24.6%) of ME/CFS patients – a far higher proportion than in the patients with other illnesses (0.003%). While the precise meaning of this finding is unclear at present, and much more work remains to be done, it is possible that immune responses to certain synthetic HSP60 peptides will come to have a role as biomarkers of ME/CFS – at least in a subset of patients.
 

halcyon

Senior Member
Messages
2,482
However, the study also showed the same high rate of enterovirus in functional dyspepsia whether or not they have mecfs, suggesting that enterovirus infection alone is unlikely to be the cause of mecfs.
That isn't what the paper suggests. Dr. Chia very much believes that enteroviruses are one of the major causes of ME. Obviously I can't speak for him, but from talking to him, he seems to believe that the symptoms of disease caused by persistent enterovirus depend on where the virus is located, and he seems confident that a lot of our ME symptoms are due to the virus being in certain parts of the brain.
 

Simon

Senior Member
Messages
3,789
Location
Monmouth, UK
However, the study also showed the same high rate of enterovirus in functional dyspepsia whether or not they have mecfs, suggesting that enterovirus infection alone is unlikely to be the cause of mecfs.
That isn't what the paper suggests.
Dr. Chia very much believes that enteroviruses are one of the major causes of ME. Obviously I can't speak for him, but from talking to him, he seems to believe that the symptoms of disease caused by persistent enterovirus depend on where the virus is located, and he seems confident that a lot of our ME symptoms are due to the virus being in certain parts of the brain.

I must be missing something:
The paper said:
5. Conclusion
In summary, our studies provided evidence for the pathogenic role of enteroviral dsRNA in the stomach biopsies of patients who had FD/chronic gastritis with and without ME/CFS. Much more research will be needed to define the mechanism of virus-mediated tissue injury and host responses. Development of antiviral therapy against enteroviruses and/or dsRNA cannot be overemphasized, and the importance of enteroviruses in FD/chronic gastritis can only be realized with a randomized, placebo-controlled antiviral drug trial.
Nothing there about a causative role in ME/CFS.
 

halcyon

Senior Member
Messages
2,482
Nothing there about a causative role in ME/CFS.
It's not a paper about ME/CFS. It's a paper about FD in a gastroenterology journal. He's just publishing about some of his secondary findings while researching ME. Nothing about this paper is ruling out enteroviruses in ME.

If you haven't already, I'd highly suggest reading all of Dr. Chia's papers on enterovirus:

Acute enterovirus infection followed by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and viral persistence 2009
Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach 2007
The role of enterovirus in chronic fatigue syndrome 2005
Ribavirin and Interferon-a for the Treatment of Patients with Chronic Fatigue Syndrome Associated with Persistent Coxsackievirus B Infection: A Preliminary Observation 2004
Diverse Etiologies for Chronic Fatigue Syndrome 2003

Beyond the association with ME, he has also published various papers where he found associations with enterovirus infection and intestinal intussusception, carcinoid tumors, VZV reactivation, pityriasis rosea, and leukocytoclastic vasculitis.
 

Hip

Senior Member
Messages
17,820
Certainly the more chronic diseases are connected to enteroviruses, the more likely it is that pharmaceutical companies will invest money in enterovirus antivirals, and enterovirus vaccines.

Dr Chia is certainly doing sterling work in discovering which diseases are linked to enteroviruses.
 
Messages
53
Location
Oregon
Well done, Dr. Chia! He told me about this study a while back and I am thrilled to see it in print! As a pathologist, I see mild chronic gastritis in stomach biopsies frequently. Some pathologists just blow it off as "normal". I have never felt comfort with that approach. I think he is really on to something here. H. Pylori is frequently discussed in context of gastritis, but from my experience, it is not common. Maybe 5-10% of gastritis cases.
 

oceiv

Senior Member
Messages
259
Well done, Dr. Chia! He told me about this study a while back and I am thrilled to see it in print! As a pathologist, I see mild chronic gastritis in stomach biopsies frequently. Some pathologists just blow it off as "normal". I have never felt comfort with that approach. I think he is really on to something here. H. Pylori is frequently discussed in context of gastritis, but from my experience, it is not common. Maybe 5-10% of gastritis cases.

