14 Responses for "Metagenomic symbiosis between bacterial and viral pathogens in autoimmune disease"

1. Todd LePine, MD June 9th, 2010 at 8:45 am 1

   Hi Amy, This is a great talk and you are on the cutting edge of getting to the bottom of autoimmune disease. I recently gave a talk at a conf. on autoimmune disease: http://www.kintera.org/site/c.hpLGJNOsHmE/b.5157911/k.F77B/CME_General_Session.htm Too bad you were not there. Are you familiar with the work of Paul Ewald, author of the book Plague Time the new germ theory of disease? Would like to correspond with you more about your work. Best, TL

2. Amy Proal June 10th, 2010 at 12:29 pm 2

   Hi Todd,

   Thanks for you interest in my work and your encouragement. Too bad I missed a chance to go to Vegas and see you speak! I am definitely a big fan of Paul Ewald. In fact, if you look at the upper side bar of the site you can see that I interviewed him.

   I’m pretty swamped right now but I’ll try to shoot you an email soon so that maybe we can swap papers and perspectives.

   Best,
   Amy

3. Tim Ayers June 12th, 2010 at 8:36 am 3

   Olmesartan (benicar) is going to be pulled from the market in less than one year (likely in the next 6 months). Recent studies have indicated an increased risk of stroke and infarction with its use.

   http://topnews.co.uk/26415-fda-assessing-effects-olmesartan-heart-diseases

   “But an unexpected finding in both trials was a greater number of deaths from heart attack, stroke or sudden death in the Benicar-treated patients compared with those who took a placebo, the FDA said.”

   Interesting on how you never post news or data that refute any of your ideas, only that which supports them. You owe your “followers” ALL of the indformation not just pieces

4. Amy Proal June 12th, 2010 at 6:41 pm 4

   Hi Tim,

   This is definitely worth discussing, but please have a little patience with me. I haven’t written an article for this site in over a year and this FDA communication (not yet a published study result, mind you) came out 18 hours ago. I haven’t written a post, and I’m not sure I will. Also, Prof Marshall has been discussing the studies on the MP site for the last day, so I figured people could look for info over there.

   First, I don’t believe that your prediction about Benicar being pulled from the market will be true. This is what the FDA has said so far:

   FDA’s review is ongoing and the Agency has not concluded that Benicar increases the risk of death. FDA currently believes that the benefits of Benicar in patients with high blood pressure continue to outweigh its potential risks.

   Second, I’m not necessarily sure that the data in the studies does refute the validity of the MP, in fact it potentially adds strength to our understanding of how Olmesartan works at the molecular level.

   If I had to interpret the results thus far (and I may be wrong!) I would say that what might have caused the extra cardiovascular-related deaths in patients taking Olmesartan was that the drug caused the immune response to become activated in people who were too sick to be able to handle the resulting increase in inflammation (immunopathology). These were extremely sick patients, and what we have been saying forever is, “Listen, we believe diabetes is caused by microbes. If you start Olmesartan and begin to kill those microbes, you are going to get worse temporarily because when those microbes die, inflammation goes up.” That’s why we continually warn patients about immunopathology and how best to handle it. So seeing really sick people have problems with Olmesartan is not really shocking but not inconsistent with what we’d expect.

   But there is also a key difference in Olmesartan dosing on the MP and in these studies. We have found that one of the best ways to keep immunopathology under control is by taking Olmesartan more frequently – MP patients must take the pill 3-4 times a day, or more. This is because Olmesartan also has anti-inflammatory effects via the TNF-alpha pathways, but only if the drug is taken more frequently than once a day. Because of this, we work very hard with patient and their doctors to see that people get on higher-dose Olmesartan ASAP. However, in the FDA communication you reference, Olmesartan was only being administered once a day, and that changes the playing field quite a bit. It doesn’t seem like those patients were getting the anti-inflammatory protection I’ve discussed above.

   Honestly, when it comes to people who are very, very ill though, none of the above means that the MP can’t be dangerous. If a patient is at a point where their body is handling about as much symptoms as it can take and then the patient begins the MP and starts to feel worse because of the immunopathology then perhaps they CAN have an event that just pushes their bodies over the edge. So yes, putting very ill people on the MP or on Olmesartan without being very aware about powerful immunopathology can pose problems. And these researchers have no idea that Olmesartan might be causing immunopathology, which I see as the biggest problem of all here.

   So the real message that I took away from these studies is “the FDA must become aware of Benicar can cause immunopathology” and “very ill people need to be very careful about immunopathology when starting the MP”, but then again we already knew that.

   Hope this helps,
   Amy

5. Tim Ayers June 13th, 2010 at 8:30 am 5

   Sorry if I seemed in-patient. I work in the drug industry (ARBs are a specialty for me) and there have been rumblings about olmesartan for a few years (behind the scenes). I do prediict it will not be around much longer, there are several other ARB that have much better efficacy and olmesartan will likely fall victim to poor sales at the very least and go by the wayside.

   We have known (in the ARB field) for a long time that ARBs have effects on the immune system. We belive at this time that the effects are largely mediated through the AT1 recptor cascade and the down regulation of several cytokines, with TGFb being the one of major focus right now.

   TGFb is known to reduce innate immune response by acting as a sort of off swich for cell infiltration. Excessive TGFb signalling MAY cause poor innate immune response or effect cell mediated immunity by preventing the differentiation of T-cells. All ARBs (class effect) have been shown to reduce TGFb signalling as this is up regulated in after AT1 agonism.

   The usage of ARBs and ACEi have been associated with drug induced lupus, at this time we think that it may be due to the reduction in TGFb signalling allowing excessive infitration of of antigen presenting cells into tissue. “Self” cells undergoing normal apoptosis release TGFb as a signal to keep Antigen presenting cells away. The reduction of TGFb may allow atigen presenting cells to consume and present self nuclear material as antigen thus kicking off an autoimmune condition, generating so called autoantibodies against nuclear material. (anti nuclear antibodies). This theory is supported by findings that lupus patients have lowered levels of TGFB.

   Again this is a theory and not FACT..as it is wrong to present theories as fact untill they are supported by IN-VIVO results.

   As far as your ideas on immunopathology, I never put down anyones ideas, however as far as I know there is no INVIVO experimentation that confirms this. The issue I have is that the language you use suggests that it is a settled matter…when indeed you havent any evidence to confirm this. That is unfair to the non-scientific readers who may interperate a working hypothesis as scientifically proven fact. That is a tad bit disingenuous dont you think ????

   I think what bothers most scientists about the MP and its ideas is not so much that a free thinking idea has been presented (god bless all free thinkers) BUT it is that you are presenting a scientific theory as FACT when is no where near settled, in fact there has not been one invivo study to date that confirms your idea that olmesartan binds to the VDR invivo.
   I do however find it hard to believe that it would do alot of interaction invivo. Olmesartan is very tighly bonded to the AT1 receptor as it was designed to do. Considering the volume of distribution of olmesartan and the amount of AT1 receptors that sample the blood stream it is unlikely that any of the drug is available for interaction with other weaker ligands…..remember that at typical doses (even 3 times the normal dose as you suggest) there is still 100s of times the AT1 receptors as there is drug in the serum. This is further compromised as blockade of AT1 leads to an up regulation of AT1 on vascular SM cells…thus as time goes by there are more and more recptors available for bonding.

   The computer studies you are basing your theory on at this time are based on statistics and likely interactions which anynone in the industry will tell you almost NEVER pans out. If we had a dime for everytime a computer predicted an interaction that never panned out invivo we would be quite rich indeed. Seriously Amy, its like 1 out of every 100.

   In closing I admire you and the passion that you have for helping people. You are quite a good person and knowledgeable in science, my only advice to you as someone who has been doing this a long time is to temper yourself a bit as not to set your self up for a let down, or blind yourself when invivo evidence takes you in another direction from your original idea…believe me IT HAPPENS ALLL THE TIME. I cant count the times I have worked things out on paper only to get in the lab and see it all go south.
   I dont know why the MP seems to work for some people. It may be totally unrelated to anything you or anyone else thinks. Perhaps AT1 blockade is simply allowing better homeostasis in the cytokine signalling that controlls immune response, maybe you guys are 100% correct in your bacteria ideas….who knows ??? I would love it if you got in the lab and did some real work to find out !!!!