Good information, thank you. Is there more info on what ME patients with gastritis have done for treatment, somewhere?

On the study, since there are enteroviruses found but no definitive cause for ME/CFS stated, it could be that this research is one more study of a viral trigger for the disease. IMHO, the difference between ME/CFS patients and healthy people with this virus seems likelier to be a genetic predisposition to having ME/CFS. The enterovirus plus genetics would explain different outcomes. This theory would then fit in with the multiple triggers theories out there.
 

halcyon

Senior Member
Messages
2,482
Good information, thank you. Is there more info on what ME patients with gastritis have done for treatment, somewhere?
https://www.google.com/patents/US20130203798

On the study, since there are enteroviruses found but no definitive cause for ME/CFS stated, it could be that this research is one more study of a viral trigger for the disease.
Again, this isn't an ME/CFS paper. Dr. Chia's assertion is that an enterovirus triggers the disease and persistence of the infection perpetuates the symptoms.
 

adreno

PR activist
Messages
4,841
IMHO, the difference between ME/CFS patients and healthy people with this virus seems likelier to be a genetic predisposition to having ME/CFS. The enterovirus plus genetics would explain different outcomes.
I doubt genetics can explain this. Our genes simply doesn't seem to be that different, compared with the normal population.

What could explain it, is differences in gut microbiota. This paper discusses how the microbiota influences viral susceptibility.

Interestingly, the microbiota not only influences viral susceptibility, but also modulates the immune response to viral pathogens.

The Intestinal Microbiota and Viral Susceptibility
 
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oceiv

Senior Member
Messages
259

Thank you.


Again, this isn't an ME/CFS paper. Dr. Chia's assertion is that an enterovirus triggers the disease and persistence of the infection perpetuates the symptoms.

I see what you're saying about Dr. Chia's opinion. But I must say that the abstract and results do seem to describe a CFS/ME and controls research study. Also, the OP said Dr. Chia was playing down the CFS/ME aspect in order to get more scientific interest. I'm confused.

Personally, I believe there are multiple triggers, which set of an unending immune response.

I doubt genetics can explain this. Our genes simply doesn't seem to be that different, compared with the normal population.

What could explain it, is differences in gut microbiota. This paper discusses how the microbiota influences viral susceptibility.

Interestingly, the microbiota not only influences viral susceptibility, but also modulates the immune response to viral pathogens.

The Intestinal Microbiota and Viral Susceptibility

In my family, there are several with CFS/ME and/or the usual co-morbid disorders. We grew up and live in different cities and countries. I also have a relative in the same branch of the family who battled lymphoma. This and related conditions are too prevalent in my family not to be genetic, especially without other common factors (such as local diet, places of birth, places of living). But I agree in part: microbiome will turn out to be one influential factor.

Basically, I think all of the physical prerequisites need to happen all together in genetically susceptible people to create the perfect immune storm. I realize now that @halcyon pointed out, that Dr, Chia has focused mostly on enteroviruses as the cause.

I will look at @halcyon 's Dr. Chia links and your micribiota/viral susceptibility link. I'm definitely curious to read them. I'm also reading through Dr. Chia's site and found this:

Everyone’s immune system is different. The infection can be stopped in an early stage if the immune system is strong. If a patient has had prior enterovirus infections or a weak immune system, then more severe infections can occur, which would continue on if the immune response is still inappropriate.

From this explanation, it seems he thinks there's an underlying immune problem, which makes patients more susceptible to the infections. Only more research will tell us what causes that underlying susceptibility. He acknowledges non-enterovirus cases though, it seems.

Interesting stuff, glad @halcyon got me looking further into Chia. Thanks for posting this study, @thegodofpleasure .
 
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cigana

Senior Member
Messages
1,095
Location
UK
I doubt genetics can explain this. Our genes simply doesn't seem to be that different, compared with the normal population.

What could explain it, is differences in gut microbiota. This paper discusses how the microbiota influences viral susceptibility.

Interestingly, the microbiota not only influences viral susceptibility, but also modulates the immune response to viral pathogens.
If gut microbiota explain it, why don't people who have fecal transplants recover?