   Tim

6. Amy Proal June 13th, 2010 at 2:56 pm 6

   Hi Tim,

   Thank you for your comment. It may be that other ARBs are more effective at lowering blood pressure, but for our purposes Olmesartan is the only ARB that has the properties we seek. We have recently applied to the FDA for the use of Olmesartan in two of the diseases the MP treats and Prof Marshall will be speaking to the FDA at the end of the month about how/why we use Olmesartan. So it may be that at some point Olmesartan will be approved for uses other than low blood pressure, in which case it would remain on the market for other reasons. Just to be clear, would you mind sharing if you are a researcher, doctor, drug rep., etc. just so the readers can get a better sense of where you might be hearing these rumors about Olmesartan?

   Anyway, I agree with you about the way we should discuss the MP. In my previous comment, I tried to imply that I was looking at the situation through my own interpretive lens. I said I might even be wrong but still wanted to try to put out some ideas as to what might be happening based on the observations I’ve noted about Olmesartan use in patients on the MP.

   To level with you, when I first started to get better on the MP, I was so excited about what was happening – a whole bunch of us were getting better (and still are). I had suffered so much and our improvements seemed to support the Marshall Pathogenesis very well. After starting this site, I was probably over-exuberant in my language when discussing the MP. The other thing is that this site is a blog – I originally started it because I wanted to be able to express an opinion about the MP. But gradually it turned into a site that some people literally started to use as a more authoritative source for information on the treatment. Those people need to also go to mpkb.org, the MP Knowledge Base, where the articles are written in a more moderate tone (and also include more recent research).

   But nevertheless, and especially after several more years of direct contact with the scientific community, I do absolutely acknowledge that we are still dealing with a set of hypotheses, albeit hypotheses that have pretty deep roots in the medical literature.

   For example, my “About the MP” article does start out by saying:

   “The Marshall Protocol is based on the hypothesis that chronic diseases (termed Th1 illnesses), are the result of infection by an intraphagocytic, metagenomic microbiota of chronic bacterial forms that are often referred to as the Th1 pathogens.”

   It was actually in going to meetings or reading papers or statements put out by several vitamin D advocates that really inspired me to re-calibrate *my* tone. These researchers’ tendency to overstate their conclusions, paint their data in far too optimistic a fashion, and, honestly, refuse to even slightly engage in a discussion in which they might have to consider an alternate hypothesis in relation to some of their conclusions was very disconcerting. At a certain point, I decided that I would hold myself to a higher standard.

   So, over the past few years (after many of the posts on Bacteriality have been written), I have embraced a more moderate tone when writing or speaking about the MP. It’s not that I feel any less excited about the potential of MP-related science or the treatment itself. It’s just that I do agree that one’s tone should reflect upon the evidence…. which you can see in my last couple papers and talks. I know I have often been thought of as an advocate, but I now try to approach the questions the MP raises from the perspective of a scientist. Objectivity is always a tall order (can anyone ever be truly objective?), but that’s what I’m striving for these days.

   In that vein, I certainly welcome comments from people who challenge the MP science, etc. (I certainly engage in respectful dialogue with people who have different points of view at conferences). But, some of the more personal accusations (i.e. “the MP is a cult,” etc.) are just not fair. I’m not referring to your remarks, but if I’m going to establish better dialogue about the MP with the public, it also means that I need to be dealing with people who are committed to considering alternative explanations.

   There’s a whole body of research that explains disease in a new light. Because this research does not fit into the current narrative of disease, it is largely ignored by most. To re-explain disease through this lens, is a completely valid thing to do. I hope that in discussing the science behind the MP I am able to inspire researchers and physicians to test its propositions. Anyone who believes I or the members of ARF are not continually looking for ways to do MP-related trials is under a severe misapprehension. At this point, I hope to spend my career testing aspects of the Pathogenesis.

   Due to limitations of laboratory experiments, which I have discussed on Bacteriality, I continue to believe the best way to test the hypotheses behind the MP is in a controlled in vivo trial. However, we face quite a few challenges. For example, the human microbiota has only been partially characterized (aka, only a fraction of bacteria in the body have been named and can be referenced in databases). It’s tempting to wait until a larger fraction of bacteria are in reference databases before doing a long and expensive trial because we already know from the get-go that we’ll be missing many potential correlations. There’s a lot of challenges along these lines.

   However, to say we have no in vivo evidence of how Olmesartan affects people on the MP isn’t accurate. I agree that we need to do the controlled studies discussed above, but for now, we do have data or at least reports given to us from many doctors working with MP patients that help support the hypotheses we are advancing. There have been a number of conference presentations on patients’ response to the MP. This is not ideal, but it isn’t “nothing,” as some people have argued.

   The one area where I tend to be most forceful with language is when discussing what we view as immunopathology. We have hundreds of case reports pointing to what really seems to be this kind of near-universal reaction taking place in MP patients, and I feel it’s very dangerous if I don’t warn other potential MP patients about the possibility. I think most people on the MP realize that we haven’t done any big trials on immunopathology and are willing to accept the reaction as a very plausible hypothesis for the increases in inflammation they experience and, in many cases, their subsequent improvement.

   Best,

   Amy

7. Tim Ayers June 14th, 2010 at 9:24 am 7

   Dear Amy

   I wish you the best of luck in what will likely become your lifes work in exploring these ideas, possibly adjusting them as you go on. There is nothing more honorable than trying to cure human suffering. I think that you are moving more on to the right track in light of your comments above.

   I admire your conviction and once had a full head of steam myself. I have long been an advocate of ARB usage above FDA reccomended doses for numerous afflictions. The tissue protective effects are well documented in the literature…GOOD LUCK GETTING ANYONE ELSE TO CARE !!! Due to years of frustration I have sort of moved away from trying to prove hypothesis in my life, I dont know if its maturation, realization or just some form of half hearted acceptance. It is hard when the exuberence of a new idea runs head long into the mechanical working of “real life”.

   When one first starts running with a new idea the tendency is to become so “in love” that you turn up the volume on the papers that support it and turn down the volume on things that may challenge it…we are all guilty of that at one time or another. I think that it is a defence mechanism so that in the early stages of something you can focus all of your energy on developing the idea. With myself it was the function of the angiotensin type 2 (at2) receptor that gets hammered during high dose ARB usage. No one knew what it did…the reports were conflicting, so I did what any good scientist would do at the time….I ignored it !!!!!

   I finally came to the conclusion that human homeostasis is the result of trillions of interations all simultaneously changing from mili second to mili second and at the end of the day it is just not possible fully understand how it all works.

   My thoughts on the MP is that if it works for some reason than people should be free to try it. I dont see it as being particularly dangeous as some others have suggested. I know high dose ARB is is generally safe and the antibiotics used are not particularly difficult to metabolize. If I were a MD and a patient wanted to try it I would let them.

   I do feel that you will be “up against it” trying to prove its efficacy. Invivo lab studies will be costly indeed and results may muddy the waters even further as your hypothesis is very broad and the pathways involved nearly endlessly complicated. Clinical trials may prove to be difficult also as many of the diseases such as cronic fatiuge, serum negative lyme, fibromyalgia, ect..have no real way of monitoring progress out side of subjective reports on “how the patient is feeling”

   This will be wrought full of frustrations. You will find these types of patients very difficult to deal with. There accounts will be contridictory and any side effects will be amplified GREATLY by FDA even if they are a small percent of the popoulation. My likely prediction is that the FDA will blow side effects out of proportion and efficacy will be challenged due to conflicting subjective reports by patients reporting how they feel. ITs a classic story.

   Anyway, best of luck with it all…perhaps you are correct in all you ideas and I have had a talk with a future Noble Prize winner !!!! If not then I have had a nice talk with some one who has a real desire to help people…and helping people is what it should be about….as for me a I am going to go help myself to a beer !!!

   Good Luck

   Tim

8. Tim Ayers June 14th, 2010 at 3:42 pm 8

   Amy

   I thought that my above (kindly worded) post would be my last….BUT

   There is breaking news to day that ARBs are linked to a modest increase in cancer. See the Lancet Oncolgy Article or read the press releases, there all over the place…

   Here is the funny thing that made me think of you, the greatest increase was seen specifically with Telmisartan (in fact its the only one with measurable increase. If I remember correctly while skimming over one of Marshalls papers (or perhaps from an email I had with him long ago) he had predicted that telmisartan antagonized the VDR and was the only one to do so (out of the ARB class)…….hmmm sort of interesting…kind of supports your case

   see I told you I was open minded…

   ps..to answer your question from before I am a chemist for a large medical (not drug) company (Id rather not say which) I work in R&D and am not involved in sales (eww) what so ever.

9. Amy Proal June 15th, 2010 at 4:47 pm 9

   Hi Tim,

   I hope you enjoyed your beer!

   On a more serious note, I am already very familiar with the frustrations you have faced while researching ARBs. I’m sorry that your research has faced so many challenges and I certainly acknowledge that mine will as well. But I’ve got to try! I realize that maybe I won’t end up proving what I thought I would prove, or my results will lead me in a new direction but if there’s a chance that any of the research will continue to move in a direction that helps suffering patients then you have definitely realized what drives me to continually push forward.

   I am encouraged that maybe we will succeed where others have failed due in large part to the advances in genomic technology and molecular techniques that are booming at this point. I see the metabolome as a very promising place to look for metabolites that can reflect the presence of microbes, and single cell sampling can allow me to prove the presence/absence of microbes in ways that researchers in the past could only dream of. Creating new tests and finding new markers to track what seems to be immunopathology will also be key, and we have some promising leads.

   Thanks for sharing the ARB/cancer study. I think that lumping all the ARBs together into a meta-analysis makes it harder to account for the unique properties that each drug has (each drug seems to hit quite different receptors). And yes, you are correct, Dr. Marshall has warned against Telmisartan use because his work shows that it’s a strong VDR antagonist – and one wouldn’t want a disabled VDR when dealing with cancer!

   This study on Telmisartan describes some of its other properties that separate it from the other ARBs:

   http://www.ncbi.nlm.nih.gov/pubmed/20222053

   Well thanks for your vote of confidence when it comes to my potential to do unbiased work and let’s see where the future leads.

   Take care,
   Amy

10. Rosie June 17th, 2010 at 3:48 pm 10

    Dear Amy,

    Thank you for your presentation and professionalism.

    I really enjoyed reading the comments on this thread.

    Thanks to Todd for caring for people who many physicians hate to see coming and can’t wait to get rid of.

    Thanks to Tim. You have good character and we need all the ethical researchers we can get.

11. Todd LePine, MD June 18th, 2010 at 5:05 pm 11

    Hi Again Amy, In terms of the microbiome and its effect on our body, take a look at this recent article as it relates to bacteria and autism, very interesting:

    http://insciences.org/article.php?article_id=9085

12. Amy Proal June 19th, 2010 at 6:18 pm 12

    Hi Todd,

    Definitely very interesting and thanks for sharing! I actually read that article hot off the press because I follow the work of Jeremy Nicholson and colleagues at the Imperial College of London very closely.

    If fact, Jeremy is one of my top role models because he’s great at developing new techniques and coming up with ways to analyze microbial populations in new ways. The metabolomics techniques he describes in the autism paper are key because they allow researchers to follow changes in large microbial populations rather than just gauging changes in the composition of single microbes.

    Best,
    Amy

13. Andy June 20th, 2010 at 1:09 am 13

    Hi Amy,

    My Father was diagnosed with Lou Gehrig’s Disease.

    The research I have done makes me believe it may be an autoimmune disease.

    Do you have know anyone with ALS that has used the Marshall Protocol?

    Please email me if you can offer any help.

    Andy

14. Paul Albert June 29th, 2010 at 11:10 am 14

    Hi Andy,

    Thanks for your patience. Check out these links:
    http://www.ncbi.nlm.nih.gov/pubmed/14582618

    Here’s a patient with ALS trying the MP:
    http://www.marshallprotocol.com/forum19/13414.html
    http://www.marshallprotocol.com/forum30/13432.html

    If you have any further questions, please ask at CureMyTh1.org. Also, have a look at our Knowledge Base, MPKB.org. I’m sorry to say that the article on ALS is not up to date, but it is certainly on the list.

    Best,
    Paul